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.

Silica-supported palladium: Sustainable catalysts for cross-coupling reactions

“…Not only products containing the nitrile group are biologically important [113] but the nitriles are also valuable in installation of functionalities such as aldehydes, amines, amidines, acids, and acid derivatives [114]. For many years, the only method for cyanation of an aryl halide required stoichiometric CuCN and harsh conditions [115].…”

Mechanisms of Cellular Resistance to Camptothecins

“…The structural model demonstrates that the positions C7, C9, and C10 face into the major groove of the DNA, and modifications in such positions, aimed at improving the solubility and stability of the compounds, would not sterically interfere with drug binding. In addition, several lines of evidence suggest that the formation of certain additional ring structures, e.g., between C7 and C9 or C10 and C11, increases activity [10][11][12][13]. As mentioned above, one of the main chemical features of CPTs is the presence of a lactone functionality in the E ring, which is not only essential for antitumor activity, but it also confers a degree of instability on these agents in aqueous solutions [14].…”

A Synthetic Hybrid Molecule for the Selective Removal of Human Pluripotent Stem Cells from Cell Mixtures

“…[19] High proliferation rates are important for the pluripotencya nd self-renewal of PSCs. [21] Thehigh selectivity of conjugate 17 appears to stem from asynergy between its ABCB1/G2-mediated efflux and Topo I inhibition. Conjugate 17 inhibited Topo Ie ven more strongly than SN38 did.…”