The Conjugates of 5'-deoxy-5-fluorocytidine and Hydroxycinnamic Acids - Synthesis, Anti-pancreatic Cancer Activity and Molecular Docking Studies

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2024 Apr 24

PMID 38655481

Authors

Marcin Cybulski

Magdalena Zaremba-Czogalla

Bartosz Trzaskowski

Marek Kubiszewski

Joanna Tobiasz

Anna Jaromin

Piotr Krzeczynski

Jerzy Gubernator

Olga Michalak

Affiliations

Soon will be listed here.

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.

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