SYNTHESIS, TOPOISOMERASE-I INHIBITORY ACTIVITY, AND IN-VIVO EVALUATION OF 11-AZACAMPTOTHECIN ANALOGS

A series of analogs based on a novel template, 11-aza-(20S)-camptothec in, were obtained from total synthesis and tested as potential antican cer drugs in the topoisomerase I enzyme cleavable complex assay. The p arent compound 11-aza-(20S)-camptothecin (8) was derived from a Friedl ander condensation between the known aminopyridine derivative 3-(3-ami no-4-picolylidene)-p-toluidine and optically active tricyclic ketone 7 . Compound 8 had activity approximately twice that of (20S)-camptothec in in the calf thymus topoisomerase I cleavable complex assay. Compoun ds were prepared wherein the Il-aza nitrogen atom was quaternized as e ither the corresponding N-oxide or methyl iodide. Compounds with quate rnized N-11 showed improved water solubility and were equipotent to th e clinically investigated camptothecin analog topotecan in the cleavab le complex assay. These compounds were evaluated in vivo in nude mice bearing HT-29 human colon carcinoma xenografts. The analog 11-aza(20S) -camptothecin 11-N-oxide was found to significantly retard tumor growt h when compared to untreated controls. Finally, 7,10-disubstituted 11- azacamptothecin analogs were synthesized using Pd(0) coupling reaction s of 10-bromo-7-alkyl-11-aza-(20S)-camptothecins 19 and 20, which in t urn were available from a Friedlander condensation of the novel bromop yridine derivatives 17a and 17b with 7. Among the 10-substituted serie s, a number of analogs displayed extremely high in vitro potency again st topoisomerase I and improved aqueous solubility. A significant numb er of the compounds were found to be active in whole cell cytotoxicity assays and several were evaluated in nude mice bearing the HT-29 tumo r xenografts. The most effective of these proved to be za-7-ethyl-10-( aminohydroximinomethyl)camptothecin trifluoracetic acid salt (27), a p otent topoisomerase I inhibitor which demonstrated excellent efficacy in both short term and in extended in vivo assays. A comparison betwee n in vitro enzyme data and in vivo data from nude mouse studies in oth er compounds in this series revealed a poor overall correlation betwee n topoisomerase inhibition in vitro and antitumor efficacy in vivo.