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3. Standardized testing and written communication improve patient understanding of beta-lactam allergy testing outcomes: A multicenter, prospective study

Author

Loprete, Jacqueline, Katelaris, Constance H., Evans, Louise, Kane, Alisa, McMullan, Brendan, Wainstein, Brynn, Wong, Melanie, Post, Jeffrey, Suan, Daniel, Swaminathan, Sanjay, Richardson, Robyn, Rogers, Jamie, Torda, Adrienne, Campbell, Dianne E., Kelleher, Anthony D., Law, Matthew, Carr, Andrew, and Tong, Winnie W.Y.

Published
2022
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5. Delabeling, safety, and impact of β-lactam allergy testing: A systematic review

Author

Loprete, Jacqueline, primary, Richardson, Robyn, additional, Bramah, Valerie, additional, Comben, Simon, additional, Li, Timothy, additional, Beiglari, Liam, additional, O’Neill, Robert, additional, McEwan, Callum, additional, Carr, Andrew, additional, Tong, Winnie, additional, Campbell, Dianne, additional, Wong, Melanie, additional, Evans, Louise, additional, Post, Jeffrey, additional, Torda, Adrienne, additional, Kane, Alisa, additional, Kelleher, Anthony, additional, Wainstein, Brynn, additional, McMullan, Brendan, additional, and Law, Matthew, additional

Published
2023
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7. A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids

Author

Zhu, Mingzhao, Harshbarger, Wayne D., Robles, Omar, Krysiak, Joanna, Hull, Kenneth G., Cho, Sung Wook, Richardson, Robyn D., Yang, Yanyan, Garcia, Andres, Spiegelman, Lindsey, Ramirez, Bianca, Wilson, Christopher T., Yau, Ju Anne, Moore, James T., Walker, Caitlen B., Sacchettini, James C., Liu, Wenshe R., Sieber, Stephan A., Smith, Jeffrey W., and Romo, Daniel

Published
2017
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8. Predictors of severe and recurrent adult anaphylaxis, and gaps in the cascade of care: a retrospective, single‐centre study 2009–2018.

Author

Loprete, Jacqueline, Montemayor, Jonathan, Bramah, Valerie, McEwan, Callum, Richardson, Robyn, Green, Jessica, Carr, Andrew, and Tong, Winnie

Subjects
ASTHMA risk factors, ANAPHYLAXIS, AUDITING, CONFIDENCE intervals, RETROSPECTIVE studies, SEVERITY of illness index, DISEASE relapse, RISK assessment, CONTINUUM of care, T-test (Statistics), DATA analysis software, ODDS ratio, DISEASE risk factors, ADULTS
Abstract

Background: Anaphylaxis is a severe, potentially fatal, systemic allergic reaction. Understanding predictors of recurrent and severe anaphylaxis in adults, and identifying gaps in ongoing anaphylaxis care, is needed to minimise its impact. Aims: To evaluate the risk factors in adults with severe and recurrent anaphylaxis presentations and to evaluate the management of patients in regard to the recommended cascade of care. Methods: We completed a retrospective audit of adults with confirmed anaphylaxis who presented to an inner‐city emergency department from 1 January 2009 through 31 December 2018. Data recorded included demographics, background history, medication use, severity, co‐factors, triggers, management, discharge disposition and referral for follow‐up. Data were managed in REDCap and analysed using Stata. Associations were assessed through odds ratios (ORs) and t tests. Results: Six hundred sixteen individuals had 689 episodes of anaphylaxis over the audit period. Age over 65 (OR: 5.4 (95% confidence interval, CI: 2.3–13.2), P < 0.0001) and history of asthma (OR: 1.6 (95% CI: 1.03–2.5), P = 0.03) were independent risk factors for severe anaphylaxis. History of food allergy (P < 0.001) and food as the trigger were associated with recurrent presentations (OR: 2.1, 95% CI: 1.1–3.9, P = 0.01). Only 19% of patients met the recommended cascade of care, with post‐adrenaline monitoring and recommending follow‐up with an allergy specialist demonstrating the largest gaps. There were increased presentations with time but no difference in triggers or severity. Conclusions: Increased age and asthma were identified as risk factors for severe presentations. History of food allergy was a risk factor for recurrent presentations. Further research is needed on the gaps in care for adults with anaphylaxis to identify the reasons why, so we can better care for these patients. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Practical, catalytic, asymmetric synthesis of beta-lactones via a sequential ketene dimerization/hydrogenation process: Inhibitors of the thioesterase domain of fatty acid synthase

Author

Purohit, Vikram C., Richardson, Robyn D., Smith, Jeffrey W., and Romo, Daniel

Subjects
Lactones -- Chemical properties, Orlistat -- Chemical properties, Hydrogenation -- Analysis, Fatty acids -- Synthesis, Fatty acids -- Analysis, Biological sciences, Chemistry
Abstract

A concise and practical asymmetric route to pseudosymmetric 3,4-dialkyl-ciz-beta-lactones was developed with the finding that the FDA-approved antiobesity agent orlistat is a potential inhibitor of the thioesterase domain of fatty acid synthase FAS. The described route to 3,4-dialkyl-ciz-beta-lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facial-selective hydrogenation.

Published
2006

16. A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers

Author

Fujita, Ryo, primary, Blot, Vincent, additional, Wong, Eley, additional, Stewart, Christine, additional, Lieuw, Vincent, additional, Richardson, Robyn, additional, Banah, Ammar, additional, Villicana, Jose, additional, Timmer, Anjuli, additional, Coronella, Julia, additional, Newman, Roland, additional, and Gymnopoulos, Marco, additional

Published
2020
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19. Socioeconomic and psychosocial factors are associated with poor treatment outcomes in Australian adults living with HIV: a case-control study

Author

Siefried, Krista J, Kerr, Stephen, Richardson, Robyn, Mao, Limin, Rule, John, McAllister, John, de Wit, John, Carr, Andrew, Leerstoel de Wit, and Public Health

Subjects
ART failure, antiretroviral therapy, finance, HIV cascade
Abstract

Background:A substantial minority of patients living with HIV refuse or cease antiretroviral therapy (ART), have virological failure (VF) or develop an AIDS-defining condition (ADC) or serious non-AIDS event (SNAE). It is not understood which socioeconomic and psychosocial factors may be associated with these poor outcomes. Methods: Thirty-nine patients with poor HIV treatment outcomes, defined as those who refused or ceased ART, had VF or were hospitalised with an ADC or SNAE (cases), were compared with 120 controls on suppressive ART. A self-report survey recorded demographics, physical health, life stressors, social supports, HIV disclosure, stigma or discrimination, health care access, treatment adherence, side effects, health and treatment perceptions and financial and employment status. Socioeconomic and psychosocial covariates significant in bivariate analyses were assessed with conditional multivariable logistic regression, adjusted for year of HIV diagnosis. Results: Cases and controls did not differ significantly with regard to sex (96.2% (n = 153) male) or age (mean (± s.d.) 51 ± 11 years). Twenty cases (51%) had refused or ceased ART, 35 (90%) had an HIV viral load >50 copies mL-1, 12 (31%) were hospitalised with an ADC and five (13%) were hospitalised with a new SNAE. Three covariates were independently associated with poor outcomes: foregoing necessities for financial reasons (adjusted odds ratio (aOR) 3.1, 95% confidence interval (95% CI) 1.3-7.6, P = 0.014), cost barriers to accessing HIV care (aOR 3.1, 95% CI 1.0-9.6, P = 0.049) and lower quality of life (aOR 3.8, 95% CI 1.5-9.7, P = 0.004). Conclusions: Despite universal health care, socioeconomic and psychosocial factors are associated with poor HIV outcomes in adults in Australia. These factors should be addressed through targeted interventions to improve long-term successful treatment.

Published
2019

22. Prolonged Effect of Zoledronic Acid on Bone Mineral Density and Turnover in HIV‐Infected Adults on Tenofovir: A Randomized, Open‐Label Study.

Author

Carr, Andrew, Kerr, Stephen J, Richardson, Robyn, Ebeling, Peter, Pocock, Nicholas, Rojas, Jhon, Martinez, Esteban, and Hoy, Jennifer

Abstract

Zoledronic acid (ZOL) 5 mg annually was more effective than tenofovir disoproxil fumarate (TDF) switching at increasing bone mineral density (BMD) over 24 months in HIV‐infected, osteopenic adults. To determine whether the effects of ZOL would persist without further infusions, we compared changes in left hip and spine BMD over 36 months in participants randomized to ZOL 5 mg at baseline and month 12 (and to continue TDF) or to switch TDF (without receiving ZOL). We also compared changes in the plasma bone turnover markers (BTMs) C‐terminal telopeptide of type 1 collagen (CTX; bone resorption), and procollagen type 1 N propeptide (P1NP; bone formation) and determined whether CTX and P1NP changes at month 3 predicted BMD changes at month 36. Changes were compared in the per‐protocol populations, which included 32 (74%) of 43 participants randomized to ZOL and 37 (88%) of 42 participants who switched TDF. Despite not receiving ZOL after month 12, mean hip and spine BMD change from baseline were stable and remained greater with ZOL at month 36 than with TDF switching (spine: 7.5% versus 2.7%, mean difference 4.7%, p < 0.001; hip: 5.5% versus 1.5%, mean difference 4.0%, p < 0.001). CTX and P1NP levels declined in both groups but significantly more with ZOL. Only percent changes in P1NP at month 3 correlated inversely with BMD changes at month 36 (spine: rho = −0.442, p < 0.001; hip: rho = −0.373, p = 0.002). Two infusions of ZOL (in the presence of ongoing TDF) yielded sustained BMD increases through month 36 that remained greater than with TDF switching. © 2019 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Published
2019
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33. Practical, Catalytic, Asymmetric Synthesis of β-Lactones via a Sequential Ketene Dimerization/Hydrogenation Process: Inhibitors of the Thioesterase Domain of Fatty Acid Synthase.

Author

Purohit, Vikram C., Richardson, Robyn D., Smith, Jeffrey W., and Romo, Daniel

Subjects
*LACTONES, *ASYMMETRIC synthesis, *FATTY acid synthesis, *KETENES, *LIPASE inhibitors, *ORLISTAT, *ANTIOBESITY agents, *ESTERASES
Abstract

The recent finding that the FDA-approved antiobesity agent orlistat (tetrahydrolipstatin, Xenical) is a potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and practical asymmetric route to pseudosymmetric 3,4-dialkyl-cis-β-lactones. The well-documented upregulation of FAS in cancer cells makes this enzyme complex an interesting therapeutic target for cancer. The described route to 3,4-dialkyl-β-lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facial-selective hydrogenation leading to cis-substituted-β-lactones. Importantly, the ketene dimer intermediates were found to be stable to flash chromatography, enabling opportunities for subsequent transformations of these optically active, reactive intermediates. Subsequent α-epimerization and α-alkylation or acylation led to trans-β-lactones and β-lactones bearing α-quaternary carbons, respectively. Several of the ketene dimers and β-lactones displayed antagonistic activity (apparent Ki in the low micromolar range) in competition with a fluorogenic substrate toward a recombinant form of the thioesterase domain of fatty acid synthase. The best antagonist, a simple phenyl-substituted cis-β-lactone 3d, displayed an apparent Ki (2.5 ± 0.5 μM) of only ∼10-fold lower than that of orlistat (0.28 ± 0.06 μM). In addition, mechanistic studies of the ketene dimerization process by ReactionView infrared spectroscopy support previous findings that ketene formation is rate determining. [ABSTRACT FROM AUTHOR]

Published
2006
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34. Fluorogenic Phospholipid Substrate to Detect Lysophospholipase D/Autotaxin Activity

Author

G. Ferguson, Colin, S. Bigman, Cleve, D. Richardson, Robyn, A. van Meeteren, Laurens, H. Moolenaar, Wouter, and D. Prestwich, Glenn

Abstract

Lysophospholipase D (lysoPLD), also known as autotaxin (ATX), is an important source of the potent mitogen lysophosphatidic acid (LPA). Two fluorogenic substrate analogues for lysoPLD were synthesized in nine steps from (S)-PMB-glycerol. The substrates (FS-2and FS-3) show significant increases in fluorescence when treated with recombinant ATX and have potential applications in screening for this emerging drug target.

Published
2006
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35. Predictors of CD4 count change over 8 months of follow up in HIV-1-infected patients with a CD4 count >= 300 cells/mu L who were assigned to 7.5 MIU interleukin-2

Author

Fox, Zoe, Antunes, Francisco, Davey, Rick, Gazzard, Brian, Klimas, Nancy, Labriola, Ann, Losso, Marcelo, Neaton, James D., Phillips, Andrew N., Ruxrungtham, Kiat, Staszewski, Schlomo, Weiss, Laurence, Lundgren, Jens D., Abrams, Donald I., Cooper, David A., Darbyshire, Janet H., Duncan, William R., Emery, Sean, Lane, H. Clifford, Lehrman, Sandra, Aguilar, Liliana, Betina Angel, Eleonora, Aquilia, Silvia, Belloso, Waldo, Benetucci, Jorge, Bittar, Victor, Cahn, Pedro, Casiro, Arnaldo, Contarelli, Jorge, Corral, Jorge, Daciuk, Lucia, David, Daniel, Ferrari, Ines, Fridman, Diego, Galache, Viviana, Guaragna, Graciela, Ivalo, Silvina, Laplume, Hector, Lanusse, Isabel, Lasala, Maria B., Lattes, Roberta, Lasovsky, Jaime, Lopardo, Gustavo, Lourtau, Leonardo, Lupo, Sergio, Maranzana, Aldo, Marson, Cristina, Massera, Lucila, Del Lujan Sanchez, Marisa, Somenzini, Carla, Tocci, Mariel, Algar, Sally, Anderson, Jonathan, Baker, David, Blavius, Kathy, Bloch, Mark, Boyle, Michael, Bradford, David, Britton, Phillip, Carrall, Leah, Carr, Andrew, Chuah, John, Curry, Michael, D Arcy-Evans, Clive, Dobson, Pauline, Doong, Nicholas, Egan, Cari, Ferguson, Wendy, Finlayson, Robert, French, Martyn, Frater, Anthony, Gold, Julian, Habel, Philip, Haig, Kay, Holland, Rohan, Hyland, Natalie, Hoy, Jennifer, Hudson, Jeff, James, Robyn, Leung, Jenny, Lowe, Kaye, Macrae, Karen, Mcmurchie, Marilyn, Medland, Nicholas, Miller, Samantha, Murray, Jo, Newman, Rosie, Orth, David, Patching, Julie, Primrose, Ruth, Ree, Hugo, Richardson, Robyn, Rogers, Gary, Roney, Janine, Roth, Norman, Sarangapany, Jeganathan, Shaw, David, Silberberg, Carol, Skett, Jenny, Williams, Leah, Soo, Tuck Meng, Sowden, David, Street, Alan, Vale, Robyn, Villella, Claudio, Walker, Alan, Watson, Ashley, Wendt, Ngaire, Wood, Helen, Youds, David, Aichelburg, Alexander, Rieger, Armin, Vetter, Norbert, Clumeck, Nathan, Wit, Stephane, Kabeya, Kabamba, O Doherty, Elizabeth, Amorim, Cristiane Sales, Basso, Caritas Relva, Lewi, David Salamao, Pereira, Luiz Carlos, Da Silva, Mariliza, Lobato Souza, Tamara Newman, Angel, Jonathan, Bouchard, Pierrette-Rolande, Clark, Fran, Cohen, Jeff, Dambreville, Mimose, Ellis, Michele, Fiset, Stephan, Foster, Andrea, Fraser, Christopher, Gagnon, Susan, Gilmour, Janet, Guenette, Richard, Haldane, Heather, Hawley-Foss, Nanci, Hyndman, Susan, Johnston, Lynn, Jubinville, Nathalie, Juneau, Francoise, Kelleher, Lynn, Lapointe, Lyne, Latendre-Paquette, Judy, Lindemulder, Adeline, Mashinter, Laura, Lefebvre, Eric, Mcfarland, Nancy, Morisseau, Chantal, O Neill, Robert, Piche, Alain, Ralph, Edward, Rouleau, Danielle, Routy, Jean-Pierre, Sandre, Roger, Schmidt, Shelley, Shafran, Stephen, Smaill, Fiona, Stromberg, Dale, Trepanier, Jean-Marc, Trottier, Sylvie, Veal, Susanne, Walmsley, Sharon, Weiss, Karl, Williams, Kurt, Young, Mavis, Zaleschuk, Barbara, Zarowny, Don, Baadegaard, Bente, Black, Finn, Boedker, Kirsten, Gerstoft, Jan, Jensen, Lene, Mathiesen, Lars, Nielsen, Henrik, Pedersen, Court, Petersen, Dorthe, Aboulker, Jean-Pierre, Baakili, Adyb, Bengrait, Nafissa, Bensalem, Maryse, Berthe, Huguette, Bloche, Martin, Bazin, Claude, Boue, Francois, Bouvet, Elisabeth, Brancon, Christiane, Capitant, Catherine, Ceppi, Carole, Cheneau, Christine, Coutellier, Anne, Chennebault, Jean Marie, Coquet, Fabienne, Truchis, Pierre, Delavalle, Anne-Marie, Frixon-Marin, Veronique, Gastaut, Jean-Albert, Delfraissy, Francois, Eliaszeicz, Muriel, Gallais, Herve, Gataut, Jean-Albert, Gilquin, Jacques, Gonzalez-Canali, Gustavo, Gaudebout, Chrisiane, Goujard, Cecile, Hoen, Bruno, Honore, Patricia, Jarousse, Bernard, Lang, Jean-Marie, Lefebvre, Benedict, Levy, Yves, Loison, Jocelyne, Maignan, Aline, Meynard, Jean-Luc, Michon, Christophe, Mole, Martin, Marsal, Laurence, Matheron, Sophie, Mortier, Emmanuel, Oksenhendler, Eric, Poirier, Sandrine, Picard-Dahan, Catherine, Ravaux, Isabelle, Raffi, Francois, Raguin, Gilles, Reynes, Jacque, Rozenbaum, Willy, Salmon, Dominique, Simon, Anne, Spiridon, Gabriella, Viard, Jean-Paul, Vidal, Michele, Zucman, David, Bergmann, Frank, Brockmeyer, Norbert, Faetkenheuer, Gerd, Fenske, Stefan, Gey, Daniela, Goebel, Frank-Detlef, Goetsch, Martina, Hartmann, Martin, Klinker, Hartwig, Kremer, Gisela, Mantzsch, Kathleen, Mauss, Stefan, Rockstroh, Juergen, Rotty, Jessica, Rund, Ellen, Schneider, Katrin, Schuermann, Dirk, Staszweski, Schlomo, Tilmann, Klaus, Vogel, Martin, Bentwich, Zvi, Drora, Goldstain, Kedem, Eynat, Lang, Ruth, Levi, Itzic, Maayan, Shlomo, Magen, Eli, Mamorsky, Merav, Pilpul, Anat, Pollack, Shimon, Sthoeger, Zev, Vered, Hadas, Yust, Israel, Lyons, Fiona, Mulcahy, Fiona, Rochford, Annette, Auiti, Fernando, Angarano, Gioacchino, Bertelli, Davide, Bini, Teresa, Bruno, Raffaele, Cadeo, Gian Pietro, Carosi, Giampietro, D Arminio Monforte, Antonella, Del Giacco, Sergio, Di Pietro, Massimo, Esposito, Roberto, Filice, Gaetano, Gavazzeni, Gabriella, Guaraldi, Giovanni, Indiveri, Francesco, Lazzarin, Adriano, Mazzotta, Francesco, Minolli, Lorenzo, Montroni, Maria, Moroni, Mauro, Nozza, Silvia, Pastor, Guiseppe, Poli, Guido, Raise, Enzo, Romagnani, Sergio, Rusconi, Vega, Sacchi, Paolo, Suter, Fredy, Tambussi, Giuseppe, Tirelli, Umberto, Fraser, Helen, Iwamoto, Aikichi, Kikuchi, Yoshida, Mori, Masahiko, Nakamura, Tetsuya, Odawara, Takashi, Oka, Shinichi, Shirasaka, Takuma, Takano, Misao, To, Junichiro, Ueta, Chisato, El Filali, Kamal, Erradey, Ikbale, Himmich, Hakima, Blok, W., Borleffs, J., Bravenboer, B., Bronveld, W., Claessen, F., Duurvoort, Maurice, Ferwerda, J., Frissen, P., Hulshoff, Nicolette, Juttman, Job, Kauffmann, R., Koopmans, P., Kroon, F., Lowe, Selwyn, Leemhuis, M., Meenhorst, P., Boer, Lieselotte Posthuma, Reiss, Peter, Reinders-Folmer, S., Richter, C., Santegoets, Rick, Schoemaker, Marijke, Schrey, G., Sprenger, Herman, Ten Veen, Jacob, Tessalaar, Judith, Ende, M., Vall, H., Eeden, Arne, Leeuwen, Remko, Vermeulen, Joost, Ten Kate, Reinier W., Boxtel, Renee, Eden, Arne, Ven, Bernadette, Meulen, Piet, Ten Napei, C., Vriesendrop, R., Bruun, Johann, Bakowska, Elzbieta, Beniowski, Marek, Boron-Kaczmarska, Anna, Gasiorowski, Jacek, Gxadysz, Andrzej, Horban, Andrzej, Knysz, Brygida, Mularska, Elzbieta, Pynka, Magdelena, Szymczak, Aleksandra, Aldir, Isabel, Doroana, Manuela, Duque, Luis, Mansinho, Kamal, Pinto, Inez, Valadas, Emilia, Vera, Jose, Foo, Estelle, Panchalingham, Anushia, Lim, Poh Lian, Paton, Nick, Peperstraete, Bernard, Quek, Angela, Alcazar-Caballero, Rosario, Arrizabalaga, Julio, Bouza, Emilio, Cepeda, Concepcion, Barron, Xabier, Cervero Jimenez, Miguel, Clotet, Bonaventura, Cortes, Luis, Domingo, Pere, Fernandez, Pompeyo, Fernandez-Cruz, Eduardo, Fuster, Montserrat, Gatell, Jose, Gijon, Paloma, Gil, Ignacio, Gonzales-Lahoz, Juan, Gonzalez, Alicia, Hernandez, Manuel, Iribarren, Jose, Jimenez, Miguel, Knobel, Hernando, Leon, Agathe, Carlos Lopez, Juan, Lozano, Angeles, Lopez, Paco, Moreno, Jose, Munoz, Rosa, Padilla, Belen, Parras, Angeles, Pastor, Antoni, Pedreira, Jose, Pristo, Julio, Pena, Jose, Roca, Victor, Rubio, Rafael, Sanchez Rivera, Jose, Sanz, Jesus, Tamargo, Lara, Torres, Rafael, Pehrson, Pehr O., Sandstrom, Eric, Bernasconi, Enos, Gurtner, Vanina, Magenta, Lorenzo, Ampunpong, Uangarun, Bowonwatnuwong, Chureeratana, Chanchai, Patimoaporn, Chetchotisakd, Ploenchan, Chuenyam, Thesinee, Duncombe, Chris, Horsakulthai, Mannassinee, Kantipong, Pacharee, Liddy, John, Phanuphak, Praphan, Pongsurachet, Vithaya, Seekaew, Samroeng, Sonjai, Areerat, Subsri, Nuramon, Suwanagool, Surapol, Techasathit, Wichai, Wankoon, Jaturaporn, Adebiyi, Aderonke, Aldam, Diana, Alexander, Ian, Angus, Brian, Barber, Tristan, Bonnington, Sue, Care, Chris, Carroll, Anne, Cornforth, David, Donaldson, Oscar, Druiff, Laurance, Easterbrook, Philippa, Edwards, Beverley, Ellis, Chris, Fisher, Martin, Fox, Ray, Harrison, Allan, Herman, Sandra, Heald, Lisa, Higgs, Christopher, Jendrulek, Isabelle, Johnson, Margaret, Judges, Lucy, Karim, Fatimah, Kinghorn, George, Laurenti, Julie, Lee, Christine, Leen, Clifford, Legg, Ken, Maw, Raymond, Macconachie, Alisdair, Mckernan, Sinead, Mclean, Lorna, Mcmillan, Andrew, Mguni, Sifiso, Morris, Sheila, Mulchay, Fiona, Mullan, Dee, Mullaney, Scott, Murphy, Maurice, Nunn, Andrew, Ong, Edmund, Owen, Maxine, Palfreeman, Adrian, Perry, Nicky, Peters, Barry, Pozniak, Anton, Ronan, Agnes, Skinner, Cecilia, Stroud, Carol, Takawira, Martin, Tamm, Norbert, Thomas, Rachel, Yee, Thynn Thynn, Vanthuyne, An, Wansborough-Jones, Mark, Weber, Jonathan, White, David, Wilkins, Ed, Wiselka, Martin, Williams, Ian, Waugh, Mike, Wotherspoon, Joyce, Youle, Mike, Doyle, Margaret, Goodwin, Edward, Luskin-Hawk, Roberta, Sullivan, James, Verheggen, Rita, Abrams, Donald, Baxter, John, Besch, C. Lynn, Child, Carroll, Cohn, David, Cooper, Pam, El-Sadr, Wafaa, Farrough, Martha, Fisher, Evelyn, Fuentes, Luis, Gordin, Fred, Graeber, Carol, Kelly, Mary Ellen, Kostman, Jay, Lattanzi, Kelly, Macarthur, Rodger, Makohon, Linda, Markowitz, Norman P., Martinez, Norma, Mastro-Polak, Diane, Mitchell, Vinnie, Mushatt, David, Patterson, Kathryn, Perez, George, Rosmarin, Corey, Rouff, Jack R., Saldanha, Jennifer, Sampson, James, Sawyer, Robert, Standridge, Barbara, Sweeton, Bentley, Tedaldi, Ellen, Thompson, Melanie, Valencia, Patricia, Verlinghieri, Gwen, Walker, Janice, Watson, Vicky, Williams, Bruce, Armstrong, Adam, Banks, Susan, Blazes, David, Barile, Anthony, Coelho, Linda, Dennis, Marilyn, Flaks, Hannah, Gilcrest, Joyce, Gittens, Kathleen, Hopper, Shelia, Humphries, M. J., Spooner, Katherine, Tamminga, Cindy L., Vita, Jean, Wegner, Scott A., Wortmann, Glenn, Bisby, Nicole, Blake, William, Brown, Sheldon, Chilliade, Phillippe, Cole, Teresa, Elliot, Katherine, Geisler, Christiane, Goetz, Matthew, Gomez-Perez, Elizabeth, Helman, Jami, Nahass, Ronald, Leflore, Dirk, Marston, Barbara, Obregon, Maria, Petrolati, Jennifer, Pitrak, David L., Roland, Robert, Rosa, Carol, Rossman, Barbara, Schlueter Wirtz, Susan, Schuck, Suzanne, Scretchings, Tiffany, Simon, Gary, Smith, Mack, Summers, Kimberley, Werhane, Mary Jo, Arduino, Roberto, Bell, Brian, Breaux, Katherine, Cuervo, Hilda, Hale, Carl, Lewis, Stanley, Mall, Mark, Mora, Fransisco, Diez, Martine M., Okhuysen, Pablo, Rodriguez-Barradas, Maria, Schrader, Shannon R., Healy, Lynn, Kaszubski, Chris, Kolber, Michael, Tanner, Tom, Armstrong, Joann, Dahlke, Jennifer, Johnson, Leonard, Kaminski, Patricia, Rhame, Frank, Shoden, Cheryl, Temesgen, Zelalem, Urbanich, Marcy, Valenti, Sharon, Zervos, Marcus, Barrick, Bill, Chaitt, Doreen, Hahn, Barbara, Lane, Cliff, Martell, Dennis, Mcnay, Laura, Metcalf, Julia, Powers, April, Tavel, Jorge A., Loveless, Karen, Peterson, Sue, Sweek, Suzanne, Albrecht, Helmut, Antoine, Nicole, Pell, Paula, Gatell, Jose Maria, Hoy, Jenny, Lifson, Alan, Pederson, Court, Borup, Liselotte, Dragsted, Ulrik Bak, Greve, Anne Fau, Jensen, Karoline, Jens Lundgren, Mollerup, David, Pearson, Mary, Phillips, Andrew, Aboulhab, Jamila, Babiker, Abdel, Cordwell, Brooke, Darbyshire, Janet, Hack, Lisa, Hooker, Malcolm, Moraes, Yolanda, Newberry, Douglas, Nuwagaba-Biribonwoha, Harriet, Hooff, Fionna, Denning, Eileen, Holland Klemme, Leslie, Carey, Cate, Chan, Fonnie, Cooper, David, Courtney-Rodgers, David, Drummond, Fraser, Jacoby, Simone, Law, Matthew, Stewart, Morgan, Pett, Sarah, Alloo, Zarina, Bebchuk, Judy, Bollenbeck, Patty, Duchene, Alain G., Fosdick, Lisa, Harrison, Merrie, Krum, Eric, Larson, Gregg, Meger, Sue, Neaton, James, Nelson, Ray, Quan, Siu-Fun L., Schultz, Terri, Telke, Susan, Thackeray, Lisa, Thompson, Greg, Wentworth, Deborah, Wyman, Nicole, Duncan, William, Ferguson, Elaine, Fox, Lawrence, Gettinger, Nikki, Herrera, Janet, Luzar, Mary Anne, Maeshiro, Mieko, Martinez, Ana, Oseekey, Karen, Baigent, Greg, Capra, William, Duliege, Anne-Marie, Fitzgerald, Linda, Kwakkelstein, Marthin, Maral, Jean, O Hara, Mary, Sahner, David, Weber, Claire, Adam-Perchec, Christine, Barron, Nigel, Bell, Mary Louise, Dolan, Sandra, Eckstrand, Julie, Hicks, Steven, Mcauley, George, Beck, Sharon, Brown, Shawn, and Rupert, Adam

37. Synthesis of novel beta-lactone inhibitors of fatty acid synthase.

Author

Richardson RD, Ma G, Oyola Y, Zancanella M, Knowles LM, Cieplak P, Romo D, and Smith JW

Subjects
Cell Death drug effects, Cell Line, Tumor, Fibroblasts, Humans, Lactones pharmacology, Neoplasms drug therapy, Neoplasms pathology, Orlistat, Solubility, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Fatty Acid Synthases antagonists & inhibitors, Lactones chemical synthesis
Abstract

Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the alpha- and beta-alkyl chains, their chemical composition, and amino ester substitutions were altered and the resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display an increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings support the idea that an orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.

Published
2008
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38. Beta-lactam congeners of orlistat as inhibitors of fatty acid synthase.

Author

Zhang W, Richardson RD, Chamni S, Smith JW, and Romo D

Subjects
Anti-Obesity Agents chemical synthesis, Antineoplastic Agents chemical synthesis, Binding Sites, Enzyme Inhibitors chemical synthesis, Humans, Inhibitory Concentration 50, Lactones chemistry, Models, Chemical, Orlistat, Stereoisomerism, Structure-Activity Relationship, beta-Lactams chemical synthesis, Anti-Obesity Agents pharmacology, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Fatty Acid Synthases antagonists & inhibitors, Lactones pharmacology, beta-Lactams pharmacology
Abstract

Beta-lactam derivatives of orlistat were prepared and their inhibitory activities toward the thioesterase domain of fatty acid synthase (FAS-TE) were evaluated using a recombinant form of the enzyme. While in general these derivatives showed lower potency compared to beta-lactones, a reasonably potent, lead compound (-)-9 (IC(50)=8.6microM) was discovered that suggests that this class of compounds should be evaluated further.

Published
2008
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