Design, Synthesis, and Biological Evaluation of New-Generation Taxoids

• Published in: Journal of medicinal chemistry 2008-06, Vol.51 (11), p.3203-3221
• Main Authors: Ojima, Iwao, Chen, Jin, Sun, Liang, Borella, Christopher P, Wang, Tao, Miller, Michael L, Lin, Songnian, Geng, Xudong, Kuznetsova, Larisa, Qu, Chuanxing, Gallager, David, Zhao, Xianrui, Zanardi, Ilaria, Xia, Shujun, Horwitz, Susan B, Mallen-St. Clair, Jon, Guerriero, Jennifer L, Bar-Sagi, Dafna, Veith, Jean M, Pera, Paula, Bernacki, Ralph J
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biopolymers; Cell Line, Tumor; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; General aspects; Humans; Male; Medical sciences; Mice; Mice, Nude; Neoplasm Transplantation; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Point Mutation; Structure-Activity Relationship; Taxoids - chemical synthesis; Taxoids - chemistry; Taxoids - pharmacology; Transplantation, Heterologous; Tubulin - chemistry; Tubulin - genetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800086e

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 β-tubulin as well, wherein the drug resistance is mediated by the β-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.