Synthesis and Evaluation of a New Generation of Orally Efficacious Benzimidazole-Based Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors as Anticancer Agents
| العنوان: | Synthesis and Evaluation of a New Generation of Orally Efficacious Benzimidazole-Based Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors as Anticancer Agents |
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| المؤلفون: | Xuesong Liu, Vincent L. Giranda, Luis E. Rodriguez, Paul A. Ellis, Donald J. Osterling, Magdalena Przytulinska, David Frost, Thomas D. Penning, Jason Stavropoulos, Cherrie K. Donawho, Yunsong Tong, Eric F. Johnson, Joel D. Leverson, Jennifer J. Bouska, Yan Shi, Patrick A. Marcotte, Amanda M. Olson, Sheela A. Thomas, Nirupama B. Soni, Yan Luo |
| المصدر: | Journal of Medicinal Chemistry. 52:6803-6813 |
| بيانات النشر: | American Chemical Society (ACS), 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Male, Benzimidazole, Pyridines, Poly ADP ribose polymerase, Transplantation, Heterologous, Melanoma, Experimental, Poly (ADP-Ribose) Polymerase-1, Administration, Oral, Biological Availability, Antineoplastic Agents, Poly(ADP-ribose) Polymerase Inhibitors, Chemical synthesis, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Cell Line, Tumor, Drug Discovery, Temozolomide, Animals, Humans, Cytotoxicity, Antineoplastic Agents, Alkylating, IC50, Oxadiazoles, biology, Drug Synergism, Biological activity, Small molecule, Dacarbazine, Mice, Inbred C57BL, chemistry, Biochemistry, Enzyme inhibitor, biology.protein, Molecular Medicine, Benzimidazoles, Female, Neoplasm Transplantation |
| الوصف: | Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles to replace the saturated cyclic amine derivatives appended to the benzimidazole core. Not only did a variety of these new generation compounds maintain high enzymatic potency, many of them also displayed robust cellular activity. For example, the enzymatic IC(50) and cellular EC(50) values were as low as 1 nM or below. Compounds 24 (EC(50) = 3.7 nM) and 44 (EC(50) = 7.8 nM), featuring an oxadiazole and a pyridine moiety, respectively, demonstrated balanced potency and PK profiles. In addition, these two molecules exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm900697r |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::adaa42993a9837a478796b4a1a429391 https://doi.org/10.1021/jm900697r |
| رقم الانضمام: | edsair.doi.dedup.....adaa42993a9837a478796b4a1a429391 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/jm900697r |