Implementation of a radical cascade cyclization in drug discovery: Total synthesis of the silatecans and homosilatecans

The camptothecin family of antineoplastic agents have cured a wide range of tumors both in vitro and in vivo. Unfortunately, the success of these drugs in human cancer patients has been limited, because the key pharmacophore, namely the α-hydroxy-δ-lactone ring, undergoes rapid hydrolysis in the blood stream; thereby, severely diminishing the bioavailability of the drug.; The [4+1] radical cascade, discovered by Curran and Liu, was used as a rapid means of preparing irinotecan and exploring the QSAR of two new series of trialkylsilyl camptothecins. The radical cascade provided access to the first convergent total synthesis of irinotecan, not proceeding through the active principle (SN-38). The first series of silyl camptothecins, the silatecans, combined the traditional 6-membered lactone ring with a variety of silyl group modifications at the 7-position with and without A ring modifications. Those analogs containing both a 10-hydroxy group and a 7-silyl group displayed enhanced human blood stability and antitumor activity relative to their 10-deoxy analogs. 7-tert-Butyldimethylsilyl-10-hydroxy-camptothecin (DB-67) displayed a blood-lactone stability at equilibrium of 30% compared to CPT (5%) and 9-AC (<1%). Glioblastoma xenograft and intracranial mouse models showed that a dose of 30 mg/kg of DB-67 induced complete tumor regression. Addition of a permanent water soluble amino group to the silatecans resulted in diminished in vitro activity; whereas, a novel silyl irinotecan analog displayed enhanced activity relative to irinotecan. The second series of analogs involved merging the silatecans with a ring expanded β-hydroxylactone group resulting in a new class of analogs referred to as the homosilatecans, which displayed good in vitro activity against glioblastoma and breast cancer cell lines. After 3 h of incubation in whole human blood, these agents displayed markedly enhanced lactone stabilities (>80%), thereby, largely eliminating the marked interspecies variability normally observed with many camptothecins. Finally, an intramolecular radical cascade resulting in an A,B ring bridged model analog is described, but the poor yield of the final cyclization prevents practical applications.