Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, PO Box 3288, 71345, Shiraz, Iran.
Arch Pharm Res. 2013 Nov;36(11):1392-402. doi: 10.1007/s12272-013-0149-8. Epub 2013 May 15.
Multidrug resistance (MDR) is an important obstacle that limits the efficacy of chemotherapy in many types of cancer. In this study, 14 novel asymmetrical DHPs possessing pyridyl alkyl carboxylate substitutions at C3 and alkyl carboxylate groups at C5 in addition to a nitroimidazole or nitrophenyl moiety at C4 position were synthesized. Calcium channel blocking (CCB) activity was measured in guinea pig ileal longitudinal smooth muscle. Cytotoxicity was tested on 4 human cancer cell lines, while MDR reversal capacity was examined on P-glycoprotein overexpressing doxorubicin resistant MES-SA-DX5 and compared with non-resistant MES-SA cells. Compounds showed different CCB (IC50: 29.3 nM-4.75 μM) and cytotoxic activities (IC50: 6.4 to more than 100 μM). Several compounds having nitrophenyl moiety at C4, could significantly reverse resistance to doxorubicin at 0.5 and 1 μM. The most active ones were 7e and 7g containing ethyl carboxylate and isopropyl carboxylate at C5, respectively. CCB activity, which is considered an undesirable effect for these agents, of 7e and 7g were 33 and 20 times lower than nifedipine, respectively. In conclusion, the newly synthesized asymmetrical DHP compounds showed promising MDR reversal and antitumoral activities with low CCB effects and could be of therapeutic value in drug resistant cancer.
多药耐药性（MDR）是许多类型癌症化疗疗效的重要障碍。在这项研究中，合成了 14 种新型不对称 DHPs，它们在 C3 位具有吡啶基烷基羧酸取代基，在 C5 位具有烷基羧酸取代基，此外在 C4 位还具有硝基咪唑或硝基苯基部分。在豚鼠回肠纵向平滑肌中测量钙通道阻断（CCB）活性。在 4 个人类癌细胞系上测试细胞毒性，同时在 P-糖蛋白过表达多柔比星耐药 MES-SA-DX5 上检查 MDR 逆转能力，并与非耐药 MES-SA 细胞进行比较。化合物表现出不同的 CCB（IC50：29.3 nM-4.75 μM）和细胞毒性活性（IC50：6.4 至超过 100 μM）。几种在 C4 位具有硝基苯基部分的化合物可以在 0.5 和 1 μM 时显著逆转多柔比星的耐药性。最活跃的是 7e 和 7g，它们在 C5 位分别含有乙酯基和异丙酯基。7e 和 7g 的 CCB 活性分别比硝苯地平低 33 和 20 倍，被认为是这些药物的不良作用。总之，新合成的不对称 DHP 化合物具有有希望的 MDR 逆转和抗肿瘤活性，同时具有低 CCB 作用，可能在耐药性癌症的治疗中有价值。
