Design and synthesis of simplified taxol analogs based on the T-Taxol bioactive conformation

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 24; pp. 7664 - 7678
• Main Authors: Zhao, Jielu, Bane, Susan, Snyder, James P., Hu, Haipeng, Mukherjee, Kamalika, Slebodnick, Carla, Kingston, David G.I.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.12.2011; Elsevier
• Subjects: alcohols; Antineoplastic agents; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Antiproliferative activity; beta-lactams; Bioactive conformation; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; chemistry; Crystallography, X-Ray; cytotoxicity; Drug Design; General aspects; Humans; Medical sciences; Modeling; Models, Molecular; Molecular Conformation; Neoplasms - drug therapy; Paclitaxel; Paclitaxel - analogs & derivatives; Paclitaxel - chemical synthesis; Paclitaxel - chemistry; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Simplified paclitaxel; T-Taxol; Taxol; Tubulin; Tubulin - metabolism; X-ray; Antiproliferative activity; Taxol; APQNUDLGDPTPLT-VASYMWTCSA-N; Simplified paclitaxel; T-Taxol; Modeling; FXHOZWWSCCJRPU-GOPAMZTCSA-N; Bioactive conformation; Tubulin; RXCWJGYKZBVKPD-GGHUVPMOSA-N; Paclitaxel; FOCMUWGDUIERRP-YREBQOROSA-N; RHUFDRUJAUOZAP-UJKOFHHOSA-N; RMNBCQONWRRLRH-DBZGNIOYSA-N; DIFJYAJUVYFOAA-SWQNAEFKSA-N; X-ray; UTFCQQAIHHBQRA-MISQFGSZSA-N; Antineoplastic agent; Pentacyclic compound; Angular nitrogen heterocycle; Cytotoxicity; Pactitaxel; Macrocycle; Ovary; Structure activity relation; Aromatic compound; Cyclophane; Chemical synthesis; Antimitotic; Tumor cell; Oxygen nitrogen heterocycle; Human; Antitubulin; Lactone; Tricyclic compound; In vitro; Cell line
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.10.010

A series of compounds designed to adopt a conformation similar to the tubulin-binding T-Taxol conformation of the anticancer drug paclitaxel has been synthesized. Both the internally bridged analogs 37–39, 41 and the open-chain analogs 27–29 and 43 were prepared. The bridged analogs 37–39 and 41 were synthesized by Grubbs’ metatheses of compounds 30–32 and 33, which, in turn, were prepared by coupling β-lactams 24–26 with alcohols 22 and 23. Both the bridged and the open-chain analogs showed moderate to good cytotoxicity.