Lavergne O, Lesueur-Ginot L, Pla Rodas F, Kasprzyk P G, Pommier J, Demarquay D, Prévost G, Ulibarri G, Rolland A, Schiano-Liberatore A M, Harnett J, Pons D, Camara J, Bigg D C
Institut Henri Beaufour, 5, avenue du Canada, F-91966 Les Ulis, France.
J Med Chem. 1998 Dec 31;41(27):5410-9. doi: 10.1021/jm980400l.
Homocamptothecin (hCPT), a camptothecin (CPT) analogue with a seven membered beta-hydroxylactone which combines enhanced plasma stability and potent topoisomerase I (Topo I)-mediated activity, is an attractive template for the elaboration of new anticancer agents. Like CPT, hCPT carries an asymmetric tertiary alcohol and displays stereoselective inhibition of Topo I. The preparation and biological screening of racemic hCPT analogues are described. The 10 hCPTs tested were better Topo I inhibitors than CPT. Fluorinated hCPTs 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 MCF7mdr cell lines, which overexpress a functionally active P-glycoprotein. Fluorinated 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.
高喜树碱（hCPT）是一种喜树碱（CPT）类似物，具有七元β-羟基内酯结构，兼具增强的血浆稳定性和有效的拓扑异构酶I（Topo I）介导的活性，是开发新型抗癌药物的一个有吸引力的模板。与CPT一样，hCPT带有一个不对称叔醇，并表现出对Topo I的立体选择性抑制。本文描述了外消旋hCPT类似物的制备和生物学筛选。所测试的10种hCPT是比CPT更好的Topo I抑制剂。发现氟化hCPT 23c、d、f、g对A427和PC-3肿瘤细胞系具有强大的细胞毒性活性。它们对过表达功能活性P-糖蛋白的K562adr和MCF7mdr细胞系的细胞毒性仍然很高。在HT-29异种移植模型中，氟化hCPT在体内比CPT更有效。在该模型中，每天剂量为0.32 mg/kg的hCPT 23g可使肿瘤生长延迟25天，而每天剂量为0.625 mg/kg的CPT仅使肿瘤生长延迟4天。因此，二氟化hCPT 23g作为一种对肿瘤细胞具有高细胞毒性且体内疗效有望的新型Topo I抑制剂值得进一步研究。
