抗钙调蛋白吖啶酮衍生物可调节多药耐药（MDR）癌细胞对长春碱的耐药性。

Anti-calmodulin acridone derivatives modulate vinblastine resistance in multidrug resistant (MDR) cancer cells.

作者信息

Hegde Ravi, Thimmaiah Padma, Yerigeri Mayur C, Krishnegowda Gowdahalli, Thimmaiah Kuntebommanahalli N, Houghton Peter J

机构信息

Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570006, India.

出版信息

Eur J Med Chem. 2004 Feb;39(2):161-77. doi: 10.1016/j.ejmech.2003.12.001.

DOI:10.1016/j.ejmech.2003.12.001

PMID:14987825

Abstract

Multidrug resistance (MDR) is one of the main obstacles limiting the efficacy of chemotherapy treatment of tumors. Parent acridones 1A and 1B were prepared by the Ullmann reaction followed by cyclization and N-alkylation. N-(omega-Chloroalkyl) analogues were subjected to iodide catalyzed nucleophilic substitution reaction with secondary amines to get the compounds 3A-13A and 3B-13B, which enhanced the uptake of vinblastine in KBChR-8-5 cells to a greater extent (2.6-13.1-fold relative to control) than verapamil. The study on the structure-activity relationship revealed that substitution of -H at position C-4 in acridone nucleus by -OCH3 increased the cytotoxic and anti-MDR activities. The ability of acridones to inhibit calmodulin dependent cyclic AMP phosphodiesterase has been determined and the results have shown a strong positive correlation between anti-calmodulin activity and cytotoxicity in KBChR-8-5 cells or anti-MDR activity.

摘要

多药耐药性（MDR）是限制肿瘤化疗疗效的主要障碍之一。母体吖啶酮1A和1B通过乌尔曼反应制备，随后进行环化和N-烷基化。N-（ω-氯烷基）类似物与仲胺进行碘催化的亲核取代反应，得到化合物3A-13A和3B-13B，它们在KBChR-8-5细胞中对长春碱的摄取增强程度（相对于对照为2.6-13.1倍）大于维拉帕米。构效关系研究表明，吖啶酮核中C-4位的-H被-OCH3取代可提高细胞毒性和抗MDR活性。已测定了吖啶酮抑制钙调蛋白依赖性环磷酸腺苷磷酸二酯酶的能力，结果表明在KBChR-8-5细胞中抗钙调蛋白活性与细胞毒性或抗MDR活性之间存在强正相关。