ABSTRACT
Versatile intermediates 12'-iodovinblastine, 12'-iodovincristine and 11'-iodovinorelbine were utilized as substrates for transition metal based chemistry which led to the preparation of novel analogues of the vinca alkaloids. The synthesis of key iodo intermediates, their transformation into final products, and the SAR based upon HeLa and MCF-7 cell toxicity assays is presented. Selected analogues 27 and 36 show promising anticancer activity in the P388 murine leukemia model.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Vinblastine/analogs & derivatives , Vinca Alkaloids/chemical synthesis , Vinca Alkaloids/pharmacology , Vincristine/analogs & derivatives , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Disease Models, Animal , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Leukemia P388 , Mice , Molecular Structure , Structure-Activity Relationship , Vinblastine/chemical synthesis , Vinblastine/chemistry , Vinblastine/pharmacology , Vinca Alkaloids/chemistry , Vincristine/chemical synthesis , Vincristine/chemistry , Vincristine/pharmacologyABSTRACT
[Structure: see text] Epoxidation of highly strained cyclobutenes followed by thermal rearrangement provides a new entry into oxepine-containing bicyclo[5.3.0] ring systems. In contrast to the rearrangement of the corresponding cyclopropanated systems, the strained epoxides in this study are believed to fragment through two competing pathways leading to a mixture of diastereomeric 5-7 ring systems.
