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

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 in vitro against pancreatic cancer lines (PDAC). The compounds showed slightly higher efficacy against primary BxPC-3 cells (IC 50 values...

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Bibliographic Details
Published in:RSC advances 2024-04, Vol.14 (19), p.13129-13141
Main Authors: Cybulski, Marcin, Zaremba-Czogalla, Magdalena, Trzaskowski, Bartosz, Kubiszewski, Marek, Tobiasz, Joanna, Jaromin, Anna, Krzeczy ski, Piotr, Gubernator, Jerzy, Michalak, Olga
Format: Article
Language:English
Subjects:
Binding sites
Cancer
Chemical synthesis
Chemistry
Circulatory system
Conjugates
Hydrogen bonding
Hydroxycinnamic acid
Molecular docking
Pancreatic cancer
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Summary: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 in vitro against pancreatic cancer lines (PDAC). The compounds showed slightly higher efficacy against primary BxPC-3 cells (IC 50 values of 14-45 μM) than against metastatic AsPC-1 (IC 50 values of 37-133 μM), and similar to that of 5-FU for both PDAC lines. Compound 1 , which has a para -(acetyloxy)coumaroyl substituent, was found to be the most potent (IC 50 = 14 μM) with a selectivity index of approximately 7 to normal dermal fibroblasts (IC 50 = 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 via 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. New conjugates 1-6 containing 5-dFCR and selected hydroxycinnamic acids were synthesized and tested in vitro against pancreatic cancer (PDAC) lines. The ADME properties and molecular docking to CES2 or human albumin were discussed.
ISSN:2046-2069
2046-2069
DOI:10.1039/d4ra01683a