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5'-脱氧-5-氟胞苷与羟基肉桂酸的缀合物——合成、抗胰腺癌活性及分子对接研究

The conjugates of 5'-deoxy-5-fluorocytidine and hydroxycinnamic acids - synthesis, anti-pancreatic cancer activity and molecular docking studies.

作者信息

Cybulski Marcin, Zaremba-Czogalla Magdalena, Trzaskowski Bartosz, Kubiszewski Marek, Tobiasz Joanna, Jaromin Anna, Krzeczyński Piotr, Gubernator Jerzy, Michalak Olga

机构信息

Pharmacy, Cosmetic Chemistry and Biotechnology Research Group, Łukasiewicz Research Network-Industrial Chemistry Institute Rydygiera 8 01-793 Warsaw Poland

Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw Fryderyka Joliot-Curie 14a 50-383 Wroclaw Poland.

出版信息

RSC Adv. 2024 Apr 23;14(19):13129-13141. doi: 10.1039/d4ra01683a. eCollection 2024 Apr 22.

DOI:10.1039/d4ra01683a
PMID:38655481
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11036175/
Abstract

New amide conjugates 1-6 of hydroxycinnamic acids (HCA) and 5'-deoxy-5-fluorocytidine (5-dFCR), the prodrug of 5-fluorouracil (5-FU), were synthesized and tested against pancreatic cancer lines (PDAC). The compounds showed slightly higher efficacy against primary BxPC-3 cells (IC values of 14-45 μM) than against metastatic AsPC-1 (IC values of 37-133 μM), and similar to that of 5-FU for both PDAC lines. Compound 1, which has a -(acetyloxy)coumaroyl substituent, was found to be the most potent (IC = 14 μM) with a selectivity index of approximately 7 to normal dermal fibroblasts (IC = 96 μM). The potential pharmacological profiles were discussed on the basis of the ADME data. Docking to the carboxylesterase CES2 showed that the synthesized compounds have the ability to bind hydrogen bonding between a specific acetate group of the sugar moiety and Ser228, which belongs to the catalytic triad that causes hydrolysis. Docking to albumin, a major transport protein in the circulatory system, revealed a strong interaction of the conjugates at the binding site which is native to warfarin and responsible for its transport in the body.

摘要

合成了羟基肉桂酸（HCA）与5-氟尿嘧啶（5-FU）的前体药物5'-脱氧-5-氟胞苷（5-dFCR）的新型酰胺缀合物1-6，并对胰腺癌细胞系（PDAC）进行了测试。这些化合物对原发性BxPC-3细胞（IC值为14 - 45 μM）的疗效略高于转移性AsPC-1细胞（IC值为37 - 133 μM），且对两种PDAC细胞系的疗效与5-FU相似。具有-(乙酰氧基)香豆酰取代基的化合物1被发现是最有效的（IC = 14 μM），对正常皮肤成纤维细胞的选择性指数约为7（IC = 96 μM）。基于ADME数据讨论了潜在的药理特性。与羧酸酯酶CES2对接显示，合成的化合物能够在糖部分的特定乙酸基团与Ser228之间形成氢键结合，Ser228属于导致水解的催化三联体。与循环系统中的主要转运蛋白白蛋白对接显示，缀合物在华法林的天然结合位点有强烈相互作用，该位点负责其在体内的转运。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/913d/11036175/c70490c348b0/d4ra01683a-f7.jpg
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