Novel Cytotoxic Oxopyridoindolizines: iso-Propyl-7,8,9-trichloro-6,7,8,9-tetrahydro-5-oxopyrido[2,3-a]-indolizine-10-carboxylates (OPIC)

A series of eight new alkyl-7,8,9-trichloro-6,7,8,9-tetrahydro-5-oxopyrido[2,3-a]-indolizine-10-carboxylates (OPIC), analogues of camptothecin (CPT), were prepared in a one-pot reaction of 2,2'-bipyridine-3,3'-dicarboxylic acid (BPA) with a mixture of thionyl chloride/chlorine, followed by addition of the appropriate alcohol. This led to a mixture of OPIC compounds 3a-d, 4a-d and 3,3'-dialkoxycarbonyl-2,2'-bipyridines (BPE, 2a-d). The isopropyl OPIC 3c and its corresponding diastereoisomer 4c showed marked activity against three cancer cell lines compared to other analogs. These same diastereoisomers also displayed high cytotoxic activity against five leukemia cell lines, thus the presence of an isopropyl substituent on the carboxylic ester, as opposed to other alkyl substituents, appears to play a key role in the cytotoxic potency of this new class of compounds.