Synthesis and anti-leukemia activity of phorbol 13,20-diesters and phorbol 12,13,20-triesters

Yan Wang, Y. Shan, Rui Feng, Siyu Wang, Linwei Li, Shuang Xu, Yu Chen, Xu Feng, Jin Luo, Fei Liu
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引用次数: 1

Abstract

Phorbol esters and their derivatives, such as TPA, have been reported as potential natural antitumor products, with some derivatives entering clinical research for leukemia treatment. In this study, 16 phorbol derivatives were synthesized from phorbol, and their anti-leukemia activity against Jurkat, HL-60, and K562 were tested. The results showed that several derivatives had anti-leukemia activity, with 5B demonstrating the strongest cytotoxic activity against the K562 cell line (IC50 = 0.24 ± 0.04 μM). Based on the IC50 values, a structure-activity relationship was established. When the substituent contained an aromatic group, phorbol derivatives esterified with long-chain organic acids at three reactive hydroxyl groups (C12-OH, C13-OH, and C20-OH) had better activity. When aryl groups were absent from the substituent groups, phorbol derivatives esterified with short-chain organic acids at two hydroxyl groups had better activity. Derivatives esterified with heterocyclic acids, either tri-substituted or di-substituted, showed a significant decrease in cytotoxicity. The mechanism of anti-leukemia activity was explored through flow cytometry, which indicated that phorbol esters inhibited the growth of leukemia cells by inducing apoptosis, leading to cell death. Molecular docking data of compound 5B docking to PKCδC1B suggested that substituent groups should not be too large, and caution should be taken when substituting C20-OH. Overall, these findings provide valuable insights into the design of more effective phorbol esters as anti-leukemia agents, but further research is needed to confirm their safety and efficacy in clinical settings.
佛波尔13、20-二酯和佛波尔12、13、20-三酯的合成及抗白血病活性
佛波酯及其衍生物,如TPA,已被报道为潜在的天然抗肿瘤产品,一些衍生物已进入白血病治疗的临床研究。本研究以phorbol为原料合成了16个phorbol衍生物,并检测了它们对Jurkat、HL-60和K562的抗白血病活性。结果表明,多种衍生物均具有抗白血病活性,其中5B对K562细胞株的细胞毒活性最强(IC50 = 0.24±0.04 μM)。根据IC50值,建立构效关系。当取代基中含有芳香族基团时,与长链有机酸在3个活性羟基(C12-OH、C13-OH和C20-OH)上酯化的苯酚衍生物具有较好的活性。取代基不含芳基时,与短链有机酸在两个羟基上酯化的磷衍生物活性较好。与杂环酸酯化的衍生物,无论是三取代的还是二取代的,都显示出细胞毒性的显著降低。通过流式细胞术探索其抗白血病活性的机制,发现佛博尔酯通过诱导细胞凋亡抑制白血病细胞生长,导致细胞死亡。化合物5B与PKCδC1B对接的分子对接数据表明,取代基不能太大,在取代C20-OH时要谨慎。总的来说,这些发现为设计更有效的佛博尔酯作为抗白血病药物提供了有价值的见解,但需要进一步的研究来确认其在临床环境中的安全性和有效性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Chemical Research-s
Journal of Chemical Research-s 化学科学, 有机化学, 有机合成
自引率
0.00%
发文量
0
审稿时长
1 months
期刊介绍: The Journal of Chemical Research is a peer reviewed journal that publishes full-length review and research papers in all branches of experimental chemistry. The journal fills a niche by also publishing short papers, a format which favours particular types of work, e.g. the scope of new reagents or methodology, and the elucidation of the structure of novel compounds. Though welcome, short papers should not result in fragmentation of publication, they should describe a completed piece of work. The Journal is not intended as a vehicle for preliminary publications. The work must meet all the normal criteria for acceptance as regards scientific standards. Papers that contain extensive biological results or material relating to other areas of science may be diverted to more appropriate specialist journals. Areas of coverage include: Organic Chemistry; Inorganic Chemistry; Materials Chemistry; Crystallography; Computational Chemistry.
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