The conjugates of 5'-deoxy-5-fluorocytidine and hydroxycinnamic acids - synthesis, anti-pancreatic cancer activity and molecular docking studies.
Marcin CybulskiMagdalena Zaremba-CzogallaBartosz TrzaskowskiMarek KubiszewskiJoanna TobiaszAnna JarominPiotr KrzeczyńskiJerzy GubernatorOlga MichalakPublished in: RSC advances (2024)
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.
Keyphrases
- molecular docking
- molecular dynamics simulations
- cancer therapy
- protein protein
- molecular dynamics
- induced apoptosis
- squamous cell carcinoma
- cell cycle arrest
- small cell lung cancer
- small molecule
- atrial fibrillation
- single cell
- drug delivery
- venous thromboembolism
- electronic health record
- binding protein
- extracorporeal membrane oxygenation
- direct oral anticoagulants
- cell proliferation
- cell death
- amino acid
- case control
- signaling pathway
- data analysis
- wound healing
- crystal structure