title: Synthesis, topoisomerase I inhibitory activity, and in vivo evaluation of 11-azacamptothecin analogs.
abstract: A series of analogs based on a novel template, 11-aza-(20S)-camptothecin, were obtained from total synthesis and tested as potential anticancer drugs in the topoisomerase I enzyme cleavable complex assay. The parent compound 11-aza-(20S)-camptothecin (8) was derived from a Friedlander condensation between the known aminopyridine derivative 3-(3-amino-4-picolylidene)-p-toluidine and optically active tricyclic ketone 7. Compound 8 had activity approximately twice that of (20S)-camptothecin in the calf thymus topoisomerase I cleavable complex assay. Compounds were prepared wherein the 11-aza nitrogen atom was quaternized as either the corresponding N-oxide or methyl iodide. Compounds with quaternized N-11 showed improved water solubility and were equipotent to the clinically investigated camptothecin analog topotecan in the cleavable 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 growth when compared to untreated controls. Finally, 7,10-disubstituted 11-azacamptothecin analogs were synthesized using Pd(0) coupling reactions of 10-bromo-7-alkyl-11-aza-(20S)-camptothecins 19 and 20, which in turn were available from a Friedlander condensation of the novel bromopyridine derivatives 17a and 17b with 7. Among the 10-substituted series, a number of analogs displayed extremely high in vitro potency against topoisomerase I and improved aqueous solubility. A significant number of the compounds were found to be active in whole cell cytotoxicity assays and several were evaluated in nude mice bearing the HT-29 tumor xenografts. The most effective of these proved to be (S)-11-aza-7-ethyl-10-(aminohydroximinomethyl)camptothecin trifluoracetic acid salt (27), a potent topoisomerase I inhibitor which demonstrated excellent efficacy in both short term and in extended in vivo assays. A comparison between in vitro enzyme data and in vivo data from nude mouse studies in other compounds in this series revealed a poor overall correlation between topoisomerase inhibition in vitro and antitumor efficacy in vivo.
authors.affiliation: Department of Medicinal Chemistry, Glaxo Inc., Research Triangle Park, North Carolina 27709, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Uehling
authors.forename: S S
authors.initials: SS
authors.lastname: Nanthakumar
authors.forename: D
authors.initials: D
authors.lastname: Croom
authors.forename: D L
authors.initials: DL
authors.lastname: Emerson
authors.forename: P P
authors.initials: PP
authors.lastname: Leitner
authors.forename: M J
authors.initials: MJ
authors.lastname: Luzzio
authors.forename: G
authors.initials: G
authors.lastname: McIntyre
authors.forename: B
authors.initials: B
authors.lastname: Morton
authors.forename: S
authors.initials: S
authors.lastname: Profeta
authors.forename: J
authors.initials: J
authors.lastname: Sisco
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D012995:Solubility; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin