Design and Synthesis of Cyclolipopeptide Mimics of Dysoxylactam A and Evaluation of the Reversing Potencies against P‑Glycoprotein-Mediated Multidrug Resistance

Inspired by the structure of dysoxylactam A (DLA) that has been demonstrated to reverse P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) effectively, 61 structurally simplified cyclolipopeptides were thus designed and synthesized via an effective method, and their reversing P-gp-mediated MDR potentials were evaluated, which provided a series of more potent analogues and allowed us to explore their structure–activity relationship (SAR). Among them, a well-simplified compound, 56, with only two chiral centers that all derived from amino acids dramatically reversed drug resistance in KBV200 cells at 10 μM in combination with vinorelbine (VNR), paclitaxel (PTX), and adriamycin (ADR), respectively, which is more promising than DLA. The mechanism study showed that 56 reversed the MDR of tumor cells by inhibiting the transport function of P-gp rather than reducing its expression. Notably, compound 56 effectively restored the sensitivity of MDR tumors to VNR in vivo at a dosage without obvious toxicity.

本研究受已被证实可有效逆转P-糖蛋白（P-glycoprotein, P-gp）介导的多药耐药性（multidrug resistance, MDR）的洋翠雀酰胺A（dysoxylactam A, DLA）结构启发，通过高效合成方法设计并合成了61种结构简化的环脂肽类化合物，并对其逆转P-gp介导的MDR的活性进行了评估，由此获得了一系列活性更强的衍生物，并得以深入探究其构效关系（structure–activity relationship, SAR）。其中化合物56结构高度简化，仅含有两个均源自氨基酸的手性中心，在10 μM浓度下分别与长春瑞滨（VNR）、紫杉醇（PTX）及阿霉素（ADR）联用时，可显著逆转KBV200细胞的多药耐药性，其活性优于DLA。机制研究表明，化合物56通过抑制P-gp的转运功能而非降低其表达来逆转肿瘤细胞的多药耐药性。值得注意的是，化合物56在无明显毒性的给药剂量下，可在体内有效恢复多药耐药肿瘤对长春瑞滨的敏感性。