Development of new camptothecin analogs as cancer chemotherapeutic agents: Library synthesis of homosilatecans and the first asymmetric synthesis of homocamptothecin and related homosilatecans.

摘要

A new racemic route to homocamptothecin (hCPT) and analogs has been developed. The synthetic strategy allowed a practical and efficient preparation of the previously described key DE-fragment precursor (±)-5-ethyl-5-hydroxy-1-methoxy-3-(trimethylsilanyl)-5,9-dihydro-6- H-8-oxa-2-aza-benzocyclohepten-7-one. This pivotal precursor was synthesized in 5 steps and 31% overall yield, starting from a known intermediate in the total synthesis of camptothecin (CPT) via a cascade radical annulation. Furthermore, a new irradiation protocol was implemented, increasing the radical reaction yields of hCPT and related homosilatecans from 10–30% to 40–60%.; Subsequently, the efficient synthetic methodology developed was applied to the solution phase parallel elaboration of racemic homosilatecan libraries. More than 100 homosilatecans, with two elements of diversity, were prepared. Key steps in the combinatorial synthetic plan were: (a) N-alkylation of a pyridone D/E-ring fragment, and (b) [4 + 11 cascade radical annulation. Automated purification of 80 library members allowed rapid product isolation. Biological evaluation of these homosilatecans, having a diverse range of functions at the C7 and C10 positions, may provide important data concerning structure/activity relationships. Ultimately, these ongoing studies may identify a camptothecin analog that has both high human blood stability and high inhibitory activity against a variety of tumor cell lines.; Importantly, the first asymmetric route to synthesize (R)-hCPT and homosilatecans was successfully accomplished. A convenient and highly enantioselective synthetic route to the DE-fragment precursor (5R )-5-ethyl-5-hydroxy-1-methoxy-3-(trimethylsilanyl)-5,9-dihydro-6- H-8-oxa-2-aza-benzocyclohepten-7-one was achieved. The synthetic strategy relied on the application of a Stille-Corey reaction and a Sharpless asymmetric epoxidation to install the crucial configuration at C20 (90% ee). The process to this key DE-fragment has the scope to produce (R)-hCPT, (R)-homosilatecans and any (R)-hCPT analog in an enantioenriched form, by exploiting a convergent and flexible [4 + 1] cascade radical annulation strategy. This asymmetric route made possible the preparation of 800 mg of enantiomerically enriched 7-tert-butyldimethylsilyl-10-hydroxy-hCPT for further biological studies.