Homocamptothecins: Synthesis and antitumor activity of novel E-ring-modified camptothecin analogues

Homocamptothecin (hCPT), a camptothecin (CPT) analogue with a seven membere d beta-hydroxylactone which combines enhanced plasma stability and potent t opoisomerase I (Topo I)-mediated activity, is an attractive template for th e elaboration of new anticancer agents. Like CPT, hCPT carries an asymmetri c tertiary alcohol and displays stereoselective inhibition of Topo I. The p reparation and biological screening of racemic hCPT analogues are described . The 10 hCPTs tested were better Topo I inhibitors than CPT. Fluorinated h CPTs 23c,d,f,g were found to have potent cytotoxic activity on A427 and PC- 3 tumor cell lines. Their cytotoxicity remained high on the K562adr and MCF 7mdr cell. lines, which overexpress a functionally active P-glycoprotein. F luorinated hCPTs were more efficacious in vivo than CPT on HT-29 xenografts . In this model, a tumor growth delay of 25 days was reached with hCPT 23g at a daily dose of 0.32 mg/kg, compared to 4 days with CPT at 0.625 mg/kg. Thus difluorinated hCPT 23g warrants further investigation as a novel Topo I inhibitor with high cytotoxicity toward tumor cells and promising in vivo efficacy.