具有纸莎草酸结构的衍生物作为肿瘤多药耐药逆转剂

Papyriferic acid derivatives as reversal agents of multidrug resistance in cancer cells.

机构信息

Graduate School of Pharmaceutical Sciences, University of Tokushima, Tokushima 770-8505, Japan.

出版信息

Bioorg Med Chem. 2010 Apr 15;18(8):2964-75. doi: 10.1016/j.bmc.2010.02.046. Epub 2010 Mar 6.

DOI:10.1016/j.bmc.2010.02.046

PMID:20363142

Abstract

Forty-one derivatives of papyriferic acid were prepared based on our previous finding that methyl papyriferate (3) showed potent reversing effect on cytotoxicity of colchicine against multidrug resistance (MDR) human cancer cells (KB-C2), and evaluated for their cytotoxicity and effect on reversing P-gp-mediated MDR against KB-C2 cells. 3-O-(Morpholino-beta-oxopropanoyl)-12beta-acetoxy-3alpha,25-dihydroxy-(20S,24R)-epoxydammarane (37) significantly increased the sensitivity of colchicine against KB-C2 cells by 185-fold at 5microg/mL (7.4microM), and the cytotoxicity of colchicine was recovered to nearly that of sensitive (KB) cells. The other several new amide derivatives also exhibited potent reversal activity comparable to or more potent than methyl papyriferate and verapamil.

摘要

基于我们之前的发现，即甲基 papyriferate（3）对长春新碱（colchicine）对多药耐药（MDR）人癌细胞（KB-C2）的细胞毒性具有很强的逆转作用，我们制备了 41 种 papyriferic 酸衍生物，并对其进行了细胞毒性评价及其对 P-糖蛋白（P-gp）介导的 MDR 对 KB-C2 细胞的逆转作用。3-O-（吗啉基-β-氧代丙酰基）-12β-乙酰氧基-3α，25-二羟基-（20S，24R）-环氧达玛烷（37）在 5μg/mL（7.4μM）时使长春新碱对 KB-C2 细胞的敏感性提高了 185 倍，并且长春新碱的细胞毒性恢复到接近敏感（KB）细胞的水平。其他几种新酰胺衍生物也表现出与甲基 papyriferate 和维拉帕米相当或更强的有效逆转活性。