124 results on '"BALZARINI, J."'
Search Results
2. Optimization of xanthatin extraction from Xanthium spinosum L. and its cytotoxic, anti-angiogenesis and antiviral properties
- Author
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Romero, M., Zanuy, M., Rosell, E., Cascante, M., Piulats, J., Font-Bardia, M., Balzarini, J., De Clerq, E., and Pujol, M.D.
- Published
- 2015
- Full Text
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3. Program and abstracts for the 2011 Meeting of the Society for Glycobiology
- Author
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Hollingsworth, MT, Hart, GW, Paulson, JC, Stansell, E, Canis, K, Huang, IC, Panico, M, Morris, H, Haslam, S, Farzan, M, Dell, A, Desrosiers, R, von Itzstein, M, Matroscovich, M, Luther, KB, Hülsmeier, AJ, Schegg, B, Hennet, T, Nycholat, C, McBride, R, Ekiert, D, Xu, R, Peng, W, Razi, N, Gilbert, M, Wakarchuk, W, Wilson, IA, Gahlay, G, Geisler, C, Aumiller, JJ, Moremen, K, Steel, J, Labaer, J, Jarvis, DL, Drickamer, K, Taylor, M, Nizet, V, Rabinovich, G, Lewis, C, Cobb, B, Kawasaki, N, Rademacher, C, Chen, W, Vela, J, Maricic, I, Crocker, P, Kumar, V, Kronenberg, M, Paulson, J, Glenn, K, Mallinger, A, Wen, H, Srivastava, L, Tundup, S, Harn, D, Menon, AK, Yamaguchi, Y, Mkhikian, H, Grigorian, A, Li, C, Chen, HL, Newton, B, Zhou, RW, Beeton, C, Torossian, S, Tatarian, GG, Lee, SU, Lau, K, Walker, E, Siminovitch, KA, Chandy, KG, Yu, Z, Dennis, JW, Demetriou, M, Pandey, MS, Baggenstoss, BA, Washburn, JL, Weigel, PH, Chen, CI, Keusch, JJ, Klein, D, Hofsteenge, J, Gut, H, Szymanski, C, Feldman, M, Schaffer, C, Gao, Y, Strum, S, Liu, B, Schutzbach, JS, Druzhinina, TN, Utkina, NS, Torgov, VI, Szarek, WA, Wang, L, Brockhausen, I, Hitchen, P, Peyfoon, E, Meyer, B, Albers, SV, Chen, C, Newburg, DS, Jin, C, Dinglasan, RD, Beverley, SM, Guo, H, Novozhilova, N, Hickerson, S, Elnaiem, DE, Sacks, D, Turco, SJ, McKay, D, Castro, E, Takahashi, H, Straus, AH, Stalnaker, SH, Live, D, Boons, GJ, Wells, L, Stuart, R, Aoki, K, Boccuto, L, Zhang, Q, Wang, H, Bartel, F, Fan, X, Saul, R, Chaubey, A, Yang, X, Steet, R, Schwartz, C, Tiemeyer, M, Pierce, M, Kraushaar, DC, Condac, E, Nakato, H, Nishihara, S, Sasaki, N, Hirano, K, Nasirikenari, M, Collins, CC, Lau, JT, Devarapu, SK, Jeyaweerasinkam, S, Albiez, RS, Kiessling, L, Gu, J, Clark, GF, Gagneux, P, Ulm, C, Mahavadi, P, Müller, S, Rinné, S, Geyer, H, Gerardy-Schahn, R, Mühlenhoff, M, Günther, A, Geyer, R, Galuska, SP, Shibata, T, Sugihara, K, Nakayama, J, Fukuda, M, Fukuda, MN, Ishikawa, A, Terao, M, Kimura, A, Kato, A, Katayama, I, Taniguchi, N, Miyoshi, E, Aderem, A, Yoneyama, T, Angata, K, Bao, X, Chanda, S, Lowe, J, Sonon, R, Ishihara, M, Talabnin, K, Wang, Z, Black, I, Naran, R, Heiss, C, Azadi, P, Hurum, D, Rohrer, J, Balland, A, Valliere-Douglass, J, Kodama, P, Mujacic, M, Eakin, C, Brady, L, Wang, WC, Wallace, A, Treuheit, M, Reddy, P, Schuman, B, Fisher, S, Borisova, S, Coates, L, Langan, P, Evans, S, Yang, SJ, Zhang, H, Hizal, DB, Tian, Y, Sarkaria, V, Betenbaugh, M, Lütteke, T, Agravat, S, Cholleti, S, Morris, T, Saltz, J, Song, X, Cummings, R, Smith, D, Hofhine, T, Nishida, C, Mialy, R, Sophie, D, Sebastien, F, Patricia, C, Eric, S, Stephane, H, Mokros, D, Joosten, RP, Dominik, A, Vriend, G, Nguyen, LD, Martinez, J, Hinderlich, S, Reissig, HU, Reutter, W, Fan, H, Saenger, W, Moniot, S, Asada, H, Nakahara, T, Miura, Y, Stevenson, T, Yamazaki, T, De Castro, C, Burr, T, Lanzetta, R, Molinaro, A, Parrilli, M, Sule, S, Gerken, TA, Revpredo, L, Thome, J, Cardenas, G, Almeida, I, Leung, MY, Yan, S, Paschinger, K, Bleuler-Martinez, S, Jantsch, V, Wilson, I, Yoshimura, Y, Adlercreutz, D, Mannerstedt, K, Wakarchuk, WW, Dovichi, NJ, Hindsgaul, O, Palcic, MM, Chandrasekaran, A, Bharadwaj, R, Deng, K, Adams, P, Singh, A, Datta, A, Konasani, V, Imamura, A, Lowry, T, Scaman, C, Zhao, Y, Zhou, YD, Yang, K, Zhang, XL, Leymarie, N, Hartshorn, K, White, M, Cafarella, T, Seaton, B, Rynkiewicz, M, Zaia, J, Acosta-Blanco, I, Ortega-Francisco, S, Dionisio-Vicuña, M, Hernandez-Flores, M, Fuentes-Romero, L, Newburg, D, Soto-Ramirez, LE, Ruiz-Palacios, G, Viveros-Rogel, M, Tong, C, Li, W, Kong, L, Qu, M, Jin, Q, Lukyanov, P, Zhang, W, Chicalovets, I, Molchanova, V, Wu, AM, Liu, JH, Yang, WH, Nussbaum, C, Grewal, PK, Sperandio, M, Marth, JD, Yu, R, Usuki, S, Wu, HC, O'Brien, D, Piskarev, V, Ramadugu, SK, Kashyap, HK, Ghirlanda, G, Margulis, C, Brewer, C, Gomery, K, Müller-Loennies, S, Brooks, CL, Brade, L, Kosma, P, Di Padova, F, Brade, H, Evans, SV, Asakawa, K, Kawakami, K, Kushi, Y, Suzuki, Y, Nozaki, H, Itonori, S, Malik, S, Lebeer, S, Petrova, M, Balzarini, J, Vanderleyden, J, Naito-Matsui, Y, Takematsu, H, Murata, K, Kozutsumi, Y, Subedi, GP, Satoh, T, Hanashima, S, Ikeda, A, Nakada, H, Sato, R, Mizuno, M, Yuasa, N, Fujita-Yamaguchi, Y, Vlahakis, J, Nair, DG, Wang, Y, Allingham, J, Anastassiades, T, Strachan, H, Johnson, D, Orlando, R, Harenberg, J, Haji-Ghassemi, O, Mackenzie, R, Lacerda, T, Toledo, M, Straus, A, Takahashi, HK, Woodrum, B, Ruben, M, O'Keefe, B, Samli, KN, Yang, L, Woods, RJ, Jones, MB, Maxwell, J, Song, EH, Manganiello, M, Chow, YH, Convertine, AJ, Schnapp, LM, Stayton, PS, Ratner, DM, Yegorova, S, Rodriguez, MC, Minond, D, Jiménez-Barbero, J, Calle, L, Ardá, A, Gabius, HJ, André, S, Martinez-Mayorga, K, Yongye, AB, Cudic, M, Ali, MF, Chachadi, VB, Cheng, PW, Kiwamoto, T, Na, HJ, Brummet, M, Finn, MG, Hong, V, Polonskaya, Z, Bovin, NV, Hudson, S, Bochner, B, Gallogly, S, Krüger, A, Hanley, S, Gerlach, J, Hogan, M, Ward, C, Joshi, L, Griffin, M, Demarco, C, Deveny, R, Aggeler, R, Hart, C, Nyberg, T, Agnew, B, Akçay, G, Ramphal, J, Calabretta, P, Nguyen, AD, Kumar, K, Eggers, D, Terrill, R, d'Alarcao, M, Ito, Y, Vela, JL, Matsumura, F, Hoshino, H, Lee, H, Kobayashi, M, Borén, T, Jin, R, Seeberger, PH, Pitteloud, JP, Cudic, P, Von Muhlinen, N, Thurston, T, von Muhlinen, N, Wandel, M, Akutsu, M, Foeglein, AÁ, Komander, D, Randow, F, Maupin, K, Liden, D, Haab, B, Dam, TK, Brown, RK, Wiltzius, M, Jokinen, M, Andre, S, Kaltner, H, Bullen, J, Balsbaugh, J, Neumann, D, Hardie, G, Shabanowitz, J, Hunt, D, Hart, G, Mi, R, Ding, X, Van Die, I, Chapman, AB, Cummings, RD, Ju, T, Aryal, R, Ashley, J, Feng, X, Hanover, JA, Wang, P, Keembiyehetty, C, Ghosh, S, Bond, M, Krause, M, Love, D, Radhakrishnan, P, Grandgenet, PM, Mohr, AM, Bunt, SK, Yu, F, Hollingsworth, MA, Ethen, C, Machacek, M, Prather, B, Wu, Z, Kotu, V, Zhao, P, Zhang, D, van der Wel, H, Johnson, JM, West, CM, Abdulkhalek, S, Amith, SR, Jayanth, P, Guo, M, Szewczuk, M, Ohtsubo, K, Chen, M, Olefsky, J, Marth, J, Zapater, J, Foley, D, Colley, K, Kawashima, N, Fujitani, N, Tsuji, D, Itoh, K, Shinohara, Y, Nakayama, K, Zhang, L, Ten Hagen, K, Koren, S, Yehezkel, G, Cohen, L, Kliger, A, Khalaila, I, Finkelstein, E, Parker, R, Kohler, J, Sacoman, J, Badish, L, Hollingsworth, R, Tian, E, Hoffman, M, Hou, X, Tashima, Y, Stanley, P, Kizuka, Y, Kitazume, S, Yoshida, M, Kunze, A, Nasir, W, Bally, M, Hook, F, Larson, G, Mahan, A, Alter, G, Zeidan, Q, Copeland, R, Pokrovskaya, I, Willett, R, Smith, R, Morelle, W, Kudlyk, T, Lupashin, V, Vasudevan, D, Takeuchi, H, Majerus, E, Haltiwanger, RS, Boufala, S, Lee, YA, Min, D, Kim, SH, Shin, MH, Gesteira, T, Pol-Fachin, L, Coulson-Thomas, VJ, Verli, H, Nader, H, Liu, X, Yang, P, Thoden, J, Holden, H, Tytgat, H, Sánchez-Rodríguez, A, Schoofs, G, Verhoeven, T, De Keersmaecker, S, Marchal, K, Ventura, V, Sarah, N, Joann, P, Ding, Y, Jarrell, K, Cook, MC, Gibeault, S, Filippenko, V, Ye, Q, Wang, J, Kunkel, JP, Arteaga-Cabello, FJ, Arciniega-Fuentes, MT, McCoy, J, Ruiz-Palacios, GM, Francoleon, D, Loo, RO, Loo, J, Ytterberg, AJ, Kim, U, Gunsalus, R, Costello, C, Soares, R, Assis, R, Ibraim, I, Noronha, F, De Godoy, AP, Bale, MS, Xu, Y, Brown, K, Blader, I, West, C, Chen, S, Ye, X, Xue, C, Li, G, Yu, G, Yin, L, Chai, W, Gutierrez-Magdaleno, G, Tan, C, Wu, D, Li, Q, Hu, H, Ye, M, Liu, D, Mink, W, Kaese, P, Fujiwara, M, Uchimura, K, Sakai, Y, Nakada, T, Mabashi-Asazuma, H, Toth, AM, Scott, DW, Chacko, BK, Patel, RP, Batista, F, Mercer, N, Ramakrishnan, B, Pasek, M, Boeggeman, E, Verdi, L, Qasba, PK, Tran, D, Lim, JM, Liu, M, Mo, KF, Kirby, P, Yu, X, Lin, C, Costello, CE, Akama, TO, Nakamura, T, Huang, Y, Shi, X, Han, L, Yu, SH, Zhang, Z, Knappe, S, Till, S, Nadia, I, Catarello, J, Quinn, C, Julia, N, Ray, J, Tran, T, Scheiflinger, F, Szabo, C, Dockal, M, Niimi, S, Hosono, T, Michikawa, M, Kannagi, R, Takashima, S, Amano, J, Nakamura, N, Kaneda, E, Nakayama, Y, Kurosaka, A, Takada, W, Matsushita, T, Hinou, H, Nishimura, S, Igarashi, K, Abe, H, Mothere, M, Leonhard-Melief, C, Johnson, H, Nagy, T, Nairn, A, Rosa, MD, Porterfield, M, Kulik, M, Dalton, S, Pierce, JM, Hansen, SF, McAndrew, R, Degiovanni, A, McInerney, P, Pereira, JH, Hadi, M, Scheller, HV, Barb, A, Prestegard, J, Zhang, S, Jiang, J, Tharmalingam, T, Pluta, K, McGettigan, P, Gough, R, Struwe, W, Fitzpatrick, E, Gallagher, ME, Rudd, PM, Karlsson, NG, Carrington, SD, Katoh, T, Panin, V, Gelfenbeyn, K, Freire-de-Lima, L, Handa, K, Hakomori, SI, Bielik, AM, McLeod, E, Landry, D, Mendoza, V, Guthrie, EP, Mao, Y, Wang, X, Moremen, KW, Meng, L, Ramiah, AP, Gao, Z, Johnson, R, Xiang, Y, Rosa, MDEL, Wu, SC, Gilbert, HJ, Karaveg, K, Chen, L, Wang, BC, Mast, S, Sun, B, Fulton, S, Kimzey, M, Pourkaveh, S, Minalla, A, Haxo, T, Wegstein, J, Murray, AK, Nichols, RL, Giannini, S, Grozovsky, R, Begonja, AJ, Hoffmeister, KM, Suzuki-Anekoji, M, Suzuki, A, Yu, SY, Khoo, KH, van Alphen, L, Fodor, C, Wenzel, C, Ashmus, R, Miller, W, Stahl, M, Stintzi, A, Lowary, T, Wiederschain, G, Saba, J, Zumwalt, A, Meitei, NS, Apte, A, Viner, R, Gandy, M, Debowski, A, Stubbs, K, Witzenman, H, Pandey, D, Repnikova, E, Nakamura, M, Islam, R, Kc, N, Caster, C, Chaubard, JL, Krishnamurthy, C, Hsieh-Wilson, L, Pranskevich, J, Rangarajan, J, Guttman, A, Szabo, Z, Karger, B, Chapman, J, Chavaroche, A, Bionda, N, Fields, G, Jacob, F, Tse, BW, Guertler, R, Nixdorf, S, Hacker, NF, Heinzelmann-Schwarz, V, Yang, F, Kohler, JJ, Losfeld, ME, Ng, B, Freeze, HH, He, P, Wondimu, A, Liu, Y, Zhang, Y, Su, Y, Ladisch, S, Grewal, P, Mann, C, Ditto, D, Lardone, R, Le, D, Varki, N, Kulinich, A, Kostjuk, O, Maslak, G, Pismenetskaya, I, Shevtsova, A, Takeishi, S, Okudo, K, Moriwaki, K, Terao, N, Kamada, Y, Kuroda, S, Li, Y, Peiris, D, Markiv, A, Dwek, M, Adamczyk, B, Thanabalasingham, G, Huffman, J, Kattla, J, Novokmet, M, Rudan, I, Gloyn, A, Hayward, C, Reynolds, R, Hansen, T, Klimes, I, Njolstad, P, Wilson, J, Hastie, N, Campbell, H, McCarthy, M, Rudd, P, Owen, K, Lauc, G, Wright, A, Goletz, S, Stahn, R, Danielczyk, A, Baumeister, H, Hillemann, A, Löffler, A, Stöckl, L, Jahn, D, Bahrke, S, Flechner, A, Schlangstedt, M, Karsten, U, Goletz, C, Mikolajczyk, S, Ulsemer, P, Gao, N, Cline, A, Flanagan-Steet, H, Sadler, KC, Lehrman, MA, Coulson-Thomas, YM, Gesteira, TF, Mader, AM, Waisberg, J, Pinhal, MA, Friedl, A, Toma, L, Nader, HB, Mbua, EN, Johnson, S, Wolfert, M, Dimitrievska, S, Huizing, M, Niklason, L, Perdivara, I, Petrovich, R, Tokar, EJ, Waalkes, M, Fraser, P, Tomer, K, Chu, J, Rosa, S, Mir, A, Lehrman, M, Sadler, K, Lauer, M, Hascall, V, Calabro, A, Cheng, G, Swaidani, S, Abaddi, A, Aronica, M, Yuzwa, S, Shan, X, Macauley, M, Clark, T, Skorobogatko, Y, Vosseller, K, Vocadlo, D, Banerjee, A, Baksi, K, Banerjee, D, Melcher, R, Kraus, I, Moeller, D, Demmig, S, Rogoll, D, Kudlich, T, Scheppach, W, Scheurlen, M, Hasilik, A, Steirer, L, Lee, J, Moe, G, Troy, FA, Wang, F, Xia, B, Wang, B, Yi, S, Yu, H, Suzuki, M, Kobayashi, T, Sato, Y, Zhou, H, Briscoe, A, Lee, R, Wolfert, MA, Matsumoto, Y, Hamamura, K, Yoshida, T, Akita, K, Okajima, T, Furukawa, K, Urano, T, Ruhaak, LR, Miyamoto, S, and Lebrilla, CB
- Subjects
Embryogenesis ,Cancer screening ,Cancer research ,medicine ,Cell migration ,Neural cell adhesion molecule ,Biology ,medicine.disease ,Biochemistry ,Metastasis - Abstract
Cell surface mucins configure the cell surface by presenting extended protein backbones that are heavily O-glycosylated. The glycopeptide structures establish physicochemical properties at the cell surface that enable and block the formation of biologically important molecular complexes. Some mucins, such as MUC1, associate with receptor tyrosine kinases and other cell surface receptors, and engage in signal transduction in order to communicate information regarding conditions at the cell surface to the nucleus. In that context, the MUC1 cytoplasmic tail (MUC1CT) receives phosphorylation signals from receptor tyrosine kinases and serine/threonine kinases, which enables its association with different signaling complexes that conduct these signals to the nucleus and perhaps other subcellular organelles. We have detected the MUC1CT at promoters of over 500 genes, in association with several different transcription factors, and have shown that promoter occupancy can vary under different growth factor conditions. However, the full biochemical nature of the nuclear forms of MUC1 and its function at these promoter regions remain undefined. I will present evidence that nuclear forms of the MUC1CT include extracellular and cytoplasmic tail domains. In addition, I will discuss evidence for a hypothesis that the MUC1CT possesses a novel catalytic function that enables remodeling of the transcription factor occupancy of promoters, and thereby engages in regulation of gene expression.
- Published
- 2016
4. Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses
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Ren, J, Diprose, J, Warren, J, Esnouf, RM, Bird, LE, Ikemizu, S, Slater, M, Milton, J, Balzarini, J, Stuart, DI, and Stammers, DK
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virus diseases - Abstract
Most non-nucleoside reverse transcriptase (RT) inhibitors are specific for HIV-1 RT and demonstrate minimal inhibition of HIV-2 RT. However, we report that members of the phenylethylthiazolylthiourea (PETT) series of non-nucleoside reverse transcriptase inhibitors showing high potency against HIV-1 RT have varying abilities to inhibit HIV-2 RT. Thus, PETT-1 inhibits HIV-1 RT with an IC(50) of 6 nM but shows only weak inhibition of HIV-2 RT, whereas PETT-2 retains similar potency against HIV-1 RT (IC(50) of 5 nM) and also inhibits HIV-2 RT (IC(50) of 2.2 microM). X-ray crystallographic structure determinations of PETT-1 and PETT-2 in complexes with HIV-1 RT reveal the compounds bind in an overall similar conformation albeit with some differences in their interactions with the protein. To investigate whether PETT-2 could be acting at a different site on HIV-2 RT (e.g. the dNTP or template primer binding site), we compared modes of inhibition for PETT-2 against HIV-1 and HIV-2 RT. PETT-2 was a noncompetitive inhibitor with respect to the dGTP substrate for both HIV-1 and HIV-2 RTs. PETT-2 was also a noncompetitive inhibitor with respect to a poly(rC).(dG) template primer for HIV-2 RT. These results are consistent with PETT-2 binding in corresponding pockets in both HIV-1 and HIV-2 RT with amino acid sequence differences in HIV-2 RT affecting the binding of PETT-2 compared with PETT-1.
- Published
- 2016
5. 1,1,3-Trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (TTD) derivatives: a new class of nonnucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors with anti-HIV-1 activity
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Witvrouw, M., Arranz, M. E., Pannecouque, C., Declercq, R., Jonckheere, H., Schmit, J. -C, Anne-Mieke Vandamme, Diaz, J. A., Ingate, S. T., Desmyter, J., Esnouf, R., Meervelt, L., Vega, S., Balzarini, J., and Clercq, E.
- Subjects
Models, Molecular ,Didanosine ,Structure-Activity Relationship ,Anti-HIV Agents ,HIV-1 ,Humans ,virus diseases ,Drug Resistance, Microbial ,Nevirapine ,Antiviral Agents ,Zidovudine ,Cells, Cultured ,HIV Reverse Transcriptase - Abstract
We report the development of a new group of nonnucleoside reverse transcriptase inhibitors (NNRTIs). One of the most active congeners of this series of 1,1,3-trioxo-2H,4H-thieno[3,4-e] [1,2,4]thiadiazine (TTD) derivatives, i.e., 2-(3-fluorobenzyl)-4-cyanomethylen-l,1,3-trioxo-2H,4H- thieno [3,4-e] [1,2,4] thiadiazine) (QM96639) was found to inhibit human immunodeficiency virus (HIV) type 1 [HIV-1 (IIIB)] replication in MT-4 cells at a concentration of 0.09 microM. This compound was toxic for the host cells only at a 1,400-fold higher concentration. The TTD derivatives proved effective against a variety of HIV-1 strains, including those that are resistant to 3'-azido-3'-deoxythymidine (AZT), but not against HIV-2 (ROD) or simian immunodeficiency virus (SIV/ MAC251). HIV-1 strains containing the L100I, K103N, V106A, E138K, Y181C, or Y188H mutations in their reverse transcriptase (RT) displayed reduced sensitivity to the compounds. Their cross-resistance patterns correlated with that of nevirapine. 2-Benzyl-4-cyanomethylen-1,1,3-trioxo-2H,4H-thieno[3,4-e] [1,2,4]thiadiazine (QM96521) enhanced the anti-HIV-1 activity of AZT and didanosine in a subsynergistic manner. HIV-1-resistant virus containing the V179D mutation in the RT was selected after approximately six passages of HIV-1 (IIIB) in CEM cells in the presence of different concentrations of QM96521. From structure-activity relationship analysis of a wide variety of TTD derivatives, a number of restrictions appeared as to the chemical modifications that were compatible with anti-HIV activity. Modelling studies suggest that in contrast to most other NNRTIs, but akin to nevirapine, QM96521 does not act as a hydrogen bond donor in the RT-drug complex.
- Published
- 2016
6. Rational Development of Nucleoside Diphosphate Prodrugs: DiPPro-Compounds
- Author
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Meier, C., primary, Jessen, H., additional, Schulz, T., additional, Weinschenk, L., additional, Pertenbreiter, F., additional, and Balzarini, J., additional
- Published
- 2015
- Full Text
- View/download PDF
7. ChemInform Abstract: Structural Analogues of Umifenovir. Part 1. Synthesis and Biological Activity of Ethyl 5‐Hydroxy‐1‐methyl‐2‐ (trans‐2‐phenylcyclopropyl)‐1H‐indole‐3‐carboxylate.
- Author
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Balzarini, J., primary, Ruchko, E. A., additional, Zakharova, E. K., additional, Kameneva, I. Yu., additional, and Nawrozkij, M. B., additional
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- 2014
- Full Text
- View/download PDF
8. Synthesis of Active 2-Aminothiophenes through the Gewald Reaction.
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THOMAS, J., JANA, S., SONAWANE, M., FIEY, B., BALZARINI, J., LIEKENS, S., and DEHAEN, W.
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- 2017
- Full Text
- View/download PDF
9. Hairpin oligonucleotides forming G-quadruplexes: New aptamers with anti-HIV activity
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Nicoletta Potenza, Armando Zarrelli, Giovanni Di Fabio, Valeria Romanucci, Maria Gaglione, Anna Messere, Jan Balzarini, Sam Noppen, Sandra Liekens, Romanucci, Valeria, Gaglione, Maria, Messere, Anna, Potenza, Nicoletta, Zarrelli, Armando, Noppen, Sam, Liekens, Sandra, Balzarini, Jan, DI FABIO, Giovanni, Romanucci, V, Gaglione, M, Zarrelli, A, Noppen, S, Liekens, S, Balzarini, J, and Di Fabio, G.
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Anti-HIV activity ,Aptamer ,Stereochemistry ,Anti-HIV Agents ,Oligonucleotides ,Microbial Sensitivity Tests ,Conjugated system ,G-quadruplex ,Solid-phase synthesis ,Conjugated hairpin oligonucleotide ,Oligonucleotide ,Drug Discovery ,G-Quadruplexe ,Molecule ,Cytotoxicity ,Solid-phase synthesi ,Pharmacology ,Molecular Structure ,Chemistry ,Microbial Sensitivity Test ,Drug Discovery3003 Pharmaceutical Science ,Medicine (all) ,Organic Chemistry ,Anti-HIV Agent ,General Medicine ,Aptamers, Nucleotide ,Surface Plasmon Resonance ,G-Quadruplexes ,Phosphodiester bond ,HIV-2 ,HIV-1 - Abstract
We describe the facile syntheses of new modified oligonucleotides based on d(TG3AG) that form bimolecular G-quadruplexes and possess a HEG loop as an inversion of polarity site 3'-3' or 5'-5' and aromatic residues conjugated to the 5'-end through phosphodiester bonds. The conjugated hairpin G-quadruplexes exhibited parallel orientation, high thermal stability, elevated resistance in human serum and high or moderate anti-HIV-1 activity with low cytotoxicity. Further, these molecules showed significant binding to HIV envelope glycoproteins gp120, gp41 and HSA, as revealed by SPR assays. As a result, these conjugated hairpins represent the first active anti-HIV-1 bimolecular G-quadruplexes based on the d(TG3AG) sequence. publisher: Elsevier articletitle: Hairpin oligonucleotides forming G-quadruplexes: New aptamers with anti-HIV activity journaltitle: European Journal of Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.ejmech.2014.10.030 content_type: article copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved. ispartof: European Journal of Medicinal Chemistry vol:89 pages:51-8 ispartof: location:France status: published
- Published
- 2015
10. Synthesis and Evaluation of Prodrugs of α-Carboxy Nucleoside Phosphonates.
- Author
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Ford A, Mullins ND, Balzarini J, and Maguire AR
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- Nucleosides pharmacology, Esters, Organophosphonates pharmacology, Prodrugs pharmacology, Anti-HIV Agents pharmacology
- Abstract
A range of lipophilic prodrugs of α-carboxy nucleoside phosphonates, potent inhibitors of HIV-1 reverse transcriptase without requiring prior phosphorylation, were synthesized to evaluate their in vivo potency against HIV in cell culture. A series of prodrug derivatives bearing a free carboxylic acid where the phosphonate was masked with bispivaloyloxymethyl, diisopropyloxycarbonyloxymethyl, bisamidate, aryloxyphosphoramidate, hexadecyloxypropyl, CycloSal, and acycloxybenzyl moieties were synthesized, adapting existing methodologies for phosphonate protection to accommodate the adjacent carboxylic acid moiety. The prodrugs were assayed for anti-HIV activity in CEM cell cultures─the bispivaloyloxymethyl free acid monophosphonate prodrug exhibited some activity (inhibitory concentration-50 (IC
50 ) 59 ± 17 μM), while the other prodrugs were inactive at 100 μM. A racemic bispivaloyloxymethyl methyl ester monophosphonate prodrug was also prepared to assess the suitability of the methyl ester as a carboxylic acid prodrug. This compound exhibited no activity against HIV in cellular assays.- Published
- 2022
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11. Enantiocontrolled Preparation of ϒ-Substituted Cyclohexenones: Synthesis and Kinase Activity Assays of Cyclopropyl-Fused Cyclohexane Nucleosides.
- Author
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Jurado S, Domínguez-Pérez B, Illa O, Balzarini J, Busqué F, and Alibés R
- Subjects
- Antiviral Agents, Cyclohexanes, Humans, Thymidine Kinase, Herpesvirus 1, Human, Nucleosides
- Abstract
The enantioselective preparation of the two isomers of 4-hydroxy-2-cyclohexanone derivatives 1a , b was achieved, starting from a common cyclohexenone, through asymmetric transfer hydrogenation (ATH) reactions using bifunctional ruthenium catalysts. From these versatile intermediates, a stereoselective route to a cytosine analogue built on a bicyclo [4.1.0]heptane scaffold is described. Nucleoside kinase activity assays with this cyclopropyl-fused cyclohexane nucleoside, together with other related nucleosides ( 2a - e ), were performed, showing that thymine- and guanine- containing compounds have affinity for herpes simplex virus Type 1 (HSV-1) thymidine kinase (TK) but not for human cytosolic TK-1, thus pointing to their selectivity for herpetic TKs but not cellular TKs.
- Published
- 2022
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12. Benzothiazole Derivatives as Multifunctional Antioxidant Agents for Skin Damage: Structure-Activity Relationship of a Scaffold Bearing a Five-Membered Ring System.
- Author
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Djuidje EN, Barbari R, Baldisserotto A, Durini E, Sciabica S, Balzarini J, Liekens S, Vertuani S, and Manfredini S
- Abstract
Skin diseases often give multifactorial damages; therefore, the development of multifunctional compounds represents a suitable approach especially against disorders that are induced by oxidative stress. Thus, taking into account the successful results we achieved on benzimidazoles, we have devised a new series of isosteric benzothiazoles and investigated their antioxidant, photoprotective, antifungal and antiproliferative activity. Particular attention has been paid to synergistic antioxidant and photoprotective properties. For compounds 9a and 10a , a multifunctional profile was outlined, supported by an excellent filtering capacity, mainly UVB, which has higher capacities than those of the reference PBSA which is currently in the market as a UV sunscreen filter. The two compounds were also the best in terms of growth inhibition of dermatophytes and Candida albicans, and 10a also showed good antioxidant activity. Furthermore, 9a was also effective on melanoma tumor cells (SK-Mel 5), making these compounds good candidates in the development of new skin protective and preventive agents.
- Published
- 2022
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13. γ-Non-Symmetrically Dimasked TriPPPro Prodrugs as Potential Antiviral Agents against HIV.
- Author
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Zhao C, Jia X, Schols D, Balzarini J, and Meier C
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Cells, Cultured, Dose-Response Relationship, Drug, Humans, Microbial Sensitivity Tests, Molecular Structure, Nucleosides chemical synthesis, Nucleosides chemistry, Phosphates chemical synthesis, Phosphates chemistry, Prodrugs chemical synthesis, Prodrugs chemistry, Structure-Activity Relationship, Anti-HIV Agents pharmacology, HIV-1 drug effects, HIV-2 drug effects, Nucleosides pharmacology, Phosphates pharmacology, Prodrugs pharmacology
- Abstract
Nucleoside analogue reverse transcriptase inhibitors (NRTI) and nucleoside analogue monophosphate prodrugs are used in combination antiretroviral therapy (cART). The design of antivirally active nucleoside triphosphate prodrugs is a recent and an important advancement in the field of nucleoside analogue drug development. Here, we report on TriPPPro-derivatives of nucleoside analogue triphosphates (NTPs) that comprised two different acyloxybenzyl-masks at the γ-phosphate of the NTP aiming to achieve the metabolic bypass. Thus, γ-non-symmetrically dimasked TriPPPro-compounds (γ-(AB,ab)-d4TTPs) were synthesized and they proved to be active against HIV-1 and HIV-2 in cultures of infected wild-type human CD4
+ T-lymphocyte (CEM/0) cells and more importantly also in thymidine kinase-deficient CD4+ T-cells (CEM/TK-). From hydrolysis studies both in phosphate buffer (PB, pH 7.3) and CEM cell extracts, there was surprisingly no differentiation in the cleavage of the two acyloxybenzyl prodrug-masks. However, if within one of the two acyloxybenzyl groups a short PEG-type methoxytriglycol group was introduced, the "standard" acyloxybenzyl-mask was cleaved with high preference., (© 2020 The Authors. ChemMedChem published by Wiley-VCH GmbH.)- Published
- 2021
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14. Prodrugs of γ-Alkyl-Modified Nucleoside Triphosphates: Improved Inhibition of HIV Reverse Transcriptase.
- Author
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Zhao C, Weber S, Schols D, Balzarini J, and Meier C
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Cells, Cultured, HIV Reverse Transcriptase metabolism, HIV-1 drug effects, HIV-2 drug effects, Humans, Microbial Sensitivity Tests, Molecular Structure, Nucleosides chemical synthesis, Nucleosides chemistry, Polyphosphates chemical synthesis, Polyphosphates chemistry, Prodrugs chemical synthesis, Prodrugs chemistry, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Anti-HIV Agents pharmacology, HIV Reverse Transcriptase antagonists & inhibitors, Nucleosides pharmacology, Polyphosphates pharmacology, Prodrugs pharmacology, Reverse Transcriptase Inhibitors pharmacology
- Abstract
The development of nucleoside triphosphate prodrugs is one option to apply nucleoside reverse transcriptase inhibitors. Herein, we report the synthesis and evaluation of d4TTP analogues, in which the γ-phosphate was modified covalently by lipophilic alkyl residues, and acyloxybenzyl prodrugs of these γ-alkyl-modified d4TTPs, with the aim of delivering of γ-alkyl-d4TTP into cells. Selective formation of γ-alkyl-d4TTP was proven with esterase and in CD4
+ -cell extracts. In contrast to d4TTP, γ-alkyl-d4TTPs proved highly stable against dephosphorylation. Primer extension assays with HIV reverse transcriptase (RT) and DNA-polymerases α, β or γ showed that γ-alkyl-d4TTPs were substrates for HIV-RT only. In antiviral assays, compounds were highly potent inhibitors of HIV-1 and HIV-2 also in thymidine-kinase-deficient T-cell cultures (CEM/TK- ). Thus, the intracellular delivery of such γ-alkyl-nucleoside triphosphates may potentially lead to nucleoside triphosphates with a higher selectivity towards the viral polymerase that can act in virus-infected cells., (© 2020 The Authors. Published by Wiley-VCH GmbH.)- Published
- 2020
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15. γ-Ketobenzyl-Modified Nucleoside Triphosphate Prodrugs as Potential Antivirals.
- Author
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Nack T, Dinis de Oliveira T, Weber S, Schols D, Balzarini J, and Meier C
- Subjects
- Anti-HIV Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents pharmacology, Cells, Cultured, HIV-1 drug effects, HIV-1 physiology, HIV-2 drug effects, HIV-2 physiology, Humans, Polyphosphates chemistry, Polyphosphates pharmacology, Prodrugs pharmacology, T-Lymphocytes drug effects, T-Lymphocytes physiology, T-Lymphocytes virology, Thiamine chemistry, Thiamine pharmacology, Anti-HIV Agents chemistry, Prodrugs chemistry
- Abstract
The antiviral activity of nucleoside reverse transcriptase inhibitors is often hampered by insufficient phosphorylation. Nucleoside triphosphate analogues are presented, in which the γ-phosphate was covalently modified by a non-bioreversible, lipophilic 4-alkylketobenzyl moiety. Interestingly, primer extension assays using human immunodeficiency virus reverse transcriptase (HIV-RT) and three DNA-polymerases showed a high selectivity of these γ-modified nucleoside triphosphates to act as substrates for HIV-RT, while they proved to be nonsubstrates for DNA-polymerases α, β, and γ. In contrast to d4TTP, the γ-modified d4TTPs showed a high resistance toward dephosphorylation in cell extracts. A series of acyloxybenzyl-prodrugs of these γ-ketobenzyl nucleoside triphosphates was prepared. The aim was the intracellular delivery of a stable γ-modified nucleoside triphosphate to increase the selectivity of such compounds to act in infected versus noninfected cells. Delivery of γ-ketobenzyl-d4TTPs was proven in T-lymphocyte cell extracts. The prodrugs were potent inhibitors of HIV-1/2 in cultures of infected CEM/0 cells and more importantly in thymidine kinase-deficient CD4
+ T-cells.- Published
- 2020
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- View/download PDF
16. Skin Damages-Structure Activity Relationship of Benzimidazole Derivatives Bearing a 5-Membered Ring System.
- Author
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Djuidje EN, Durini E, Sciabica S, Serra E, Balzarini J, Liekens S, Manfredini S, Vertuani S, and Baldisserotto A
- Subjects
- Antifungal Agents chemistry, Antifungal Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents pharmacology, Candida albicans drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Free Radical Scavengers chemistry, Free Radical Scavengers pharmacology, Humans, Skin radiation effects, Structure-Activity Relationship, Ultraviolet Rays adverse effects, Benzimidazoles chemistry, Benzimidazoles pharmacology, Radiation-Protective Agents chemistry, Radiation-Protective Agents pharmacology, Skin drug effects
- Abstract
In the search for scaffolds for multifunctional compounds we investigated the structure activity relationship of a class of benzimidazole derivatives bearing 5-membered ring. The newly synthesized and the already known compounds were divided into three classes that present different substituent at 5 position of the benzimidazole ring (-H, -COOH or -SO
3 H) and different heterocycle at position 2 (thiophene, furan or pyrrole). All the derivatives were synthesized and tested to determine their photoprotective profile against UV rays, in vitro antioxidant capacity against different radicals (DPPH and FRAP test), antifungal inhibitory activity (dermatophytes and Candida albicans ), antiviral and antiproliferative activity. A Structure-Activity Relationship study indicated compound 10 , bearing a pyrrole heterocycle on the benzimidazole ring, as the best multifunctional derivative of the series and as potential candidate for the development of drugs especially in case of melanoma.- Published
- 2020
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17. Water-soluble fullerene-based nanostructures with promising antiviral and myogenic activity.
- Author
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Kraevaya OA, Novikov AV, Shestakov AF, Ershova ES, Savinova EA, Kameneva LV, Veiko NN, Schols D, Balzarini J, Kostyuk SV, and Troshin PA
- Subjects
- Cell Line, Humans, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells drug effects, Solubility, Antiviral Agents chemistry, Antiviral Agents pharmacology, Fullerenes chemistry, Fullerenes pharmacology, Muscle Development drug effects, Nanostructures chemistry, Water chemistry
- Abstract
Here we report a straightforward method for the synthesis of a water-soluble C60 fullerene derivative decorated with five residues of phosphonic acid. Self-assembly of the synthesized compound in aqueous solution leads to the formation of nanostructures with unprecedented myogenic and antiviral activity.
- Published
- 2020
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18. Design, synthesis and evaluation of benzothiazole derivatives as multifunctional agents.
- Author
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Djuidje EN, Sciabica S, Buzzi R, Dissette V, Balzarini J, Liekens S, Serra E, Andreotti E, Manfredini S, Vertuani S, and Baldisserotto A
- Subjects
- Antifungal Agents pharmacology, Antineoplastic Agents pharmacology, Cell Proliferation drug effects, Drug Evaluation, Preclinical, HEK293 Cells, Humans, Benzothiazoles chemistry, Drug Design
- Abstract
Oxidative stress is the product or aetiology of various multifactorial diseases; on the other hand, the development of multifunctional compounds is a recognized strategy for the control of complex diseases. To this end, a series of benzothiazole derivatives was synthesized and evaluated for their multifunctional effectiveness as antioxidant, sunscreen (filter), antifungal and antiproliferative agents. Compounds were easily synthesized via condensation reaction between 2-aminothiophenols and different benzaldehydes. SAR study, particularly in position 2 and 6 of benzothiazoles, led to the identification of 4g and 4k as very interesting potential compounds for the design of multifunctional drugs. In particular, compound 4g is the best blocker of hERG potassium channels expressed in HEK 293 cells exhibiting 60.32% inhibition with IC
50 = 4.79 μM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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19. Synthesis and Biological Evaluation of New Antitubulin Agents Containing 2-(3',4',5'-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3- c ]pyridine Scaffold.
- Author
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Romagnoli R, Prencipe F, Oliva P, Cacciari B, Balzarini J, Liekens S, Hamel E, Brancale A, Ferla S, Manfredini S, Zurlo M, Finotti A, and Gambari R
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Biological Products pharmacology, Cell Death drug effects, Cell Division drug effects, Cell Line, Cell Line, Tumor, Cell Proliferation drug effects, Colchicine chemistry, Drug Screening Assays, Antitumor methods, G2 Phase drug effects, HeLa Cells, Humans, K562 Cells, Leukocytes, Mononuclear drug effects, Mice, Molecular Docking Simulation methods, Pyridines pharmacology, Structure-Activity Relationship, Antineoplastic Agents chemistry, Biological Products chemistry, Pyridines chemistry, Tubulin metabolism, Tubulin Modulators chemistry
- Abstract
Two novel series of compounds based on the 4,5,6,7-tetrahydrothieno[2,3- c ]pyridine and 4,5,6,7-tetrahydrobenzo[ b ]thiophene molecular skeleton, characterized by the presence of a 3',4',5'-trimethoxyanilino moiety and a cyano or an alkoxycarbonyl group at its 2- or 3-position, respectively, were designed, synthesized, and evaluated for antiproliferative activity on a panel of cancer cell lines and for selected highly active compounds, inhibition of tubulin polymerization, and cell cycle effects. We have identified the 2-(3',4',5'-trimethoxyanilino)-3-cyano-6-methoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3- c ]pyridine derivative 3a and its 6-ethoxycarbonyl homologue 3b as new antiproliferative agents that inhibit cancer cell growth with IC
50 values ranging from 1.1 to 4.7 μM against a panel of three cancer cell lines. Their interaction with tubulin at micromolar levels leads to the accumulation of cells in the G2/M phase of the cell cycle and to an apoptotic cell death. The cell apoptosis study found that compounds 3a and 3b were very effective in the induction of apoptosis in a dose-dependent manner. These two derivatives did not induce cell death in normal human peripheral blood mononuclear cells, suggesting that they may be selective against cancer cells. Molecular docking studies confirmed that the inhibitory activity of these molecules on tubulin polymerization derived from binding to the colchicine site.- Published
- 2020
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20. Design, synthesis and biological evaluation of 2-alkoxycarbonyl-3-anilinoindoles as a new class of potent inhibitors of tubulin polymerization.
- Author
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Romagnoli R, Prencipe F, Oliva P, Kimatrai Salvador M, Brancale A, Ferla S, Hamel E, Viola G, Bortolozzi R, Persoons L, Balzarini J, Liekens S, and Schols D
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Drug Design, Drug Screening Assays, Antitumor, Humans, Indoles chemical synthesis, Molecular Docking Simulation, Neoplasms drug therapy, Neoplasms metabolism, Tubulin Modulators chemical synthesis, Indoles chemistry, Indoles pharmacology, Tubulin metabolism, Tubulin Modulators chemistry, Tubulin Modulators pharmacology
- Abstract
A new class of inhibitors of tubulin polymerization based on the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)indole molecular skeleton was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization and cell cycle effects. The results presented show that the methoxy substitution and location on the indole nucleus plays an important role in inhibition of cell growth, and the most favorable position for the substituent was at C-6. In addition, a small-size ester function (methoxy/ethoxycarbonyl) at the 2-position of the indole core was desirable. Also, analogues that were alkylated with methyl, ethyl or n-propyl groups or had a benzyl moiety on the N-1 indolic nitrogen retained activity equivalent to those observed in the parent N-1H analogues. The most promising compounds of the series were 2-methoxycarbonyl-3-(3',4'.5'-trimethoxyanilino)-5-methoxyindole 3f and 1-methyl-2-methoxycarbonyl-3-(3',4'.5'-trimethoxyanilino)-6-methoxy-indole 3w, both of which target tubulin at the colchicine site with antitubulin activities comparable to that of the reference compound combretastatin A-4., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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21. Direct arylation of C 60 Cl 6 and C 70 Cl 8 with carboxylic acids: a synthetic avenue to water-soluble fullerene derivatives with promising antiviral activity.
- Author
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Kraevaya OA, Peregudov AS, Godovikov IA, Shchurik EV, Martynenko VM, Shestakov AF, Balzarini J, Schols D, and Troshin PA
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Benzene Derivatives chemical synthesis, Benzene Derivatives chemistry, Benzene Derivatives pharmacology, Carboxylic Acids chemical synthesis, Carboxylic Acids chemistry, Cell Line, Tumor, Fullerenes chemistry, HIV-1 drug effects, HIV-2 drug effects, Humans, Microbial Sensitivity Tests, Molecular Structure, Solubility, Thiophenes chemical synthesis, Thiophenes chemistry, Thiophenes pharmacology, Anti-HIV Agents pharmacology, Carboxylic Acids pharmacology, Fullerenes pharmacology, Water chemistry
- Abstract
We report unprecedented Friedel-Crafts arylation of chlorofullerenes C60Cl6 and C70Cl8 with unprotected carboxylic acids as an efficient single-step synthesis of the inherently stable water-soluble fullerene derivatives. Using this method, a series of previously unaccessible compounds was obtained without chromatographic purification in almost quantitative yields. Promising anti-HIV activity comparable to characteristics of commercial drugs was demonstrated for some of these compounds.
- Published
- 2020
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22. Potent antiviral activity of carbohydrate-specific algal and leguminous lectins from the Brazilian biodiversity.
- Author
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Gondim ACS, Roberta da Silva S, Mathys L, Noppen S, Liekens S, Holanda Sampaio A, Nagano CS, Renata Costa Rocha C, Nascimento KS, Cavada BS, Sadler PJ, and Balzarini J
- Abstract
Brazil has one of the largest biodiversities in the world. The search for new natural products extracted from the Brazilian flora may lead to the discovery of novel drugs with potential to treat infectious and other diseases. Here, we have investigated 9 lectins extracted and purified from the Northeastern Brazilian flora, from both leguminous species: Canavalia brasiliensis (ConBr), C. maritima (ConM), Dioclea lasiocarpa (DLasiL) and D. sclerocarpa (DSclerL), and algae Amansia multifida (AML), Bryothamniom seaforthii (BSL), Hypnea musciformis (HML), Meristiella echinocarpa (MEL) and Solieria filiformis (SfL). They were exposed to a panel of 18 different viruses, including HIV and influenza viruses. Several lectins showed highly potent antiviral activity, often within the low nanomolar range. DSclerL and DLasiL exhibited EC
50 values (effective concentration of lectin required to inhibit virus-induced cytopathicity by 50%) of 9 nM to 46 nM for HIV-1 and respiratory syncytial virus (RSV), respectively, DLasiL also inhibited feline corona virus at an EC50 of 5 nM, and DSclerL, ConBr and ConM showed remarkably low EC50 values ranging from 0.4 to 6 nM against influenza A virus strain H3N2 and influenza B virus. For HIV, evidence pointed to the blockage of entry of the virus into its target cells as the underlying mechanism of antiviral action of these lectins. Overall, the most promising lectins based on their EC50 values were DLasiL, DSclerL, ConBr, ConM, SfL and HML. These novel findings indicate that lectins from the Brazilian flora may provide novel antiviral compounds with therapeutic potential.- Published
- 2019
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23. Dolutegravir Monotherapy of Simian Immunodeficiency Virus-Infected Macaques Selects for Several Patterns of Resistance Mutations with Variable Virological Outcomes.
- Author
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Van Rompay KKA, Hassounah S, Keele BF, Lifson JD, Ardeshir A, Watanabe J, Pham HT, Chertova E, Sowder R, Balzarini J, Mesplède T, and Wainberg MA
- Subjects
- Animals, Disease Models, Animal, Drug Resistance, Viral, HIV Infections drug therapy, HIV Infections virology, HIV Integrase Inhibitors pharmacology, Heterocyclic Compounds, 3-Ring pharmacology, Humans, Macaca mulatta, Mutation, Oxazines, Piperazines, Pyridones, RNA, Viral blood, RNA, Viral drug effects, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus pathogenicity, Treatment Outcome, HIV Integrase Inhibitors administration & dosage, Heterocyclic Compounds, 3-Ring administration & dosage, Simian Acquired Immunodeficiency Syndrome drug therapy, Simian Immunodeficiency Virus drug effects
- Abstract
Drug resistance remains a major concern for human immunodeficiency virus (HIV) treatment. To date, very few resistance mutations have emerged in first-line combination therapy that includes the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG). In vitro , DTG selects for several primary mutations that induce low-level DTG resistance; secondary mutations, while increasing the level of resistance, however, further impair replication fitness, which raised the idea that DTG monotherapy may be feasible. The simian immunodeficiency virus (SIV) rhesus macaque model of HIV infection can be useful to explore this concept. Nine macaques were infected with virulent SIVmac251 and started on DTG monotherapy during either acute ( n = 2) or chronic infection ( n = 7). Within 4 weeks of treatment, all animals demonstrated a reduction in viremia of 0.8 to 3.5 log RNA copies/ml plasma. Continued treatment led to overall sustained benefits, but the outcome after 10 to 50 weeks of treatment was highly variable and ranged from viral rebound to near pretreatment levels to sustained suppression, with viremia being 0.5 to 5 logs lower than expected based on pretreatment viremia. A variety of mutations previously described to confer low-level resistance of HIV-1 to DTG or other INSTI were detected, and these were sometimes followed by mutations believed to be compensatory. Some mutations, such as G118R, previously shown to severely impair the replication capacity in vitro , were associated with more sustained virological and immunological benefits of continued DTG therapy, while other mutations, such as E92Q and G140A/Q148K, were associated with more variable outcomes. The observed variability of the outcomes in macaques warrants avoidance of DTG monotherapy in HIV-infected people. IMPORTANCE A growing number of anti-HIV drug combinations are effective in suppressing virus replication in HIV-infected persons. However, to reduce their cost and risk for toxicity, there is considerable interest in simplifying drug regimens. A major concern with single-drug regimens is the emergence of drug-resistant viral mutants. It has been speculated that DTG monotherapy may be a feasible option, because DTG may have a higher genetic barrier for the development of drug resistance than other commonly used antiretrovirals. To explore treatment initiation with DTG monotherapy, we started SIV-infected macaques on DTG during either acute or chronic infection. Although DTG initially reduced virus replication, continued treatment led to the emergence of a variety of viral mutations previously described to confer low-level resistance of HIV-1 to DTG, and this was associated with variable clinical outcomes. This unpredictability of mutational pathways and outcomes warns against using DTG monotherapy as initial treatment for HIV-infected people., (Copyright © 2019 American Society for Microbiology.)
- Published
- 2019
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24. Novel Conjugated Unsaturated Ketones with Submicromolar Potencies Towards some Leukemic and Colon Cancer Cells.
- Author
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Das S, Gul HI, Das U, Balzarini J, Dimmock SG, and Dimmock JR
- Subjects
- Cell Line, Tumor, Drug Screening Assays, Antitumor, Humans, Inhibitory Concentration 50, Structure-Activity Relationship, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Colonic Neoplasms pathology, Ketones chemistry, Ketones pharmacology, Leukemia pathology
- Abstract
Background: Cancer continues to be the major health burden worldwide. There is an urgent need for the development of novel antineoplastic compounds to treat this devastating condition. Various alkylating anticancer drugs have been employed in the clinic for treating cancers. Unsaturated conjugated ketones are a group of alkylators which are of significant interest as potent antineoplastic agents., Objective: The goal of this study is to discover unsaturated conjugated ketones which are novel potent cytotoxins displaying growth-inhibitory properties towards neoplasms and also to serve as cytotoxic warheads in drug development., Methods: A variety of 3,5-bis (benzylidene)-4-piperidones 2a-n were synthesized and evaluated against a number of neoplastic cell lines. The short-term neurotoxicity of 2a-k, n was evaluated in mice by i.p. administration using doses level of 30, 100 and 300 mg/kg. Statistical correlations for determining structure-activity relationships were performed using an SPSS software., Results: A number of compounds display cytotoxic potencies in the region of 10-7 to 10-8 M and some of the structural features contributing to the cytotoxicity were identified. Compounds 2a-d, 2h demonstrated substantially higher cytotoxic potencies compared to melphalan and 5- fluorouracil against a panel of leukemic and colon cancer cell lines. These lead cytotoxins comply with drug-likeness properties. In general, the antineoplastics 2 are well tolerated in mice using a short-term neurotoxicity screening., Conclusion: In general, this group of compounds comprises excellent cytotoxic agents, which warrant their further development as cytotoxic warheads., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2019
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25. Alpha-carboxynucleoside phosphonates: direct-acting inhibitors of viral DNA polymerases.
- Author
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Balzarini J, Ford A, Maguire NM, John J, Das K, Arnold E, Dehaen W, and Maguire A
- Subjects
- Animals, DNA-Directed DNA Polymerase, Drug Discovery, Exodeoxyribonucleases antagonists & inhibitors, Herpes Simplex drug therapy, Humans, Models, Molecular, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors pharmacology, Viral Proteins antagonists & inhibitors, Virus Diseases drug therapy, Viruses drug effects, Viruses enzymology, Antiviral Agents chemistry, Antiviral Agents pharmacology, Nucleic Acid Synthesis Inhibitors chemistry, Nucleic Acid Synthesis Inhibitors pharmacology, Nucleosides analogs & derivatives, Nucleosides pharmacology, Organophosphonates chemistry, Organophosphonates pharmacology
- Abstract
Acyclic nucleoside phosphonates represent a well-defined class of clinically used nucleoside analogs. All acyclic nucleoside phosphonates need intracellular phosphorylation before they can bind viral DNA polymerases. Recently, a novel class of alpha-carboxynucleoside phosphonates have been designed to mimic the natural 2'-deoxynucleotide 5'-triphosphate substrates of DNA polymerases. They contain a carboxyl group in the phosphonate moiety linked to the nucleobase through a cyclic or acyclic bridge. Alpha-carboxynucleoside phosphonates act as viral DNA polymerase inhibitors without any prior requirement of metabolic conversion. Selective inhibitory activity against retroviral reverse transcriptase and herpesvirus DNA polymerases have been demonstrated. These compounds have a unique mechanism of inhibition of viral DNA polymerases, and provide possibilities for further modifications to optimize and fine tune their antiviral DNA polymerase spectrum.
- Published
- 2019
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- View/download PDF
26. Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3',4',5'-trimethoxyphenyl)-3-(2'-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach.
- Author
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Preti D, Romagnoli R, Rondanin R, Cacciari B, Hamel E, Balzarini J, Liekens S, Schols D, Estévez-Sarmiento F, Quintana J, and Estévez F
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Indoles chemical synthesis, Indoles chemistry, Molecular Structure, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Apoptosis drug effects, Drug Design, Indoles pharmacology
- Abstract
Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3',4',5'-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC
50 values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3',4',5'-trimethoxyphenyl)-2-propen-1-one framework. The structure-activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC50 values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC50 : 18 μM). This derivative also displayed cytotoxic properties (IC50 values ∼1 μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G2 -M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3',4',5'-trimethoxyphenyl scaffold.- Published
- 2018
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27. Symmetrical Diamidates as a Class of Phosphate Prodrugs to Deliver the 5'-Monophosphate Forms of Anticancer Nucleoside Analogues.
- Author
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Slusarczyk M, Ferrari V, Serpi M, Gönczy B, Balzarini J, and McGuigan C
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cathepsin A chemistry, Cell Line, Tumor, Enzyme Assays, Humans, Mice, Molecular Structure, Organophosphorus Compounds chemical synthesis, Organophosphorus Compounds chemistry, Prodrugs chemical synthesis, Prodrugs chemistry, Purine Nucleosides chemical synthesis, Purine Nucleosides chemistry, Pyrimidine Nucleosides chemical synthesis, Pyrimidine Nucleosides chemistry, Antineoplastic Agents pharmacology, Organophosphorus Compounds pharmacology, Prodrugs pharmacology, Purine Nucleosides pharmacology, Pyrimidine Nucleosides pharmacology
- Abstract
The application of phosphorodiamidate technology to pyrimidine and purine nucleosides with anticancer activity to potentially overcome the resistance mechanisms associated with parent nucleosides is reported. Sixteen symmetrical phosphorodiamidates were prepared from the natural amino acids l-alanine and glycine. All the compounds were evaluated for their cytotoxic activity against a wide panel of solid and leukaemic tumour cell lines. In addition, a carboxypeptidase Y assay was performed on a representative phosphorodiamidate in order to reveal the putative bioactivation pathway for the reported phosphorodiamidate-type prodrugs., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2018
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28. Engineering Lactobacillus rhamnosus GG and GR-1 to express HIV-inhibiting griffithsin.
- Author
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Petrova MI, van den Broek MFL, Spacova I, Verhoeven TLA, Balzarini J, Vanderleyden J, Schols D, and Lebeer S
- Subjects
- Bacterial Proteins genetics, Bacterial Proteins metabolism, Cell Line, Gene Expression, HIV-1 drug effects, HIV-1 physiology, Humans, Lacticaseibacillus rhamnosus genetics, Plant Lectins genetics, Promoter Regions, Genetic, Protein Sorting Signals, Recombinant Proteins genetics, Recombinant Proteins metabolism, Virus Replication drug effects, Anti-HIV Agents metabolism, Lacticaseibacillus rhamnosus metabolism, Metabolic Engineering methods, Plant Lectins metabolism
- Abstract
Probiotic bacteria are being explored for the in situ delivery of various therapeutic agents. In this study, we aimed to express two HIV-inhibiting lectins, actinohivin (AH) and griffithsin (GRFT), in the probiotic strains Lactobacillus rhamnosus GG and L. rhamnosus GR-1 for gastrointestinal and vaginal mucosal delivery, respectively. Constructs were generated for the intracellular and extracellular production of AH and GRFT under the control of the promoter of their Major Secreted Protein Msp1. Also, intracellular expression of GRFT was investigated under the control of the nisA promoter from the inducible nisin-controlled expression (NICE) system. For the extracellular localization, the signal leader peptide of Msp1/p75 from L. rhamnosus GG was translationally fused with the genes encoding AH and GRFT. Construction of recombinant strains expressing the AH monomer and dimer was unsuccessful, probably due to the intracellular toxicity of AH for the lactobacilli. On the other hand, recombinant strains for intra- and extracellular production of GRFT by L. rhamnosus GG and GR-1 were successfully constructed. The highest expression levels of recombinant GRFT were observed for the constructs under the control of the inducible nisA promoter and we demonstrated anti-HIV activity against an M-tropic and a T-tropic HIV-1 strain. We can conclude that recombinant Lactobacillus expressing anti-HIV lectins could contribute to the development of enhanced probiotic strains that are able to inhibit HIV transmission and subsequent replication, although further research and development are required., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)
- Published
- 2018
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29. Synthesis and Antiviral Activity of Water-Soluble Polycarboxylic Derivatives of [60]Fullerene Loaded with 3,4-Dichlorophenyl Units.
- Author
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Voronov II, Martynenko VM, Chernyak AV, Balzarini J, Schols D, and Troshin PA
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Carboxylic Acids chemical synthesis, Carboxylic Acids chemistry, Cells, Cultured, Humans, Hydrophobic and Hydrophilic Interactions, Microbial Sensitivity Tests, Molecular Structure, Polymers chemical synthesis, Polymers chemistry, Solubility, Water chemistry, Anti-HIV Agents pharmacology, Carboxylic Acids pharmacology, Chlorobenzenes chemistry, Fullerenes chemistry, HIV-1 drug effects, HIV-2 drug effects, Polymers pharmacology
- Abstract
We have synthesized a series of water-soluble polycarboxylic derivatives of [60]fullerene with a gradually changed polarity by combining three to five polar (ionic) malonate addends with two to zero hydrophobic dichlorobenzene units and explored their antiviral activity. It has been shown that decreasing the number of the ionogenic carboxylic groups in the molecules enhanced their antiviral activity against HIV-1 and suppressed their action against HIV-2. The obtained results implied that the charged states and hydrophobicity of the water-soluble polycarboxylic fullerene derivatives affect significantly their biological properties., (© 2018 Wiley-VHCA AG, Zurich, Switzerland.)
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- 2018
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30. Synthesis of Guanine α-Carboxy Nucleoside Phosphonate (G-α-CNP), a Direct Inhibitor of Multiple Viral DNA Polymerases.
- Author
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Maguire NM, Ford A, Balzarini J, and Maguire AR
- Subjects
- Catalysis, Chemistry Techniques, Synthetic, HIV-1 enzymology, Nucleic Acid Synthesis Inhibitors chemistry, Organophosphonates chemistry, Palladium chemistry, DNA-Directed DNA Polymerase metabolism, Guanine chemistry, Nucleic Acid Synthesis Inhibitors chemical synthesis, Nucleic Acid Synthesis Inhibitors pharmacology, Organophosphonates chemical synthesis, Organophosphonates pharmacology, Purine Nucleosides chemistry
- Abstract
The synthesis of guanine α-carboxy nucleoside phosphonate (G-α-CNP) is described. Two routes provide access to racemic G-α-CNP 9, one via base construction and the other utilizing Tsuji-Trost allylic substitution. The latter methodology was also applied to the enantiopure synthesis of both antipodes of G-α-CNP, each of which showing interesting antiviral DNA polymerase activity. Additionally, we report an improved multigram scale preparation of the cyclopentene building block 10, starting material for the preferred Tsuji-Trost route to 9.
- Published
- 2018
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31. The ProTide Prodrug Technology: From the Concept to the Clinic.
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Mehellou Y, Rattan HS, and Balzarini J
- Subjects
- Animals, Chemistry, Pharmaceutical, Humans, Nucleosides chemical synthesis, Prodrugs chemical synthesis, Structure-Activity Relationship, Nucleosides pharmacology, Nucleosides therapeutic use, Prodrugs pharmacology, Prodrugs therapeutic use
- Abstract
The ProTide technology is a prodrug approach developed for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates. In this approach, the hydroxyls of the monophosphate or monophosphonate groups are masked by an aromatic group and an amino acid ester moiety, which are enzymatically cleaved-off inside cells to release the free nucleoside monophosphate and monophosphonate species. Structurally, this represents the current end-point of an extensive medicinal chemistry endeavor that spans almost three decades. It started from the masking of nucleoside monophosphate and monophosphonate groups by simple alkyl groups and evolved into the sophisticated ProTide system as known today. This technology has been extensively employed in drug discovery, and it has already led to the discovery of two FDA-approved (antiviral) ProTides. In this work, we will review the development of the ProTide technology, its application in drug discovery, and its role in the improvement of drug delivery and efficacy.
- Published
- 2018
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32. 2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition.
- Author
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Romagnoli R, Kimatrai Salvador M, Schiaffino Ortega S, Baraldi PG, Oliva P, Baraldi S, Lopez-Cara LC, Brancale A, Ferla S, Hamel E, Balzarini J, Liekens S, Mattiuzzo E, Basso G, and Viola G
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Membrane Potential, Mitochondrial drug effects, Mice, Models, Molecular, Molecular Structure, Polymerization drug effects, Reactive Oxygen Species metabolism, Structure-Activity Relationship, Thiophenes chemical synthesis, Thiophenes chemistry, Tubulin Modulators chemical synthesis, Tubulin Modulators chemistry, Antineoplastic Agents pharmacology, Drug Design, Microtubules drug effects, Thiophenes pharmacology, Tubulin metabolism, Tubulin Modulators pharmacology
- Abstract
Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a, 4c, 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC
50 values ranging from 0.13 to 0.84 μM against four different cancer cell lines. Three agents (4a, 4c and 4i) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c, containing the 2'-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IC50 value of 140 nM, inhibited tubulin polymerization with an IC50 value of 1.2 μM, similar to that of CA-4 (IC50 : 1.1 μM), and induced apoptosis in HeLa cells., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)- Published
- 2018
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33. 2-Amino-3-methylcarboxy-5-heptyl-thiophene (TJ191) is a selective anti-cancer small molecule that targets low TβRIII-expressing malignant T-cell leukemia/lymphoma cells.
- Author
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El-Gazzar A, Noppen S, Thomas J, Dehaen W, Balzarini J, and Liekens S
- Abstract
Current chemotherapy regimens often include non-specific cytostatic/cytotoxic drugs, which do not distinguish between normal and tumor cells, therefore causing considerable systemic toxicity. We previously reported the synthesis and anti-proliferative activity of a novel synthetic 2-aminothiophene-3-carboxylic acid ester derivative TJ191 that selectively targets certain cancer cells without affecting the proliferation of other cancer cells or normal fibroblasts or immune cells (over 600-fold selectivity). In a panel of ten human T-cell leukemia/lymphoma cell lines and peripheral blood mononuclear cells (PBMCs), we now found that transforming growth factor β type III receptor (TβRIII) expression correlates inversely with TJ191 sensitivity, but not with sensitivity against classical chemotherapeutic drugs, thus serving as a predictive marker for TJ191 sensitivity. Accordingly, CRISPR/Cas9-mediated knock-out of TβRIII partially restored the susceptibility of TJ191-resistant cells to this novel compound. Our findings highlight TJ191 as a potent and selective anti-cancer molecule with pronounced activity against human malignant T-cells expressing low levels of TβRIII., Competing Interests: CONFLICTS OF INTEREST J.B., W.D., J.T., S.L. are co-inventors on a patent application entitled “Novel antiproliferative agents” related to the TJ191 compound.
- Published
- 2017
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34. Surface Glycans: A Therapeutic Opportunity for Kinetoplastid Diseases: (Trends in Parasitology 2017).
- Author
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Castillo-Acosta VM, Balzarini J, and González-Pacanowska D
- Published
- 2017
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35. Virtual Screening of Acyclovir Derivatives as Potential Antiviral Agents: Design, Synthesis, and Biological Evaluation of New Acyclic Nucleoside ProTides.
- Author
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Derudas M, Vanpouille C, Carta D, Zicari S, Andrei G, Snoeck R, Brancale A, Margolis L, Balzarini J, and McGuigan C
- Subjects
- Cell Line, Drug Design, HIV Infections drug therapy, HIV Infections virology, HIV Reverse Transcriptase metabolism, HIV-1 enzymology, Herpes Simplex drug therapy, Herpes Simplex virology, Humans, Molecular Docking Simulation, Simplexvirus drug effects, Virus Replication drug effects, Acyclovir analogs & derivatives, Acyclovir pharmacology, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, HIV-1 drug effects, Nucleosides chemistry, Nucleosides pharmacology
- Abstract
Following our findings on the anti-human immunodeficiency virus (HIV) activity of acyclovir (ACV) phosphate prodrugs, we herein report the ProTide approach applied to a series of acyclic nucleosides aimed at the identification of novel and selective antiviral, in particular anti-HIV agents. Acyclic nucleoside analogues used in this study were identified through a virtual screening using HIV-reverse transcriptase (RT), adenylate/guanylate kinase, and human DNA polymerase γ. A total of 39 new phosphate prodrugs were synthesized and evaluated against HIV-1 (in vitro and ex vivo human tonsillar tissue system) and human herpes viruses. Several ProTide compounds showed substantial potency against HIV-1 at low micromolar range while the parent nucleosides were not effective. Also, pronounced inhibition of herpesvirus replication was observed. A carboxypeptidase-mediated hydrolysis study was performed for a selection of compounds to assess the formation of putative metabolites and support the biological activity observed.
- Published
- 2017
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36. New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity.
- Author
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Krečmerová M, Dračínský M, Snoeck R, Balzarini J, Pomeisl K, and Andrei G
- Subjects
- Antiviral Agents chemistry, Antiviral Agents pharmacology, Cell Line, Cytomegalovirus drug effects, Herpesvirus 3, Human drug effects, Humans, Organophosphonates chemical synthesis, Organophosphonates pharmacology, Prodrugs chemistry, Prodrugs pharmacology, Simplexvirus drug effects, Antiviral Agents chemical synthesis, Organophosphonates chemistry, Prodrugs chemical synthesis, Pyrimidine Nucleosides chemistry
- Abstract
New 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (PMEO-DAPy) and 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-5-azaC) prodrugs were prepared with a pro-moiety consisting of carbonyloxymethyl esters (POM, POC), alkoxyalkyl esters, amino acid phosphoramidates and/or tyrosine. The activity of the prodrugs was evaluated in vitro against different virus families. None of the synthesized prodrugs demonstrated activity against RNA viruses but some of them proved active against herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV)]. The bis(POC) and the bis(amino acid) phosphoramidate prodrugs of PMEO-DAPy inhibited herpesvirus replication at lower doses than the parent compound although the selectivity against HSV and VZV was only slightly improved compared to PMEO-DAPy. The mono-octadecyl ester of PME-5-azaC emerged as the most potent and selective PME-5-azaC prodrug against HSV, VZV and HCMV with EC
50 's of 0.15-1.12µM while PME-5-azaC only had marginal anti-herpesvirus activity. Although the bis(hexadecylamido-l-tyrosyl) and the bis(POM) esters of PME-5-azaC were also very potent anti-herpesvirus drugs, these were less selective than the mono-octadecyl ester prodrug., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
- Full Text
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37. Guanine α-carboxy nucleoside phosphonate (G-α-CNP) shows a different inhibitory kinetic profile against the DNA polymerases of human immunodeficiency virus (HIV) and herpes viruses.
- Author
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Balzarini J, Menni M, Das K, van Berckelaer L, Ford A, Maguire NM, Liekens S, Boehmer PE, Arnold E, Götte M, and Maguire AR
- Subjects
- Anti-HIV Agents chemistry, Antiviral Agents chemistry, DNA-Directed DNA Polymerase chemistry, Guanine chemistry, Guanine pharmacokinetics, HIV-1 chemistry, HIV-1 drug effects, Herpesvirus 1, Human chemistry, Herpesvirus 1, Human drug effects, Humans, Kinetics, Nucleosides chemistry, Nucleosides pharmacokinetics, Organophosphonates chemistry, Organophosphonates pharmacokinetics, Protein Structure, Secondary, Anti-HIV Agents pharmacokinetics, Antiviral Agents pharmacokinetics, DNA-Directed DNA Polymerase metabolism, HIV-1 enzymology, Herpesvirus 1, Human enzymology
- Abstract
α-Carboxy nucleoside phosphonates (α-CNPs) are modified nucleotides that represent a novel class of nucleotide-competing reverse transcriptase (RT) inhibitors (NcRTIs). They were designed to act directly against HIV-1 RT without the need for prior activation (phosphorylation). In this respect, they differ from the nucleoside or nucleotide RTIs [N(t)RTIs] that require conversion to their triphosphate forms before being inhibitory to HIV-1 RT. The guanine derivative (G-α-CNP) has now been synthesized and investigated for the first time. The (L)-(+)-enantiomer of G-α-CNP directly and competitively inhibits HIV-1 RT by interacting with the substrate active site of the enzyme. The (D)-(-)-enantiomer proved inactive against HIV-1 RT. In contrast, the (+)- and (-)-enantiomers of G-α-CNP inhibited herpes (i.e. HSV-1, HCMV) DNA polymerases in a non- or uncompetitive manner, strongly indicating interaction of the (L)-(+)- and the (D)-(-)-G-α-CNPs at a location different from the polymerase substrate active site of the herpes enzymes. Such entirely different inhibition profile of viral polymerases is unprecedented for a single antiviral drug molecule. Moreover, within the class of α-CNPs, subtle differences in their sensitivity to mutant HIV-1 RT enzymes were observed depending on the nature of the nucleobase in the α-CNP molecules. The unique properties of the α-CNPs make this class of compounds, including G-α-CNP, direct acting inhibitors of multiple viral DNA polymerases., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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38. Pronounced anti-proliferative activity and tumor cell selectivity of 5-alkyl-2-amino-3-methylcarboxylate thiophenes.
- Author
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Thomas J, Jecic A, Vanstreels E, van Berckelaer L, Romagnoli R, Dehaen W, Liekens S, and Balzarini J
- Subjects
- Alkylation, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Nucleus metabolism, Cell Proliferation drug effects, Endoplasmic Reticulum metabolism, Humans, Structure-Activity Relationship, Thiophenes pharmacokinetics, Thiophenes pharmacology, Tissue Distribution, Antineoplastic Agents pharmacology, Thiophenes chemical synthesis
- Abstract
5-(2-(4-Methoxyphenyl)ethyl)-2-amino-3-methylcarboxylate thiophene (TR560) is the prototype drug of a recently discovered novel class of tumor-selective compounds that preferentially inhibit the proliferation of specific tumor cell types (e.g. leukemia/lymphoma). Here, we further increased tumor selectivity by simplification of the molecule through replacing the 4-methoxyphenyl moiety by an alkyl chain. Several 2-amino-3-methylcarboxylate thiophene derivatives containing at C-5 an alkyl group consisting of at least 6 (hexyl) to 9 (nonyl) carbon units showed pronounced anti-proliferative activity in the mid-nanomolar range with 500- to 1000-fold tumor cell selectivity. The compounds preferentially inhibited the proliferation of T-lymphoma CEM and Molt/4, prostate PC-3, kidney Caki-1 and hepatoma Huh-7 tumor cells, but were virtually inactive against other tumor cell lines including B-lymphoma Raji and cervix carcinoma HeLa cells. The novel prototype drug 3j (containing a 5-heptyl chain) elicited a cytotoxic, rather than cytostatic activity, already after 4 h of exposure. The unusual tumor selectivity could not be explained by a differential uptake (or efflux) of the drug by sensitive versus resistant tumor cells. Exposure of a fluorescent derivative of 3j revealed pronounced uptake of the drug in the cytoplasm, no visible appearance in the nucleus, and a predominant localization in the endoplasmic reticulum. These observations may be helpful to narrow down the intracellular localization and identification of the molecular target of the 5-substituted thiophene derivatives., (Copyright © 2017 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2017
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39. A Multitarget Approach toward the Development of 8-Substituted Purines for Photoprotection and Prevention of UV-Related Damage.
- Author
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Djuidje EN, Dissette V, Bino A, Benetti S, Balzarini J, Liekens S, Manfredini S, Vertuani S, and Baldisserotto A
- Subjects
- Animals, Antifungal Agents chemical synthesis, Antifungal Agents chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antioxidants chemical synthesis, Antioxidants chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Fungi drug effects, Humans, Mice, Microbial Sensitivity Tests, Molecular Structure, Purines chemical synthesis, Radiation-Protective Agents chemical synthesis, Radiation-Protective Agents chemistry, Structure-Activity Relationship, Sun Protection Factor, Antifungal Agents pharmacology, Antineoplastic Agents pharmacology, Antioxidants pharmacology, Purines chemistry, Purines pharmacology, Radiation-Protective Agents pharmacology, Ultraviolet Rays adverse effects
- Abstract
Ultraviolet (UV) light is the most abundant and significant modifiable risk factor for skin cancer and many other skin diseases such as early photo-aging. Across the solar radiation spectrum, UV light is the main cause behind skin problems. In the search for novel photoprotective compounds, a new series of 8-substituted purines were synthesized from commercially available 6-hydroxy-4,5-diaminopyrimidine hemisulfate or 4,5-diaminopyrimidine. All title compounds were investigated for their UV filtering, antioxidant, antifungal, and antiproliferative activities. For the photoprotection assays we used a diffuse transmittance technique to determine the sun protection factor (SPF) in vitro, and 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric ion reducing antioxidant power (FRAP) tests for evaluating the antioxidant activity of the more potent compounds. Among them, 8-(2,5-dihydroxyphenyl)-7H-purin-6-ol (compound 26) proved to be a good radical scavenger and is also endowed with broad-spectrum UVA filtering capabilities, suitable for further development as a protective molecule., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2017
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40. A new four-component reaction involving the Michael addition and the Gewald reaction, leading to diverse biologically active 2-aminothiophenes.
- Author
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Thomas J, Jana S, Sonawane M, Fiey B, Balzarini J, Liekens S, and Dehaen W
- Subjects
- Cell Proliferation drug effects, Dose-Response Relationship, Drug, HeLa Cells, Humans, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Thiophenes chemistry, Thiophenes pharmacology
- Abstract
The Gewald three-component reaction yielding highly substituted 2-aminothiophene heterocycles has been known for a long time and holds an extraordinary potential in the pharmaceutical industry. Herein, we describe a four-component reaction initiated by the conjugate addition of different indole derivatives to α,β-unsaturated carbonyl compounds. This is followed by an in situ Gewald three-component reaction which results in the formation of a compound containing an indole and a 2-aminothiophene moiety separated by a methylene spacer. We also examined the impact of the use of other nucleophilic components such as pyrrole derivatives on this MG-4CR (Michael-Gewald four component reaction). All these synthesized compounds were tested for anti-proliferative activity and three of them showed activity in the nanomolar range.
- Published
- 2017
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41. 6-Benzylidene-2-[4-(pyridin-3-ylcarboxy)benzylidene]cyclohexanones: A novel cluster of tumour-selective cytotoxins.
- Author
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Panda AK, Das U, Umemura N, Sakagami H, Kawase M, Balzarini J, De Clercq E, Dimmock SG, Roayapalley PK, and Dimmock JR
- Subjects
- Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemical synthesis, Antineoplastic Agents toxicity, Benzylidene Compounds administration & dosage, Benzylidene Compounds chemical synthesis, Benzylidene Compounds toxicity, Cell Line, Tumor, Cyclohexanones administration & dosage, Cyclohexanones chemical synthesis, Cyclohexanones toxicity, Drug Screening Assays, Antitumor, G1 Phase Cell Cycle Checkpoints drug effects, Humans, Hydrolysis, Melphalan pharmacology, Mice, Niacin administration & dosage, Niacin chemical synthesis, Niacin toxicity, Poly (ADP-Ribose) Polymerase-1 chemistry, Quantitative Structure-Activity Relationship, Rats, Antineoplastic Agents pharmacology, Benzylidene Compounds pharmacology, Cyclohexanones pharmacology, Niacin analogs & derivatives, Niacin pharmacology
- Abstract
Novel cytotoxins 3-5 containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore are disclosed. The compounds in series 3 and 5 have the potential to liberate niacin which may reduce some of the side effects of antineoplastic compounds. 3a-c emerged as the most potent cytotoxic compounds with IC
50 values in the low micromolar range against human Molt4/C8 and CEM CD4 + T-lymphocytes as well as murine L1210 leukemia cells. QSAR studies revealed that cytotoxic potencies were negatively correlated with the magnitude of the Hammett sigma values of the aryl substituents. The compounds 3a-e displayed tumour-selective toxicity against human HL-60, HSC-2, HSC-3 and HSC-4 neoplasms as compared to human HGF, HPC and HPLF nonmalignant cells. A representative potent compound 3a caused PARP1 cleavage and G0 /G1 cell cycle arrest in HSC-2 cells. These compounds are well tolerated in mice at doses up to and including 300mg/kg of the compounds and no mortalities were noted after 4h. The stability studies undertaken did not reveal that a representative compound 3a underwent hydrolysis to the related phenol 2a. Some guidelines for further analog development of the novel esters 3 were made., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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42. Structure-activity relationship studies on a Trp dendrimer with dual activities against HIV and enterovirus A71. Modifications on the amino acid.
- Author
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Martínez-Gualda B, Sun L, Rivero-Buceta E, Flores A, Quesada E, Balzarini J, Noppen S, Liekens S, Schols D, Neyts J, Leyssen P, Mirabelli C, Camarasa MJ, and San-Félix A
- Subjects
- Amino Acids chemistry, Amino Acids pharmacology, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Antiviral Agents chemistry, Dendrimers metabolism, Enterovirus Infections virology, HIV Infections virology, Humans, Structure-Activity Relationship, Tryptophan analogs & derivatives, Tryptophan metabolism, Tryptophan pharmacology, Virus Replication drug effects, Antiviral Agents pharmacology, Dendrimers chemistry, Dendrimers pharmacology, Enterovirus A, Human drug effects, HIV-1 drug effects, HIV-2 drug effects, Tryptophan chemistry
- Abstract
We have recently described a new class of dendrimers with tryptophan (Trp) on the surface that show dual antiviral activities against HIV and EV71 enterovirus. The prototype compound of this family is a pentaerythritol derivative with 12 Trps on the periphery. Here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. With this aim, novel dendrimers containing different amino acids (aromatic and non-aromatic), tryptamine (a "decarboxylated" analogue of Trp) and N-methyl Trp on the periphery have been prepared. Dendrimer with N-Methyl Trp was the most active against HIV-1 and HIV-2 while dendrimer with tyrosine was endowed with the most potent antiviral activity against EV71. This tyrosine dendrimer proved to inhibit a large panel of EV71 clinical isolates (belonging to different clusters) in the low nanomolar/high picomolar range. In addition, a new synthetic procedure (convergent approach) has been developed for the synthesis of the prototype and some other dendrimers. This convergent approach proved more efficient (higher yields, easier purification) than the divergent approach previously reported., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2017
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43. Correction: Facile functionalization at the C4 position of pyrimidine nucleosides via amide group activation with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and biological evaluations of the products.
- Author
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Akula HK, Kokatla H, Andrei G, Snoeck R, Schols D, Balzarini J, Yang L, and Lakshman MK
- Abstract
Correction for 'Facile functionalization at the C4 position of pyrimidine nucleosides via amide group activation with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and biological evaluations of the products' by Hari K. Akula, et al., Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02334g.
- Published
- 2017
- Full Text
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44. Facile functionalization at the C4 position of pyrimidine nucleosides via amide group activation with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and biological evaluations of the products.
- Author
-
Akula HK, Kokatla H, Andrei G, Snoeck R, Schols D, Balzarini J, Yang L, and Lakshman MK
- Subjects
- Amides chemistry, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Cell Line, Cell Proliferation drug effects, Dogs, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HIV-1 drug effects, HIV-2 drug effects, Herpesvirus 1, Human drug effects, Humans, Madin Darby Canine Kidney Cells drug effects, Madin Darby Canine Kidney Cells virology, Mice, Microbial Sensitivity Tests, Molecular Conformation, Organophosphorus Compounds chemistry, Pyrimidine Nucleosides chemistry, Structure-Activity Relationship, Amides pharmacology, Antineoplastic Agents pharmacology, Antiviral Agents pharmacology, Organophosphorus Compounds pharmacology, Pyrimidine Nucleosides pharmacology
- Abstract
Reactions of O-t-butyldimethylsilyl-protected thymidine, 2'-deoxyuridine, and 3'-azidothymidine (AZT) with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) leads to activation of the C4 amide carbonyl by formation of putative O
4 -(benzotriazol-1-yl) derivatives. Subsequent substitution with alkyl and aryl amines, thiols, and alcohols leads to facile functionalization at this position. Reactions with amines and thiols were conducted either as a two-step, one-pot transformation, or as a one-step conversion. Reactions with alcohols were conducted as two-step, one-pot transformations. In the course of these investigations, the formation of 1-(4-pyrimidinyl)-1H-benzotriazole-3-oxide derivatives from the pyrimidine nucleosides was identified. However, these too underwent conversion to the desired products. Products obtained from AZT were converted to the 3'-amino derivatives by catalytic reduction. All products were assayed for their abilities to inhibit cancer cell proliferation and for antiviral activities. Many were seen to be active against HIV-1 and HIV-2, and one was active against herpes simplex virus-1 (HSV-1).- Published
- 2017
- Full Text
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45. Novel isoxazolidine analogues of homonucleosides and homonucleotides.
- Author
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Piotrowska DG, Balzarini J, Andrei G, Schols D, Snoeck R, Wróblewski AE, and Gotkowska J
- Abstract
Isoxazolidine analogues of homonucleos(t)ides were synthesized from nucleobase-derived nitrones 20a-20e (uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine) employing 1,3-dipolar cycloadditions with allyl alcohol as well as with alkenylphosphonates (allyl-, allyloxymethyl- and vinyloxymethyl- and vinylphosphonate). Besides reactions with vinylphosphonate the additions proceeded regioselectively to produce mixtures of major cis and minor trans 3,5-disubstituted isoxazolidines (d.e. 28-82%). From vinylphosphonate up to 10% of 3,4-disubstituted isoxazolidines was additionally produced. Vicinal couplings, shielding effects and 2D NOE correlations were employed in configurational assignments as well as in conformational analysis to find out preferred conformations for several isoxazolidines and to observe anomeric effects (pseudoaxial orientation of phosphonylmethoxy groups) for those obtained from vinyloxymethylphosphonate. None of the tested compounds were endowed in vitro with antiviral activity against a variety of DNA and RNA viruses at subtoxic concentrations (up to 250 μM) nor exhibited antiproliferative activity towards L1210, CEM, and HeLa cells (IC
50 = ≥100 μM)., (© 2016 Elsevier Ltd. All rights reserved.)- Published
- 2016
- Full Text
- View/download PDF
46. Niacin esters of chalcones with tumor-selective properties.
- Author
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Panda AK, Das U, Roayapalley PK, Sakagami H, Kawase M, Balzarini J, De Clercq E, and Dimmock JR
- Subjects
- Carbon-13 Magnetic Resonance Spectroscopy, Cell Line, Tumor, Drug Screening Assays, Antitumor, Esters, Humans, Proton Magnetic Resonance Spectroscopy, Antineoplastic Agents pharmacology, Chalcones chemistry, Chalcones pharmacology, Niacin chemistry
- Abstract
Novel series of niacin esters of chalcones 2, 4 and 6 were designed as antineoplastic agents that have the potential to release the chemoprotectant niacin. These enones are cytotoxic to human CD4(+ )T-lymphocyte Molt 4/C8 and CEM and murine leukemia L1210 cells. Quantitative structure-activity relationship (QSAR) studies of the biodata in series 4 revealed that cytotoxic potency was enhanced by placing electron-repelling groups in one of the aryl rings. The compounds are lethal to HL-60, HSC-2, HSC-3 and HSC-4 neoplasms but less toxic to nonmalignant hepatocyte growth factor, hematopoietic progenitor cell and human periodontal ligament fibroblast cells. Hence, the compounds display tumor-selective toxicity. These chalcones are well tolerated in mice and no overt toxicity was noted. The results establish that in general the compounds in series 2, 4 and 6 have positive characteristics which warrant further studies.
- Published
- 2016
- Full Text
- View/download PDF
47. ProTides of BVdU as potential anticancer agents upon efficient intracellular delivery of their activated metabolites.
- Author
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Kandil S, Balzarini J, Rat S, Brancale A, Westwell AD, and McGuigan C
- Subjects
- Amides metabolism, Amides pharmacokinetics, Animals, Antineoplastic Agents metabolism, Antineoplastic Agents pharmacokinetics, Antiviral Agents chemistry, Antiviral Agents metabolism, Antiviral Agents pharmacokinetics, Antiviral Agents pharmacology, Bromodeoxyuridine chemistry, Bromodeoxyuridine metabolism, Bromodeoxyuridine pharmacokinetics, Bromodeoxyuridine pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Humans, Mice, Neoplasms drug therapy, Phosphoric Acids metabolism, Phosphoric Acids pharmacokinetics, Amides chemistry, Amides pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Bromodeoxyuridine analogs & derivatives, Phosphoric Acids chemistry, Phosphoric Acids pharmacology
- Abstract
Nucleosides represent a major chemotherapeutic class for treating cancer, however their limitations in terms of cellular uptake, nucleoside kinase-mediated activation and catabolism are well-documented. The monophosphate pro-nucleotides known as ProTides represents a powerful strategy for bypassing the dependence on active transport and nucleoside kinase-mediated activation. Herein, we report the structural tuning of BVdU ProTides. Forty six phosphoramidates were prepared and biologically evaluated against three different cancer cell lines; murine leukemia (L1210), human CD
4 + T-lymphocyte (CEM) and human cervical carcinoma (HeLa). Twenty-fold potency enhancement compared to BVdU was achieved against L1210 cells. Interestingly, a number of ProTides showed low micromolar activity against CEM and HeLa cells compared to the inactive parent BVdU. The ProTides showed poor, if any measurable toxicity to non-tumourigenic human lung fibroblast cell cultures. Separation of four pairs of the diastereoisomeric mixtures and comparison of their spectral properties, biological activities and enzymatic activation rate is reported., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2016
- Full Text
- View/download PDF
48. Identification of an indol-based derivative as potent and selective varicella zoster virus (VZV) inhibitor.
- Author
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Musella S, di Sarno V, Ciaglia T, Sala M, Spensiero A, Scala MC, Ostacolo C, Andrei G, Balzarini J, Snoeck R, Novellino E, Campiglia P, Bertamino A, and Gomez-Monterrey IM
- Subjects
- Cell Line, Cell Proliferation drug effects, Cells, Cultured, Drug Design, Humans, Molecular Structure, Antiviral Agents chemistry, Antiviral Agents pharmacology, Herpesvirus 3, Human drug effects, Indoles chemistry, Indoles pharmacology, Virus Replication drug effects
- Abstract
We report the synthesis and antiviral activity of a new family of non-nucleoside antivirals, derived from the indole nucleus. Modifications of this template through Mannich and Friedel-Crafts reactions, coupled with nucleophilic displacement and reductive aminations led to 23 final derivatives, which were pharmacologically tested. Tryptamine derivative 17a was found to have a selective inhibitory activity against human varicella zoster virus (VZV) replication in vitro, being inactive against a variety of other DNA and RNA viruses. A structure-activity relationship (SAR) study showed that the presence of a biphenyl ethyl moiety and the acetylation at the amino group of tryptamine are a prerequisite for anti-VZV activity. The novel compound shows the same activity against thymidine kinase (TK)-competent (TK
+ ) and TK-deficient (TK- ) VZV strains, pointing to a novel mechanism of antiviral action., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)- Published
- 2016
- Full Text
- View/download PDF
49. Correction to Conformational States of HIV-1 Reverse Transcriptase for Nucleotide Incorporation vs Pyrophosphorolysis-Binding of Foscarnet.
- Author
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Das K, Balzarini J, Miller MT, Maguire AR, DeStefano JJ, and Arnold E
- Published
- 2016
- Full Text
- View/download PDF
50. High mannose-specific lectin Msl mediates key interactions of the vaginal Lactobacillus plantarum isolate CMPG5300.
- Author
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Malik S, Petrova MI, Imholz NC, Verhoeven TL, Noppen S, Van Damme EJ, Liekens S, Balzarini J, Schols D, Vanderleyden J, and Lebeer S
- Subjects
- Agglutination, Bacterial Adhesion, Bacterial Proteins pharmacology, Biofilms, Candida albicans physiology, Carbohydrate Conformation, Carbohydrate Sequence, Epithelial Cells microbiology, Female, HIV Envelope Protein gp120 chemistry, HIV Envelope Protein gp41 chemistry, HIV-1 physiology, Humans, Mannans chemistry, Mannose-Binding Lectin pharmacology, Microbial Interactions, Protein Binding, Saccharomyces cerevisiae physiology, Salmonella typhimurium drug effects, Salmonella typhimurium physiology, Bacterial Proteins physiology, Lactobacillus plantarum physiology, Mannose-Binding Lectin physiology, Vagina microbiology
- Abstract
To characterize the interaction potential of the human vaginal isolate Lactobacillus plantarum CMPG5300, its genome was mined for genes encoding lectin-like proteins. cmpg5300.05_29 was identified as the gene encoding a putative mannose-binding lectin. Phenotypic analysis of a gene knock-out mutant of cmpg5300.05_29 showed that expression of this gene is important for auto-aggregation, adhesion to the vaginal epithelial cells, biofilm formation and binding to mannosylated glycans. Purification of the predicted lectin domain of Cmpg5300.05_29 and characterization of its sugar binding capacity confirmed the specificity of the lectin for high- mannose glycans. Therefore, we renamed Cmpg5300.05_29 as a mannose-specific lectin (Msl). The purified lectin domain of Msl could efficiently bind to HIV-1 glycoprotein gp120 and Candida albicans, and showed an inhibitory activity against biofilm formation of uropathogenic Escherichia coli, Staphylococcus aureus and Salmonella Typhimurium. Thus, using a combination of molecular lectin characterization and functional assays, we could show that lectin-sugar interactions play a key role in host and pathogen interactions of a prototype isolate of the vaginal Lactobacillus microbiota.
- Published
- 2016
- Full Text
- View/download PDF
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