基于龙胆苦苷的二吲哚甲烷类拟单萜吲哚生物碱类似物合成及其抗肿瘤、逆转紫杉醇耐药活性研究

Synthesis, Antitumor and Drug Resistance Reversal Activities of Bis(indolyl)methanes Monoterpenoid Indole Alkaloid Analogues Based on Gentiopicroside

以环烯醚萜类化合物龙胆苦苷为合成模块,利用拟单萜吲哚生物碱的仿生合成途径和组合化学的研究思路,与色胺类衍生物(吲哚结构的活性单元片段)通过缩合反应,合成了23个二吲哚甲烷类拟单萜吲哚生物碱类似物。利用核磁共振和高分辨质谱等对合成化合物的结构进行了表征,并初步评价了其抗肿瘤活性和逆转耐药活性。结果表明,化合物4i脱掉糖基保护基后的化合物5i对3种肿瘤细胞系(TE-1、CAL-62和FaDu)的抑制作用强于阳性对照盐酸阿霉素(DOX)。通过与紫杉醇的联合用药,发现部分化合物如4m、4n、4o、4r等能够有效降低人肺癌细胞紫杉醇耐药株A549/Taxol对紫杉醇的耐药性,具有良好的逆转耐药潜力。

Taking the iridoid gentiopicroside as the synthesis module, 23 bis(indolyl)methanes monoterpenoid indole alkaloid analogues were synthesized via reaction with tryptamine derivatives(active fragments of indole) by the biogenic synthesis pathway of monoterpenoid indole alkaloid and combining the research ideas of combinatorial chemistry. The structures of all as-synthesized compounds were characterized by NMR and HRMS, their antitumor and drug resistance reversal activities were preliminarily evaluated. The results showed that compound 5 i, which was obtained by removing the glycosyl protective group of 4 i, exhibited stronger inhibitory effect than doxorubicin hydrochloride(dox) against three cell lines(TE-1, CAL-62, and FaDu). And it was found that compounds 4 m, 4 n, 4 o, and 4 r could effectively reduce the drug resistance of A549/Taxol cells trough the drug combination with Taxol, which implied that these compounds have the potential reversing drug resistance.