119 results on '"Antitumor Agents"'
Search Results
2. Copper‐Catalyzed Multicomponent Reaction to Construct Fluorinated Indole‐quinoxalin‐2(1H)‐ones and Their Biological Evaluation.
- Author
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Zhang, Letian, Yang, Yong, Zhang, Pengfei, Chen, Chao, and Shen, Chao
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CLICK chemistry , *TRIAZOLE derivatives , *INDOLE compounds , *TRIAZOLES , *FRIEDEL-Crafts reaction , *ANTINEOPLASTIC agents , *ERLOTINIB - Abstract
A practical and mild three‐component reaction of indoles, quinoxalin‐2(1H)‐ones, and CF3SO2Na is disclosed for the facile access of various 3‐[2‐(trifluoromethyl)1H‐indol‐3‐yl]quinoxalin‐2(1H)‐ones using low‐cost and catalytic amount of CuF2 as the catalyst. This strategy exhibits high site‐selectivity, step economy, and broad substrates scope. Synthetic utility was demonstrated by the one‐pot two‐step synthesis of N‐alkyl triazoles compounds via a click chemistry. To evaluate the antiproliferative activity of these compounds, A549 s (human lung adenocarcinoma cells) and HUVECs, as a model of toxicity, were used in MTT assay. The outcomes disclosed for 6‐CO2Me and a N‐alkyl triazole derivatives were of potent antiproliferative effect against A549 s (IC50 = 4.7 and 14.9 μM, respectively) with slight cytotoxicity in HUVECs. Morphological study was conducted by AO/EB dual staining, indicated hydrochloride 6‐CO2Me derivative was capable of inducing apoptosis of A549 cells. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
3. 6‐Methylquinazolin‐4(3H)‐one Based Compounds as BRD9 Epigenetic Reader Binders: A Rational Combination of in silico Studies and Chemical Synthesis.
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Colarusso, Ester, Gazzillo, Erica, Boccia, Eleonora, Giordano, Assunta, Chini, Maria Giovanna, Bifulco, Giuseppe, and Lauro, Gianluigi
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CHEMICAL synthesis , *EPIGENETICS , *DIGITAL libraries , *MOLECULAR docking , *COMBINATORIAL chemistry - Abstract
6‐methylquinazolin‐4(3H)‐one‐based compounds were here identified and synthesized as novel binders of bromodomain‐containing protein 9 (BRD9) epigenetic reader. Accounting a fast and efficient synthetic route aimed to easily obtain differently 2‐ and 8‐disubstituted 6‐methylquinazolin‐4(3H)‐one derivatives, a virtual library of synthesizable items was built and submitted to molecular docking experiments. Based on two 3D structure‐based pharmacophore models recently developed by us on BRD9, 16 compounds were selected and synthesized, using mild conditions with good yields in relatively short reaction times. Among them, 14, 16, 18, 22, and 26 emerged as the most potent compounds of these series, able to bind BRD9 at the low micromolar range of concentrations. These molecules also showed a promising selective behavior when tested against BRD4 bromodomain. These results highlighted the quinazolin‐4(3H)‐one chemical core as a valuable scaffold for developing promising BRD9 binders. [ABSTRACT FROM AUTHOR]
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- 2022
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4. Understanding the Alkylation Mechanism of 3‐Chloropiperidines – NMR Kinetic Studies and Isolation of Bicyclic Aziridinium Ions.
- Author
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Helbing, Tim, Georg, Mats, Stöhr, Fabian, Carraro, Caterina, Becker, Jonathan, Gatto, Barbara, and Göttlich, Richard
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ALKYLATION , *IONS , *DNA alkylation , *SILVER salts , *SINGLE crystals - Abstract
The present study describes the kinetic analysis of the 3‐chloropiperidine alkylation mechanism. These nitrogen mustard‐based compounds are expected to react via a highly electrophilic bicyclic aziridinium ion, which is readily attacked by nucleophiles. Halide abstraction using silver salts with weakly coordinating anions lead to the isolation of these proposed intermediates, whereas their structure was confirmed by single crystal XRD. Kinetic studies of the aziridinium ions also revealed notable reactivity differences of the C5 gem‐methylated compounds and their unmethylated counterparts. The observed reactivity trends were also reflected by NMR studies in aqueous solution and DNA alkylation experiments of the related 3‐chloropiperidines. Therefore, the underlying Thorpe‐Ingold effect might be considered as another option to adjust the alkylation activity of these compounds. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
5. Mechanically Interlocked Molecules for Biomedical Applications.
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Riebe, Jan and Niemeyer, Jochen
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TARGETED drug delivery , *MOLECULES - Abstract
Mechanically interlocked molecules (MIMs) carry great potential in different fields of chemistry, based on their specific structures, their internal dynamics, their stimuli‐responsive behavior, and other unique features of the mechanical bond. This minireview presents some of the most recent developments in their use for medical and biological applications. For example, they have been used to influence, enhance or block the action of therapeutic agents to enable targeted drug delivery. The dynamic structural properties have been used to generate switches and transporters, as well as sensors for various medically relevant species. Building MIMs by incorporating biomolecules like DNA and proteins has served as a novel way to control their properties. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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6. Synthesis and Biological Evaluation of an isoDGR-Paclitaxel Conjugate Containing a Cell-Penetrating Peptide to Promote Cellular Uptake.
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Bodero, Lizeth, Parente, Sara, Arrigoni, Federico, Klimpel, Annika, Neundorf, Ines, Gazzola, Silvia, and Piarulli, Umberto
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BIOSYNTHESIS , *DRUG delivery systems , *MOIETIES (Chemistry) , *INTEGRINS , *CLICK chemistry , *CELL lines , *PACLITAXEL - Abstract
Two new Drug Delivery Systems (DDS) cyclo[DKP-isoDGR]-PEG-4-Val-Ala-PTX (2) and cyclo[DKP-isoDGR]-PEG-4-sC18-Val-Ala-PTX (3), containing the cyclo[DKP-isoDGR] integrin ligand and the cytotoxic agent Paclitaxel (PTX), were synthesized to investigate the influence of a PEG-4 chain and of the sC18 cell-penetrating peptide (CPP) on the cellular uptake and the cytotoxicity of the constructs. A "double click-reaction strategy" was planned, to realize the connection of cyclo[DKP-isoDGR] and PTX to the CPP moiety. Anti-proliferative bioassays were performed on the αvβ3-positive U87 human glioblastoma cell line using a short contact time (15 min) followed by draining, washing of the cells, and re-incubation for 72 h. Compound 3 was significantly more potent (IC50=27.6 µM) than compound 2 (IC50>100 µM), and showed a reduced potency loss with respect to PTX (IC50=71 nM). [ABSTRACT FROM AUTHOR]
- Published
- 2021
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7. Synthesis of Azepino[1,2‐a]indole‐10‐amines via [6+1] Annulation of Ynenitriles with Reformatsky Reagent.
- Author
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Iioka, Ryoya, Yorozu, Kohei, Sakai, Yoko, Kawai, Rika, Hatae, Noriyuki, Takashima, Katsuki, Tanabe, Genzoh, Wasada, Hiroaki, and Yoshimatsu, Mitsuhiro
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ANNULATION , *RING formation (Chemistry) , *INDOLE , *INDOLE compounds - Abstract
Lewis acid‐catalyzed [6+1] annulation reactions of 2‐cyano‐1‐propargyl‐ and 2‐alkynyl‐1‐cyanomethyl‐indoles with Reformatsky reagent are described. 8‐Aryl, 8‐alkyl‐, 8‐hetaryl‐, 9‐aryl, and 9‐alkyl‐azepino[1,2‐a]indole amines were obtained through a 7‐endo‐mode cyclization of the β‐aminoacrylate intermediates. The antiproliferative activity of the azepino[1,2‐a]indoles analogs against the HCT‐116 cells were also examined. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
8. Structural Diversity using Hyp "Customizable Units": Proof‐of‐Concept Synthesis of Sansalvamide‐Related Antitumoral Peptides.
- Author
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Cuevas, Fernando, Saavedra, Carlos J., Romero‐Estudillo, Ivan, Boto, Alicia, Ordóñez, Mario, and Vergara, Irene
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CYCLIC peptides , *PEPTIDES , *CYCLIC compounds , *BIODIVERSITY , *PEPTIDE synthesis - Abstract
The potential of "customizable units" to generate structural diversity for biological screenings is highlighted in this proof‐of‐concept synthesis of new peptides related to the potent antitumoral Sansalvamide A. Using L‐4‐hydroxyproline (Hyp) as a customizable unit in a linear parent peptide, an improved procedure for selective peptide modification was developed. A divergent Hyp scission‐reductive amination process was carried out, affording five linear peptides with cationic residues, and notably, an N‐alkyl moiety that affected the conformation of the peptide. After two steps (saponification and macrocyclization), sixteen differently N1‐substituted linear and cyclic peptides were obtained. For the first time, the activity of the linear and cyclic compounds was compared. Not only some linear analogs but also cyclic compounds with scarcely studied cationic residues were active against MCF7 breast cancer line. Thus, the structural diversity generated from customizable units can be valuable in drug discovery. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
9. Development of Glucose Transporter (GLUT) Inhibitors.
- Author
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Reckzeh, Elena S. and Waldmann, Herbert
- Subjects
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GLUCOSE transporters , *GLYCOLYSIS , *GLUCOSE metabolism , *CHEMICAL biology , *PHARMACEUTICAL chemistry , *CANCER cells - Abstract
The discovery of novel compound classes endowed with biological activity is at the heart of chemical biology and medicinal chemistry research. This enables novel biological insights and inspires new approaches to the treatment of diseases. Cancer cells frequently exhibit altered glycolysis and glucose metabolism and an increased glucose demand. Thus, targeting glucose uptake and metabolism may open up novel opportunities for the discovery of compounds that differentiate between normal and malignant cells. This review discusses the different chemical approaches to the development of novel inhibitors of glucose uptake through facilitative glucose transporters (GLUTs), and focusses on the most advanced and potent inhibitor classes known to date. GLUT inhibitors may find application not only in the treatment of cancer, but also of other proliferative diseases that exhibit glucose addiction. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
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10. 2‐Sulfonylpyrimidines Target the Kinesin HSET via Cysteine Alkylation.
- Author
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Förster, Tim, Shang, Erchang, Shimizu, Kenshiro, Sanada, Emiko, Schölermann, Beate, Huebecker, Mylene, Hahne, Gernot, López‐Alberca, Maria Pascual, Janning, Petra, Watanabe, Nobumoto, Sievers, Sonja, Giordanetto, Fabrizio, Shimizu, Takeshi, Ziegler, Slava, Osada, Hiroyuki, and Waldmann, Herbert
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KINESIN , *ALKYLATION , *SMALL molecules , *CYSTEINE , *CENTROSOMES , *MITOSIS - Abstract
Supernumerary centrosomes are a source of aneuploidy, and cells have adopted different mechanisms to avoid multipolar mitoses. The kinesin HSET is required for pseudo‐bipolar mitoses in cancer cells with amplified centrosomes and suppression of HSET activity is regarded a potential anti‐cancer approach. We report the identification of 2‐sulfonylpyrimidine inhibitors of HSET enzymatic activity. HSET inhibition results in establishment of multipolar mitoses and simultaneous inhibition of the kinesin Eg5 restored bipolar spindle formation. Correlation of structure to activity revealed that the 2‐sulfonylpyrimidinyl group is required for the activity of the compound class and that 2‐sulfonylpyrimidines covalently modify HSET. In addition, these electrophiles react with glutathione, thereby causing oxidative stress. This general reactivity needs to be taken into account if 2‐sulfonylpyrimidines will be employed in the development of biologically active small molecules. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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11. Semisynthesis of 3‐Hydroxyoxindole Rapamycin Analogues Through Site‐ and Stereoselective Trapping of Oxonium Ylides in RhII‐Catalyzed Three‐Component Reactions.
- Author
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Qiu, Lin, Su, Meng, Wen, Zhongqing, Zhu, Xiangcheng, Duan, Yanwen, and Huang, Yong
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YLIDES , *TRAPPING , *NATURAL products , *RAPAMYCIN , *ANTINEOPLASTIC agents - Abstract
The site‐ and diastereoselective functionalization of 40‐OH in rapamycin by 3‐hydroxyoxindole moieties was efficiently achieved through the active protic oxonium ylide trapping reactions using isatins, resulting in 31 new analogues of rapamycin. This study not only significantly expanded the known active rapalogs, but showcased the broad utility of multi‐component reactions in late‐stage functionalization of complex natural products. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
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12. A Strategy toward Icetexane Natural Products.
- Author
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Moon, Daniel J., Al‐Amin, Mohammad, Lewis, Robert S., Arnold, Kimberly M., Yap, Glenn P. A., Sims‐Mourtada, Jennifer, and Chain, William J.
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NATURAL products , *DITERPENES , *POLYCYCLIC compounds , *METAL complexes , *ALKYLATION , *METATHESIS reactions - Abstract
Icetexane diterpenoids are richly complex polycyclic natural products that have been described with a variety of biological activities. We report here a general synthetic approach toward the 6‐7‐6 tricyclic core structure of these interesting synthetic targets based on a two‐step enolate alkylation and ring‐closing metathesis reaction sequence. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
13. Synthesis and Biological Evaluation of Paclitaxel Conjugates Involving Linkers Cleavable by Lysosomal Enzymes and αVβ3‐Integrin Ligands for Tumor Targeting.
- Author
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López Rivas, Paula, Ranđelović, Ivan, Raposo Moreira Dias, André, Pina, Arianna, Arosio, Daniela, Tóvári, József, Mező, Gábor, Dal Corso, Alberto, Pignataro, Luca, and Gennari, Cesare
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CHEMICAL synthesis , *PACLITAXEL , *LYSOSOMES , *LIGANDS (Chemistry) , *TUMORS - Abstract
Two cyclo[DKP‐RGD]‐PTX (PTX = paclitaxel) and two cyclo[RGDfK]‐PTX conjugates containing the Gly‐Phe‐Leu‐Gly (GFLG) linker, which is cleavable by lysosomal enzymes, were synthesized and compared to two cyclo[DKP‐RGD]‐Val‐Ala‐PTX conjugates. The conjugates were evaluated for their ability to inhibit biotinylated vitronectin binding to the isolated αvβ3 receptor, retaining good binding affinity, in the same nanomolar range of the free ligands. Cell viability assays were performed for the six conjugates in the αvβ3+ U87 and in the αvβ3– HT29 cell lines. Loss of potency was observed for all the conjugates, attenuated by the presence of a tetraethylene glycol (PEG‐4) spacer. A good Targeting Index (TI = Relative Potency in the αvβ3+ U87/Relative Potency in the αvβ3– HT29) was displayed by the conjugates, in particular by cyclo[DKP‐RGD]‐PEG‐4‐Val‐Ala‐PTX 9 (TI = 533). This conjugate was tested in the αvβ3+ U87 cell line in the presence of 50‐fold excess free cyclo[DKP‐RGD] ligand 2. In this competition experiment, a fivefold decrease of the conjugate cytotoxicity was calculated, suggesting that the conjugate is possibly internalized by an αvβ3 integrin‐mediated process. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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14. Structural Diversity using Hyp 'Customizable Units' : Proof‐of‐Concept Synthesis of Sansalvamide‐Related Antitumoral Peptides
- Author
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Irene Vergara, Alicia Boto, Ivan Romero-Estudillo, Fernando Cuevas, Mario Ordóñez, Carlos Javier Saavedra, Consejo Nacional de Ciencia y Tecnología (México), Ministerio de Economía y Empresa (España), Ministerio de Ciencia e Innovación (España), and Biosigma
- Subjects
Antitumor agents ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Library science ,Structural diversity ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Customizable units ,Work (electrical) ,Proof of concept ,Molecular diversity ,Domino reactions ,Physical and Theoretical Chemistry ,Peptides ,Selective modification - Abstract
The potential of “customizable units” to generate structural diversity for biological screenings is highlighted in this proof‐of‐concept synthesis of new peptides related to the potent antitumoral Sansalvamide A. Using L‐4‐hydroxyproline (Hyp) as a customizable unit in a linear parent peptide, an improved procedure for selective peptide modification was developed. A divergent Hyp scission‐reductive amination process was carried out, affording five linear peptides with cationic residues, and notably, an N‐alkyl moiety that affected the conformation of the peptide. After two steps (saponification and macrocyclization), sixteen differently N1‐substituted linear and cyclic peptides were obtained. For the first time, the activity of the linear and cyclic compounds was compared. Not only some linear analogs but also cyclic compounds with scarcely studied cationic residues were active against MCF7 breast cancer line. Thus, the structural diversity generated from customizable units can be valuable in drug discovery., This work was partly financed by the Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) through project 2015‐01‐807, and by MINECO‐MCIU (Spain) with European Social Funds (ESF), through Programme Plan Estatal I+D‐RETOS (project SAF‐2013‐48399‐R). C. J. S. received a postdoctoral contract from the Torres Quevedo Programme (PTQ15‐07923) by MINECO/Min. Science and Innovation, cofinanced by BIOSIGMA SL. Finally, I.R−E. and F.C. thank CONACYT for Catedra contract 942 and predoctoral grant 305283 respectively.
- Published
- 2021
15. Thiophene-Based Organic D-π-A Dyes as Potent Sensitizers for Photodynamic Therapy.
- Author
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Fuse, Shinichiro, Takizawa, Miori, Matsumura, Keisuke, Sato, Shinichi, Okazaki, Shigetoshi, and Nakamura, Hiroyuki
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THIOPHENES , *PHOTOSENSITIZERS , *PHOTODYNAMIC therapy , *ANTINEOPLASTIC agents , *REACTION mechanisms (Chemistry) , *COUPLING reactions (Chemistry) - Abstract
In this study, synthetically readily accessible, thiophene-based organic D-π-A sensitizers exerted high phototoxicity and are valuable as sensitizer templates for use in photodynamic therapy (PDT). Evaluation of the antitumor activity of our previously synthesized D-π-A sensitizers under photoirradiation revealed their potent phototoxicity. The structural requirements of the D-π-A sensitizer for phototoxicity were elucidated with the rapid synthesis of structurally simplified analogues and evaluation of their antitumor activity under photoirradiation. Our developed sensitizers mainly accumulated in mitochondria and damaged cancer cells through both Type I and Type II mechanisms. The developed new template could be useful in the future development of sensitizers that could fulfil the requirements for PDT. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
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16. Synthesis and Evaluation of the Antitumor Properties of a Small Collection of PtII Complexes with 7-Deazaadenosine as Scaffold.
- Author
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D'Errico, Stefano, Borbone, Nicola, Piccialli, Vincenzo, Di Gennaro, Elena, Zotti, Andrea, Budillon, Alfredo, Vitagliano, Carlo, Piccialli, Ilaria, and Oliviero, Giorgia
- Subjects
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PLATINUM compound synthesis , *METAL complexes , *ANTINEOPLASTIC agents , *METALS in medicine , *CHIRALITY , *LIGANDS (Chemistry) - Abstract
Herein we report on the synthesis and evaluation of the preliminary antitumor properties of a small collection of platinum(II) complexes in which a cisplatin-like unit is tethered to 7-deazaadenosine through linear alkyl chains (from two to six carbon atoms) installed at the purine C6 position. The complexation was performed by exploiting the reactivity of the bi-dentate amino ligands (R) and (S)-2,3-diaminopropanoic acids (DAPA) attached to the end of the alkyl chain spacer. By varying the length of the alkyl chain and the chirality of the DAPA moiety we obtained 10 novel nucleoside-platinum complexes, the anticancer properties of which have been evaluated against the A549 and Cal27 human cancer cell lines. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
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17. RuIII Complexes for Anticancer Therapy: The Importance of Being Nucleolipidic.
- Author
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Riccardi, Claudia, Musumeci, Domenica, Irace, Carlo, Paduano, Luigi, and Montesarchio, Daniela
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RUTHENIUM compound synthesis , *ANTINEOPLASTIC agents , *NUCLEOSIDES , *LIPIDS , *HYDROPHILIC interactions - Abstract
Ruthenium complexes are attracting increasing attention as second-generation metal-based anticancer agents, with NAMI-A and KP1019 as the major representatives of this class having undergone clinical trials. Our recent interest has been focused on the synthesis and characterization of new amphiphilic derivatives of nucleosides (nucleolipids). These compounds have been selected as core scaffolds linked to RuIII complexes and capable of self-assembly into stable nanostructures in aq. solutions so to transport the metal ions efficiently into the cell. Through the use of ribo- and deoxyribonucleosides as starting building blocks, a mini-library of nucleolipidic RuIII complexes decorated with diverse hydrophilic and lipophilic chains and incorporating the NAMI-A analogue AziRu has been prepared. When co-aggregated with biocompatible lipids, these RuIII-containing nucleolipids proved to be stable for months under physiological conditions. Detailed microstructural characterization, carried out by a combined approach including different physico-chemical techniques, allowed their stability, size and shape to be determined. Tested on a panel of human and non-human cells, all of the studied RuIII complexes showed potent in vitro anticancer activity, significantly higher than that of NAMI-A-like analogues, and minimal toxicity. Here we summarize the design and synthetic procedures developed to prepare these new Ru-containing candidate drugs, discussing the beneficial effects achievable through exploiting nucleolipid appendages in the delivery of metal-based drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
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18. Recent Advances in the Synthesis of Flavaglines, a Family of Potent Bioactive Natural Compounds Originating from Traditional Chinese Medicine.
- Author
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Zhao, Qian, Abou‐Hamdan, Hussein, and Désaubry, Laurent
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NATURAL products , *BIOACTIVE compounds , *ONCOLOGY , *CANCER treatment , *CHINESE medicine , *THERAPEUTICS - Abstract
Flavaglines constitute a distinctive family of plant metabolites isolated from medicinal plants of the genus Aglaia. These compounds exhibit a broad spectrum of distinctive pharmacological properties, including anti-inflammatory, neuroprotective, cardioprotective, and anticancer activities. These natural cyclopenta[ b]benzofurans are characterized by densely functionalized tricyclic frameworks, as exemplified by the structures of rocaglamide or silvestrol, which makes them extremely attractive targets for total synthesis, in addition to their therapeutic potential. In this review we describe the various synthetic approaches to the total synthesis of flavaglines, culminating in a new generation of diastereo- and enantioselective total syntheses. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
19. Divergent Synthesis of Styryl-Cinnamate Hybrid Analogues Inspired by the Natural Product Salvianolic Acid F as a Premise To Investigate Their Anticancer Activity and Its Metabolomic Profiling.
- Author
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Shard, Amit, Rawat, Kiran, Sinha, Arun K., Padwad, Yogendra, and Kumar, Dinesh
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STYRYL compounds , *CINNAMATES , *ANTINEOPLASTIC agents , *GLIOMAS , *CHEMICAL reactions - Abstract
Protecting-group-free synthesis of hydroxylated styryl-cinnamate hybrids (C6-C2-C6-C3 unit), inspired by the natural product salvianolic acid F, was achieved by a step-economical route involving sequential double C-C bond formation in one pot. The method involved multiple reactions (Perkin condensation/decarboxylation-Heck cross-coupling reactions) by using simple precursors (i.e., hydroxylated benzaldehyde, arylacetic acid, and acrylic acid derivatives) in one pot and yielded the desired unnatural small hybrid molecules in varying yields of 35-65 % with E selectivity under microwave irradiation, whereas the reported conventional route for the synthesis of salvianolic acid F itself requires six steps with an overall yield of 10.0 % in addition to tedious separation of E/Z isomers that arise from a Wittig reaction. Apart from an economical synthesis and product diversity, we herein report the potential of some hybrid molecules with the catechol core to selectively inhibit glioma cells. The intrinsic mode of action of our lead molecule, involving caspase 6 and the quinonemethide pathway, is also reported on the basis of 1H NMR spectroscopy guided metabolomic profiling. We emphatically demonstrate the role of our hybrid molecules, analogues of salvianolic acid F, in forcing glioma cells towards apoptosis by specifically perturbing the concentration of glutathione along with that of caspase 6. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
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20. Dimeric Pyranonaphthoquinones: Isolation, Bioactivity, and Synthetic Approaches.
- Author
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Fernandes, Rodney A., Patil, Pradnya H., and Chaudhari, Dipali A.
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ANTIBIOTIC synthesis , *NAPHTHOQUINONE , *PYRAN derivatives , *BIOACTIVE compounds , *STEREOCHEMISTRY , *FUNCTIONAL groups , *DIMERS - Abstract
The dimeric pyranonaphthoquinones, 'bis versions' of the naphtho[2,3- c]pyran-5,10-dione moiety, comprises a group of antibiotics that have been isolated from a variety of sources including plants, bacteria, fungi, and insects. This review discusses the known naturally occurring dimeric pyranonaphthoquinones, their isolation and bioactivity, and synthetic approaches towards them that have helped to confirm their structures, as well as to resolve structural uncertainties such as stereochemistry. The major focus has been on the synthetic approaches adopted to complete the challenging total synthesis of the natural isolates and analogues. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
21. Development of Glucose Transporter (GLUT) Inhibitors
- Author
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Elena S. Reckzeh and Herbert Waldmann
- Subjects
Virtual screening ,Natural products ,Antitumor agents ,010405 organic chemistry ,Drug discovery ,Chemistry ,Glucose uptake ,Organic Chemistry ,Glucose transporter ,Chemical biology ,Minireviews ,Metabolism ,Carbohydrate metabolism ,010402 general chemistry ,01 natural sciences ,3. Good health ,0104 chemical sciences ,GLUT inhibitors ,Biochemistry ,Cancer cell ,Drug Discovery ,Glycolysis ,Minireview ,Physical and Theoretical Chemistry ,Cancer - Abstract
The discovery of novel compound classes endowed with biological activity is at the heart of chemical biology and medicinal chemistry research. This enables novel biological insights and inspires new approaches to the treatment of diseases. Cancer cells frequently exhibit altered glycolysis and glucose metabolism and an increased glucose demand. Thus, targeting glucose uptake and metabolism may open up novel opportunities for the discovery of compounds that differentiate between normal and malignant cells. This review discusses the different chemical approaches to the development of novel inhibitors of glucose uptake through facilitative glucose transporters (GLUTs), and focusses on the most advanced and potent inhibitor classes known to date. GLUT inhibitors may find application not only in the treatment of cancer, but also of other proliferative diseases that exhibit glucose addiction., Potent glucose transporter (GLUT) inhibitors have been developed over the last years. This Minireview serves as an overview of the origin (natural products, natural product‐inspired, non‐natural compounds, and virtual screening) of these molecules.John Wiley & Sons, Ltd.
- Published
- 2019
22. seco-Casbanes from the Australian Rainforest: ECD Predictions Key for Determining Remote Absolute Configuration.
- Author
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Maslovskaya, Lidia A., Savchenko, Andrei I., Gordon, Victoria A., Reddell, Paul W., Pierce, Carly J., Parsons, Peter G., and Williams, Craig M.
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CROTON (Genus) , *CIRCULAR dichroism , *CYTOTOXINS , *LEUKEMIA , *BIOSYNTHESIS ,AUSTRALIAN rainforests - Abstract
The seco-casbane framework, first isolated from Croton insularis, is surprisingly rare. Further evaluation of this Australian rainforest plant unearthed two additional members, EBC-328 and EBC-363. TD DFT predicted electronic circular dichroism (ECD) spectra were critical for remote absolute stereochemical determination. EBC-328 displayed cytotoxic activity towards leukemia cells (K562). Potential biosynthetic relationships are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
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23. Improved Enzymatic Procedure for the Synthesis of Anandamide and N-Fatty Acylalkanolamine Analogues: A Combination Strategy to Antitumor Activity.
- Author
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Quintana, Paula G., García Liñares, Guadalupe, Chanquia, Santiago N., Gorojod, Roxana M., Kotler, Mónica L., and Baldessari, Alicia
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ANANDAMIDE , *ALKANOLAMINE derivatives , *ANTINEOPLASTIC agents , *BIOCATALYSIS , *CHEMOSELECTIVITY , *ENZYMATIC analysis , *ESTERIFICATION - Abstract
Twenty N-fatty acylamines from linolenic and arachidonic acids, fifteen of them new compounds, were obtained through Candida antarctica B lipase-catalyzed esterification and aminolysis reactions in very good yields and with high chemoselectivity. The optimal reaction conditions were achieved by studying the reaction parameters (temperature, E/S ratio, alcohol and alkanolamine/fatty acid ratio, time, solvent, free-solvent system, etc.). To identify ideal enzymatic methods for generating the alkanolamides we evaluated enzyme performance in three procedures: i) aminolysis of ethyl ester, ii) direct condensation between the fatty acid and the alkanolamine, and iii) a one-pot/two-step conversion of fatty acids into alkanolamides via in situ formation of the ethyl ester and subsequent aminolysis by the alkanolamine. The advantages noted with the enzymatic methodology, such as mild reaction conditions and low environmental impact, underscore biocatalysis as a convenient way to prepare the reported compounds. The cytotoxic activities of all compounds and mixtures of anandamide and its analogues were evaluated in rat glioma C6 cells. These studies reveal that some anandamide analogues enhance the antitumor effects of anandamide, suggesting their possible application as therapeutic tools in cancer treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
24. Rhodium-Catalyzed [4+3] Cycloaddition to Furans: Direct Access to Functionalized Bicyclo[5.3.0]decane Derivatives.
- Author
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Krainz, Tanja, Chow, Sharon, Korica, Natasa, Bernhardt, Paul V., Boyle, Glen M., Parsons, Peter G., Davies, Huw M. L., and Williams, Craig M.
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BICYCLODECENES , *RHODIUM , *CARBOXYLATES , *FURANS synthesis , *PROTEIN kinase C - Abstract
An efficient method to directly access the bicyclo[5.3.0]decane core was achieved by rhodium-catalyzed reaction of a novel donor-acceptor cyclopentenyl diazocarboxylate with a variety of furans. As this motif is commonly found within bioactive antitumor natural products, selected systems were further manipulated and evaluated against cancer cell lines sensitive to protein kinase C (PKC) activation. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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25. Synthesis of Easy-to-Functionalize Azabicycloalkane Scaffolds as Dipeptide Turn Mimics en Route to cRGD-Based Bioconjugates.
- Author
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Serra, Massimo, Tambini, Simone Maria, Di Giacomo, Marcello, Peviani, Elena Giulia, Belvisi, Laura, and Colombo, Lino
- Subjects
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BIOCONJUGATES , *BIOMOLECULES , *ORGANIC compounds , *ORGANIC synthesis , *ORGANIC chemistry - Abstract
In this paper we report the synthesis of new azabicycloalkane scaffolds, which could be exploited to obtain cRGD-based bioconjugates that may find promising application for targeted drug delivery, theranostic, and general cancer-cell labeling. By exploiting a Hosomi-Sakurai intramolecular allylation reaction we efficiently converted a silylated aldehyde precursor into 7,5-fused lactam scaffolds endowed with an exocyclic double bond. The presence of the vinyl function should make it possible to conjugate bioactive compounds to selectively carry them to tumor sites. The optimized synthetic sequence allows the gram-scale preparation of the target scaffolds in a few steps and good 39% overall yield from readily accessible materials. The high reactivity of the exocyclic olefin moiety was ascertained by performing a Heck coupling reaction with 1-bromo-4-nitrobenzene, which gave the corresponding functionalized derivatives in good (80-91%) yields. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
26. Synthesis and Evaluation of the Antiproliferative Properties of a Tethered Tubercidin-Platinum(II) Complex.
- Author
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D'Errico, Stefano, Oliviero, Giorgia, Borbone, Nicola, Di Gennaro, Elena, Zotti, Andrea Ilaria, Budillon, Alfredo, Cerullo, Vincenzo, Nici, Fabrizia, Mayol, Luciano, Piccialli, Vincenzo, and Piccialli, Gennaro
- Subjects
- *
NUCLEOSIDES , *CISPLATIN , *ORGANIC compounds , *ORGANIC synthesis , *ORGANIC chemistry - Abstract
Herein, the synthesis of a nucleoside platinum(II) complex in which a cisplatin-like unit is joined to 7-deazaadenosine through an amino alkyl chain installed at the C6 position of purine was explored. The capability of the new complex to react with DNA purine bases was confirmed by a model reaction with deoxyguanosine monophosphate, whereas its antiproliferative activity against A549 and Cal27 human cancer cell lines was studied by sulforhodamine B assay in comparison with its unplatinated precursor and cisplatin. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
27. Cover Feature: A Green Multicomponent Domino Mannich‐Michael Reaction to Synthesize Novel Naphthoquinone‐Polyphenols with Antiproliferative and Antioxidant Activities (Eur. J. Org. Chem. 39/2022).
- Author
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Venturini Filho, Eclair, Antoniazi, Mariana K., Ferreira, Rafael Q., dos Santos, Gabriel F. S., Pessoa, Claudia, Guimarães, Celina J., Vieira Neto, José B., Silva, Artur M. S., and Greco, Sandro J.
- Subjects
- *
ANTIOXIDANTS , *NAPHTHOQUINONE , *ANTINEOPLASTIC agents - Abstract
Keywords: Antitumor agents; Antioxidant activity; Domino reactions; Naphthoquinone; Synthetic methods EN Antitumor agents Antioxidant activity Domino reactions Naphthoquinone Synthetic methods 1 1 1 11/01/22 20221020 NES 221020 B The Cover Feature b represents the Antioxidant - "Antiox" - like an eccentric figure, because of its quality of donating what is yours, and personifies the naphthoquinone polyphenols in the paper. Antitumor agents, Antioxidant activity, Domino reactions, Naphthoquinone, Synthetic methods Cover Feature: A Green Multicomponent Domino Mannich-Michael Reaction to Synthesize Novel Naphthoquinone-Polyphenols with Antiproliferative and Antioxidant Activities (Eur. J. Org. [Extracted from the article]
- Published
- 2022
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28. Improved Strategy for the Synthesis of the Anticancer Agent Culicinin D.
- Author
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Stach, Michaela, Weidkamp, Andreas J., Yang, Sung‐Hyun, Hung, Kuo‐yuan, Furkert, Daniel P., Harris, Paul W. R., Smaill, Jeff B., Patterson, Adam V., and Brimble, Margaret A.
- Subjects
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ANTINEOPLASTIC agent synthesis , *AMINO acid synthesis , *AMINO acids , *DIASTEREOISOMERS synthesis , *CHEMICAL synthesis - Abstract
The anticancer peptaibol culicinin D was synthesised via a newly developed pathway. This route included an improved attachment of a C-terminal amino acid alcohol building block to 2-chlorotrityl chloride resin. A model system utilising readily available Fmoc-alaninol as the substitute for the unusual APAE building block was developed to investigate the resin-loading by N-anchoring of the first C-terminal residue and an intramolecular O-N acyl shift. The use of both Fmoc SPPS and the crucial O-N acyl transfer afforded a C-terminal alcohol that enabled the synthesis of a library of five related peptaibols. This model system was then applied to the synthesis of culicinin D. The C-terminal APAE building block was anchored to 2-chlorotrityl chloride resin in 67 % loading yield using the optimised conditions, and culicinin D (6.31 mg, 4 %) was prepared by SPPS prior to peptide cleavage and O-N acyl shift. This synthetic strategy was also used to prepare a diastereomer of culicinin D containing the unnatural ( S)-AHMOD amino acid. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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29. Synthesis of Diverse 6-Oxa-allocolchicinoids by a Suzuki-Miyaura Coupling, Acid-Catalyzed Intramolecular Transacetalization Strategy.
- Author
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Yadav, Dharmendra B., Taleli, Lebusetsa, van der Westhuyzen, Alet E., Fernandes, Manuel A., Dragoun, Maxim, Prokop, Aram, Schmalz, Hans‐Günther, de Koning, Charles B., and van Otterlo, Willem A. L.
- Subjects
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SUZUKI reaction , *COUPLING reactions (Chemistry) , *ANTINEOPLASTIC agents , *TUBULINS , *POLYMERIZATION research , *ORGANIC synthesis - Abstract
The synthesis of allocolchicine analogues is of importance as these compounds have been found to possess promising anticancer activity by affecting tubulin polymerization. In this paper, the synthesis of 28 novel substituted 6-oxa-allocolchicinoids is reported. The key steps involved in the synthesis were a Suzuki-Miyaura coupling reaction, followed by an acid-catalyzed intramolecular transacetalization to afford the desired 5-alkoxy-5,7-dihydrodibenzo[ c, e]oxepines. In addition, when thiophenol and phenol were used in the transacetalization step, the 5-(phenylsulfanyl)-5,7-dihydrodibenzo[ c, e]oxepine and 4-(5,7-dihydrodibenzo[ c, e]oxepin-5-yl)phenol skeletons were obtained, respectively. The cytotoxicity of the synthetic compounds was unfortunately not impressive; however, one of the compounds was shown to sensitize vincristine-resistant leukemia and lymphoma cells to vincristine, a result vindicating further synthetic studies. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
30. Synthesis of a Phosphinate Analogue of the Antitumour Phospholipid Edelfosine.
- Author
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Markoulides, Marios S. and Regan, Andrew C.
- Subjects
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PHOSPHINATES , *LYSOPHOSPHOLIPIDS , *ORGANIC synthesis , *ADDITION reactions , *PHOSPHINIC acid , *ALLYL ethers , *MICHAEL reaction - Abstract
The first concise synthesis of a phosphinate analogue of the antitumour ether phospholipid edelfosine is described. The key synthetic step comprised the free-radical addition reaction of phosphinic acid to a functionalised allyl ether, to incorporate the hydrophobic tail into a monosubstituted H-phosphinic acid. The hydrophilic head group was then added by using a silyl phosphonite based Michael addition. The reported synthetic study lays the groundwork for the synthesis of modified phosphinate phospholipid derivatives to facilitate investigations on their biological activity as membrane-targeting antitumour agents. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
31. Synthesis and DNA-Damaging Properties of Cisplatin-N-Mustard Conjugates.
- Author
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Schiesser, Stefan, Hackner, Benjamin, Vrabel, Milan, Beck, Wolfgang, and Carell, Thomas
- Subjects
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CHEMICAL synthesis , *DRUG design , *DNA damage , *DNA alkylation , *CELL-mediated cytotoxicity - Abstract
We report the synthesis of two novel cisplatin-N-mustard conjugates. In these compounds two potentially DNA-damaging molecules are combined and are separated by a spacer containing either one or four ethylene glycol units. We have shown that these conjugates are capable of forming novel clustered DNA adducts, thereby strongly increasing the lesion density in double-stranded DNA, which is thought to block DNA repair and translesion synthesis. Their ability to inhibit cell division was proven in an E. coli assay. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
32. Synthesis of Antitumor Carbazole-Amonafide Structural Hybrids.
- Author
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Rozovsky, Alex, Regozin, Elena, Oron‐Herman, Mor, Albeck, Amnon, and Gellerman, Gary
- Subjects
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PHARMACEUTICAL chemistry , *DRUG design , *ANTINEOPLASTIC agents , *NITROGEN , *POISONING , *CELL lines - Abstract
A facile synthesis of new antitumor [4,5- bc]carbazole-amonafide derivatives is described. These compounds represent a new class of structural hybrids that contain the medicinally important carbazole and amonafide cores. The synthesis involves a Suzuki-Miyaura coupling of bromoamonafide with arylboronic acid reagents followed by the introduction of an azide group and subsequent regiospecific thermal nitrene insertion to yield carbazole-amonafide hybrids in good yields. Preliminary antiproliferative assays against cancer and benign cell lines identified compounds with selective antitumor activity that exhibited submicromolar IC50 values. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
33. One-Step Synthesis of Dicarboxamides through Pd-Catalysed Aminocarbonylation with Diamines as N-Nucleophiles.
- Author
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Carrilho, Rui M. B., Almeida, Ana R., Kiss, Mercédesz, Kollár, László, Skoda‐Földes, Rita, Dąbrowski, Janusz M., Moreno, Maria José S. M., and Pereira, Mariette M.
- Subjects
- *
CARBONYLATION , *PHARMACEUTICAL chemistry , *ANTINEOPLASTIC agents , *ANTI-inflammatory agents , *MOLECULES , *AMIDES , *LUNG cancer - Abstract
An efficient one-step synthetic strategy was used to prepare a set of dicarboxamides through palladium-catalysed aminocarbonylation of iodoalkenyl and iodoaryl compounds, with use of various alkyl- and aryldiamines as N-nucleophiles. The isolated yields of the dicarboxamides depended significantly on the iodo substrate and diamine structures, as well as on the reaction conditions, the best one (ca. 70 %) being achieved with 1-iodocyclohexene as substrate and 1,4-diaminobutane as nucleophile, at 100 °C and 30 bar of CO. When iodobenzene was used as model aryl halide, the highest yield of the target dibenzamides (ca. 65 %) was obtained with 1,4-diaminobenzene as coupling amine, at 100 °C and 10 bar of CO. Preliminary studies on their in vitro cytotoxicity against human lung carcinoma A549 cells showed N, N′-(butane-1,4-diyl)dibenzamide and androst-16-ene-based dicarboxamides to be the most efficient cytotoxic agents, with IC50 values of approximately 40 μ M. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
34. One-Pot Directed Alkylation/Deprotection Strategy for the Synthesis of Substituted Pyrrole[3,4- d]pyridazinones.
- Author
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Nair, Reji N. and Bannister, Thomas D.
- Subjects
- *
METALATION , *LITHIUM , *HALOGENATION , *PHARMACEUTICAL chemistry , *ANTINEOPLASTIC agents , *TUMOR growth - Abstract
In the course of a structure-activity relationship study of pyrrole[3,4- d]pyridazinones, we optimized conditions for a one-pot directed lithiation/alkylation reaction that also promoted in situ cleavage of a tert-butoxycarbonyl (Boc) protecting group on the pyrrole ring. The efficiency of the process gave access to a number of substituted analogs of interest as possible antitumor agents. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
35. Spirangien Derivatives from the Myxobacterium Sorangium cellulosum: Isolation, Structure Elucidation, and Biological Activity.
- Author
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Bruns, Nicole, Collisi, Wera, Bernecker, Steffen, Stadler, Marc, Richter, Christian, Schwalbe, Harald, and Kalesse, Markus
- Subjects
- *
STEREOCHEMISTRY , *POLYKETIDES , *CHEMICAL synthesis , *KETENES synthesis , *ANTI-inflammatory agents , *NUCLEAR magnetic resonance - Abstract
In addition to spirangiens A ( 1) and B ( 2), 11 new spirangiens have been isolated from the myxobacterium Sorangium cellulosum (strain So ce90). Spirangiens A and B consist of a polyketide backbone with a spiroketal core, 13 stereocenters, and a conjugated pentaene chromophore with a terminal carboxylic acid. The structures of the derivatives were elucidated on the basis of NMR and MS data. The stereochemistry was determined by 1D and 2D NMR experiments as well as by biosynthetic studies. Four derivatives 6- 9 differ in the cis/ trans double-bond geometry of the pentaene chromophore side-chain and four of them ( 4- 6 and 10) are characterized by the absence of methoxy groups. Derivative 13 does not exhibit the spiroketal core due to reduction of the acetalic carbonyl group. In addition, 11 and 12 exhibit the opposite configuration at C-20 compared with the known spirangiens A and B. Derivative 3 contains an additional hydroxy group at the end of the side-chain. All the new spirangien derivatives, as well as spirangiens A and B, were tested in cytotoxicity assays against two different cell lines and showed strong cytotoxic activity. Even though spirangien A was identified as the most cytotoxic compound, other derivatives, such as 3, 4, 6, and 10, showed significantly higher activity against the KB-3-1 cell line than against the nontransformed cells (L-929). [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
36. Biosynthetically Distinct Cytotoxic Polyketides from Setophoma terrestris.
- Author
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El‐Elimat, Tamam, Figueroa, Mario, Raja, Huzefa A., Graf, Tyler N., Swanson, Steven M., Falkinham, Joseph O., Wani, Mansukh C., Pearce, Cedric J., and Oberlies, Nicholas H.
- Subjects
- *
POLYKETIDES , *CHEMICAL synthesis , *BIOSYNTHESIS , *NATURAL products , *PHARMACEUTICAL chemistry , *ANTINEOPLASTIC agents , *STRUCTURE-activity relationships - Abstract
Sixteen polyketides belonging to diverse structural classes, including monomeric/dimeric tetrahydroxanthones and resorcylic acid lactones, were isolated from an organic extract of a fungal culture Setophoma terrestris (MSX45109) by bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Of these, six were new: penicillixanthone B ( 5), blennolide H ( 6), 11-deoxyblennolide D ( 7), blennolide I ( 9), blennolide J ( 10), and pyrenomycin ( 16). The known compounds were: secalonic acid A ( 1), secalonic acid E ( 2), secalonic acid G ( 3), penicillixanthone A ( 4), paecilin B ( 8), aigialomycin A ( 11), hypothemycin ( 12), dihydrohypothemycin ( 13), pyrenochaetic acid C ( 14), and nidulalin B ( 15). The structures were elucidated by a set of spectroscopic and spectrometric techniques: the absolute configurations of compounds 1- 10 were determined by ECD spectroscopy combined with time-dependent density functional theory (TDDFT) calculations, whereas a modified Mosher's ester method was used for compound 16. The cytotoxic activities of compounds 1- 15 against the MDA-MB-435 (melanoma) and SW-620 (colon) cancer cell lines were evaluated. Compounds 1, 4, and 12 were the most potent, with IC50 values ranging from 0.16 to 2.14 μ M. When tested against a panel of bacteria and fungi, compounds 3 and 5 showed promising activity against the Gram-positive bacterium Micrococcus luteus, with MIC values of 5 and 15 μg mL-1, respectively. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
37. Synthesis and Cytotoxic Activity of Self-Assembling Squalene Conjugates of 3-[(Pyrrol-2-yl)methylidene]-2,3-dihydro-1 H-indol-2-one Anticancer Agents.
- Author
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Buchy, Eric, Valetti, Sabrina, Mura, Simona, Mougin, Julie, Troufflard, Claire, Couvreur, Patrick, and Desmaële, Didier
- Subjects
- *
SQUALENE , *ANTINEOPLASTIC agents , *PHARMACEUTICAL chemistry , *KINASE inhibitors , *VASCULAR endothelial growth factors - Abstract
Squalenoyl conjugates of semaxanib and sunitinib, two potent antiangiogenic (pyrrolyl)methylidenyl-substituted oxindole multitarget tyrosine kinase inhibitors, were synthesized with a hemiaminal-based pH-sensitive linker. The prodrugs were prepared according to a three-step sequence involving (i) N-alkylation with chloromethoxy-triisopropylsilane; (ii) desilylation; and (iii) acylation with trisnorsqualenic acid. These squalenoyl prodrugs were found to self-assemble into nanoassemblies in aqueous media without the need for any surfactant. The nanosized aggregates were characterized by dynamic light scattering and transmission electron microscopy, and appeared to be stable in water for several days, as determined by particle-size measurement. In vitro biological studies showed that squalenoyl sunitinib nanoassemblies are notably cytotoxic against the human umbilical vein endothelial cell line (HUVEC), which is involved in the tumor vessel formation. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
38. Synthesis of β-Lapachone, a Potential Anticancer Agent from the Lapacho Tree.
- Author
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Katoh, Takeru, Monma, Hiromitsu, Wakasugi, Jun, Narita, Koichi, and Katoh, Tadashi
- Subjects
- *
ANTINEOPLASTIC agents , *CANCER chemotherapy , *LAPACHO (Tea) , *RING formation (Chemistry) , *CHEMICAL reactions - Abstract
A pharmaceutically important natural product, β-lapachone, was efficiently synthesized in four steps in 70 % overall yield starting from commercially available 1,4-naphthoquinone. The key step of the synthesis was the direct conversion of 2-prenyl-1,4-naphthoquinone into β-lapachone through an advantageous cyclization/hydration/oxidation cascade process. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
39. Total Synthesis of Micromide: a Marine Natural Product.
- Author
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Han, Jianrong, Lian, Jingtang, Tian, Xia, Zhou, Shengwei, Zhen, Xiaoli, and Liu, Shouxin
- Subjects
- *
AMINO acids , *METHYLATION , *OLIGOPEPTIDES , *PEPTIDES , *CHEMICAL synthesis - Abstract
This paper describes an efficient procedure for the synthesis of micromide, a natural product that shows anti-solid-tumor activity. Our strategy involved the synthesis of N-nosyl-protected amino acids and their N-methylation with iodomethane. The hindered oligopeptides containing N-methyl amino acids were synthesized in excellent yields and high purities. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
40. Synthesis of Indole-Derived Allocolchicine Congeners through Pd-Catalyzed Intramolecular C-H Arylation Reaction.
- Author
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Sitnikov, Nikolay S., Kokisheva, Antonina S., Fukin, Georgy K., Neudörfl, Jörg‐Martin, Sutorius, Hannah, Prokop, Aram, Fokin, Valery V., Schmalz, Hans‐Günther, and Fedorov, Alexey Yu.
- Subjects
- *
CHEMICAL synthesis , *HETEROCYCLIC compounds , *ANTIMITOTIC agents , *PALLADIUM catalysts , *APOPTOSIS - Abstract
The synthesis of several new heterocyclic structural analogs of the natural antimitotic agent allocolchicine is reported. As a key step an intramolecular Pd-catalyzed C--H arylation reaction was used to close the seven-membered ring fused with two electron-rich aryl fragments. The stereostructure of the target compounds was determined by X-ray crystal analysis. The primary biological assessment of the synthesized compounds was carried out on human lymphoma cells. Several allocolchicinoids were determined to possess antiproliferative and apoptosis-inducing activity in the micromolar concentration range. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
41. Phosphatidylinositol 3-Phosphate Mimics Based on a Sulfoquinovose Scaffold: Synthesis and Evaluation as Protein Kinase B Inhibitors.
- Author
-
Gabrielli, Luca, Calloni, Ilaria, Donvito, Giulia, Costa, Barbara, Arrighetti, Noemi, Perego, Paola, Colombo, Diego, Ronchetti, Fiamma, Nicotra, Francesco, and Cipolla, Laura
- Subjects
- *
PROTEIN kinase B , *PHOSPHATIDYLINOSITOL 3-kinases , *ANTINEOPLASTIC agents , *PHARMACEUTICAL chemistry , *CHEMICAL inhibitors , *PHOSPHOLIPIDS - Abstract
New sulfoquinovose analogues of phosphatidylinositol 3-phosphate have been synthesised based on a sulfoquinovose scaffold as potential protein kinase B (PKB) inhibitors. The synthetic strategy involved the introduction into glucose of a thioacetate group at the 6-position and of an azide group at the anomeric position as precursors of the sulfonate and phosphoramidate moieties present in the final compounds. The synthesised compounds were tested in vitro on isolated PKB by means of ELISA assays and for their anti-proliferative activity against the human ovarian carcinoma cell line IGROV-1. Sulfoquinovose derivatives 2b and 2c showed inhibitory activity in the low micromolar range. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
42. Synthesis and Biological Activity of Triazole-Appended N,O-Nucleosides.
- Author
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Romeo, Roberto, Giofrè, Salvatore V., Carnovale, Caterina, Chiacchio, Maria A., Campisi, Agata, Mancuso, Raffaella, Cirmi, Santa, and Navarra, Michele
- Subjects
- *
TRIAZOLES , *NUCLEOSIDES , *RING formation (Chemistry) , *CELL lines , *ANTINEOPLASTIC agents - Abstract
1,2,3-Triazole-appended N,O-nucleosides have been synthesized by an approach combining a 1,3-dipolar cycloaddition process and an alkyne-azide click chemistry reaction. Biological assays, performed on six tumor cell lines, revealed the antiproliferative activity of the synthesized compounds. The effect was more evident in the U87MG human glioblastoma cell line. Thus, these nucleoside analogues could be promising scaffolds for the construction of new anticancer agents. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
43. Synthesis and Cytotoxic Activity of a Small Naphthoquinone Library: First Synthesis of Juglonbutin.
- Author
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Brötz, Elke, Herrmann, Jennifer, Wiese, Jutta, Zinecker, Heidi, Maier, Armin, Kelter, Gerhardt, Imhoff, Johannes F., Müller, Rolf, and Paululat, Thomas
- Subjects
- *
QUINONE , *TOXICITY testing , *ANTINEOPLASTIC agents , *PHARMACEUTICAL chemistry , *CHEMICAL synthesis - Abstract
A synthetic protocol has been designed to synthesize grecoketidone ( 2k), 5-hydroxylapachol ( 2g), and the recently discovered natural products juglonbutin ( 2o) and its derivatives, leading to a small library of different 1,4-naphthoquinones with the intention of finding new active compounds. Within our collection, 2- O-alkylated naphthoquinones with an ester functionality in the side-chain and a free OH group at C-5 showed the best activities. Compounds 2f, 2m, and 2n showed GI50 values against 12 tumor cell lines in the lower micromolar range and juglonbutin ( 2o) showed remarkably efficient inhibition of the glycogen synthase kinase 3β with an IC50 value of 2.03 μ M. Furthermore, studies on the mode of action of the most active cytotoxic compounds have been carried out. To the best of our knowledge, this is the first report on the synthesis of juglonbutin ( 2o) and its biological activity. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
44. Brønsted Acid Catalyzed Bisindolization of α-Amido Acetals: Synthesis and Anticancer Activity of Bis(indolyl)ethanamino Derivatives.
- Author
-
Mari, Michele, Tassoni, Aurora, Lucarini, Simone, Fanelli, Mirco, Piersanti, Giovanni, and Spadoni, Gilberto
- Subjects
- *
BRONSTED acids , *CATALYSIS research , *ACETAL resins , *INDOLE compounds , *HYDROLYSIS , *ALKALOIDS - Abstract
A Brønsted acid catalyzed bisindolization reaction with suitable α-amido acetals that tolerates a wide range of indoles is reported. The method allows rapid access to the biologically relevant bisindolyl ethanamine scaffold in good to excellent yields upon mild amide basic hydrolysis. In preliminary pharmacological studies, some of these compounds display cytotoxic activity in U937 cancer cells. The marine natural alkaloid 2,2-di(6′-bromo-3′-indolyl)-ethylamine was the most active compound and could be a lead candidate for further optimization. For the first time, the biological role of this brominated bisindole marine alkaloid is presented. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
45. Facile Installation of a Hydroxyalkyl Group into Hydroxyanthraquinones and Aminoanthraquinones through the Modified Marschalk Reaction.
- Author
-
Zhao, Li‐Ming, Ma, Feng‐Yan, Jin, Hai‐Shan, Ma, Jiao, Wang, Huan, and Fu, Chuan‐Zhao
- Subjects
- *
QUINONE , *ANTHRAQUINONES , *ALDEHYDES , *CHEMICAL reactions , *PHARMACEUTICAL chemistry , *ANTINEOPLASTIC agents - Abstract
1,4-Dihydroxyanthraquinones are widely featured in numerous natural products and drugs. It is important to be able to functionalize the 1,4-dihydroxyanthraquinone skeleton through a simple yet efficient transformation, which could be potentially useful for the drug discovery process. We describe herein a simple and efficient method to derivatize 1,4-dihydroxyanthraquinone by using a modified Marschalk reaction. This method provides a clear advantage over traditional approaches, which often require the protection and deprotection of the OH groups. We also demonstrate the applicability of this reaction to other hydroxyanthraquinones and aminoanthraquinones. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
46. Cuprate Addition to a 6-Substituted Pentafulvene - Preparation of sec-Alkyl-Substituted Titanocene Dichlorides and Their Biological Activity.
- Author
-
Cini, Melchior, Bradshaw, Tracey D., Lewis, William, and Woodward, Simon
- Subjects
- *
ANISOLE , *CYCLOPENTADIENE , *CELL lines , *COLON (Anatomy) , *CUPRATES - Abstract
The copper-catalysed (10 mol-% CuBr ·SMe2, CuCN ·LiCl or CuI/PPh3) addition of RMgBr to the pentafulvene 1-(cyclopenta-2,4-dien-1-ylidenemethyl)-2-methoxybenzene allows the formation of cyclopentadienyl derivatives with α-CHR(2-MeOPh) sidechains (R = Me, Et, nBu, iBu, allyl, Ph) without H- transfer. The deprotonation of these sec-alkyl-substituted cyclopentadienyls followed by the addition of TiCl4 allows the isolation of TiCl2{η5-C5H4CHR(2-OMePh)} as rac/ meso mixtures that show activity against human colon, breast and pancreatic cell lines (GI50 2.3-42.4 μ M). [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
47. Total Synthesis of (+)-Antofine and (-)-Cryptopleurine.
- Author
-
Ying, Weijiang and Herndon, James W.
- Abstract
The tylophorine alkaloid anticancer compounds antofine and cryptopleurine have been synthesized in optically active form. Both syntheses use optically pure α-amino acids as the starting materials, require only seven steps from known 2-ethynylpyrrolidine or 2-ethynylpiperidine derivatives, and are free of protecting groups. The key steps include an alkyne hydration and a chromium-carbene-complex-based net [5 + 5]-cycloaddition step. The alkyne hydration was accompanied by racemization of the β-amino ketone product under most of the conditions examined, and minimization of this side-reaction was achieved through careful pH control and choice of metal additive. The final ring closure involved a Bischler-Napieralski reaction using a carbamate (antofine) or urea (cryptopleurine) precursor. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
48. Reactivity of 4-Vinyl-2 H-1-benzopyran-2-ones in Diels-Alder Cycloaddition Reactions: Access to Coumarin-Based Polycycles with Cdc25 Phosphatase-Inhibiting Activity.
- Author
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Valente, Sergio, Xu, Zhanjie, Bana, Emilie, Zwergel, Clemens, Mai, Antonello, Jacob, Claus, Meiser, Peter, Bagrel, Denyse, Silva, Artur M. S., and Kirsch, Gilbert
- Abstract
The reactivity of 4-(1-butoxyvinyl)-2 H-chromen-2-one ( 1) and ( E)-4-(2-butoxyvinyl)-2 H-chromen-2-one ( 2) as diene in thermal Diels-Alder cycloaddition reactions with several electron-poor dienophiles is reported. Among several dienophiles used in this study 1,4-benzoquinone afforded cycloadducts 11-butoxy-1 H-naphtho[1,2- c]chromene-1,4,5-trione ( 3e) and 1 H-naphtho[1,2- c]chromene-1,4,5-trione ( 4g) that showed Cdc25 phosphatase-inhibition activity at low micromolar values, with both compounds more effective against Cdc25 A and Cdc25 C isoforms. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
49. Synthesis and Biological Evaluation of α-Tubulin-Binding Pironetin Analogues with Enhanced Lipophilicity.
- Author
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Carda, Miguel, Murga, Juan, Díaz‐Oltra, Santiago, García‐Pla, Jorge, Paños, Julián, Falomir, Eva, Trigili, Chiara, Díaz, J. Fernando, Barasoain, Isabel, and Marco, J. Alberto
- Abstract
Four new lipophilic analogues of the natural pyrone pironetin have been prepared. The C9 side-chain of the latter has been replaced in one analogue by a 4-phenylbutyl chain and in the other three analogues by C13 or C16 aliphatic chains, all of them bearing two stereogenic centres. Their cytotoxic activities and interactions with tubulin have been investigated. It was found that all four are cytotoxic towards two either sensitive or resistant tumoral cell lines with similar IC50 values in each case, which indicates that, like the parent natural compound, they also display a covalent mechanism of action. However, one of them operates in all likelihood through a mechanism very similar to pironetin, whereas the other three seem to operate through a different mechanism. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
50. Triguanide Derivatives: Synthesis, Crystal Structure and Evaluation of the Proliferation Effect on Some Tumor Cell Lines.
- Author
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Štrukil, Vjekoslav, Glasovac, Zoran, Đilović, Ivica, Matković-Čalogović, Dubravka, Šuman, Lidija, Kralj, Marijeta, and Eckert-Maksić, Mirjana
- Abstract
One-pot synthesis of new pentasubstituted triguanides 1a- e starting from the corresponding monosubstituted guanidine derivatives and diisopropylcarbodiimide is described and a mechanism for formation of the products observed is proposed. The structures of 1a- d were elucidated by spectroscopic analyses of their acetate salts. The structure of compound 1e was also confirmed by X-ray crystallography using its sulfate salt. The X-ray structure provided strong evidence of extensive electron delocalization within the triguanide core despite its non-planar structure. In addition, the effect of tautomerism on the course of the reaction, with emphasis on possible reaction paths leading to the side products, is discussed in some detail. Finally, antiproliferative effects of the acetate salts of the newly prepared compounds on five cancer lines in vitro were evaluated. It was found that acetates of 1a- c exhibit strong cytostatic and cytotoxic activity, with the strongest effect observed for the acetate of benzyl derivative 1c. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
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