College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China.
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Molecules. 2022 Jun 7;27(12):3669. doi: 10.3390/molecules27123669.
Irinotecan and Topotecan are two Camptothecin derivatives (CPTs) whose resistance is associated with the high expression of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). To reverse this resistance, two novel CPTs, FL77-28 (7-(3-Fluoro-4-methylphenyl)-10,11-methylenedioxy-20(S)-CPT) and FL77-29 (7-(4-Fluoro-3-methylphenyl)-10,11-methylenedioxy-20(S)-CPT), were synthesized by our group. In this study, the anti-tumor activities of FL77-28, FL77-29, and their parent, FL118 (10,11-methylenedioxy-20(S)-CPT), were evaluated and the results showed that FL77-28 and FL77-29 had stronger anti-tumor activities than FL118. The transport and uptake of FL118, FL77-28, and FL77-29 were investigated in Caco-2 cells for the preliminary prediction of intestinal absorption. The apparent permeability coefficient from apical to basolateral (P) values of FL77-28 and FL77-29 were (2.32 ± 0.04) × 10 cm/s and (2.48 ± 0.18) × 10 cm/s, respectively, suggesting that the compounds had moderate absorption. Since the transport property of FL77-28 was passive diffusion and the efflux ratio (ER) was less than 2, two chemical inhibitors were added to further confirm the involvement of efflux proteins. The results showed that FL77-28 was not a substrate of P-gp or BCRP, but FL77-29 was mediated by P-gp. In conclusion, FL77-28 might be a promising candidate to overcome drug resistance induced by multiple efflux proteins.
伊立替康和拓扑替康是两种喜树碱衍生物（CPTs），其耐药性与乳腺癌耐药蛋白（BCRP）和 P-糖蛋白（P-gp）的高表达有关。为了逆转这种耐药性，我们小组合成了两种新型 CPTs，FL77-28（7-（3-氟-4-甲基苯基）-10,11-亚甲基二氧基-20(S)-CPT）和 FL77-29（7-（4-氟-3-甲基苯基）-10,11-亚甲基二氧基-20(S)-CPT）。在这项研究中，评估了 FL77-28、FL77-29 和它们的母体 FL118（10,11-亚甲基二氧基-20(S)-CPT）的抗肿瘤活性，结果表明 FL77-28 和 FL77-29 比 FL118 具有更强的抗肿瘤活性。在 Caco-2 细胞中研究了 FL118、FL77-28 和 FL77-29 的转运和摄取，初步预测肠道吸收。FL77-28 和 FL77-29 的从顶侧向基底外侧的表观渗透系数（P）值分别为（2.32 ± 0.04）×10cm/s 和（2.48 ± 0.18）×10cm/s，表明这些化合物具有中等的吸收性。由于 FL77-28 的转运性质是被动扩散，外排比（ER）小于 2，因此添加了两种化学抑制剂来进一步确认外排蛋白的参与。结果表明，FL77-28 不是 P-gp 或 BCRP 的底物，但 FL77-29 是由 P-gp 介导的。总之，FL77-28 可能是克服多种外排蛋白诱导的耐药性的有前途的候选药物。
