Design, Synthesis, and Biological Evaluation of New-Generation Taxoids
| Autor: | Ilaria Zanardi, Jon Mallen-St. Clair, Iwao Ojima, Susan Band Horwitz, Shujun Xia, Xianrui Zhao, Dafna Bar-Sagi, David Gallager, Jin Chen, Tao Wang, Xudong Geng, Michael L. Miller, Ralph J. Bernacki, Larisa V. Kuznetsova, Songnian Lin, Jean M. Veith, Jennifer L. Guerriero, Chuanxing Qu, Liang Sun, Christopher P. Borella, Paula Pera |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Male
Paclitaxel Transplantation Heterologous Mice Nude Antineoplastic Agents Article Taxoid Mice Structure-Activity Relationship chemistry.chemical_compound Biopolymers Tubulin In vivo Cell Line Tumor Drug Discovery Animals Humans Point Mutation Structure–activity relationship Cytotoxicity biology Chemistry Discodermolide Biochemistry Drug Resistance Neoplasm Cell culture Drug Design biology.protein Molecular Medicine Female Taxoids Drug Screening Assays Antitumor Neoplasm Transplantation |
| Zdroj: | Journal of Medicinal Chemistry. 51:3203-3221 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm800086e |
| Popis: | Novel second-generation taxoids with systematic modifications at the C2, C10, and C3'N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third-generation taxoids". 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in beta-tubulin as well, wherein the drug resistance is mediated by the beta-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|