Heteroaryl-Capped Hydroxamic Acid Derivatives with Varied Linkers: Synthesis and Anticancer Evaluation with Various...

Area of Science:

• Medicinal Chemistry
• Oncology
• Computational Chemistry

Background:

• Cancer presents significant therapeutic challenges due to a lack of targeted treatments and high recurrence rates.
• Existing therapies often lack specificity, leading to side effects and limited efficacy.
• Structural modification of known pharmacophores, like vorinostat, offers a strategy for developing novel anticancer agents.

Purpose of the Study:

• To synthesize and evaluate a new series of hydroxamate analogs based on the 2H-1,2,3-triazole scaffold.
• To investigate the anticancer potential of these compounds, with a specific focus on their efficacy against breast cancer.
• To elucidate the molecular mechanisms underlying the observed anticancer effects and assess their binding interactions with target proteins.

Main Methods:

• Synthesis of 15 novel 2H-1,2,3-triazole-based hydroxamide analogs.
• In vitro evaluation of antiproliferative and cytotoxic activities using GI50 and MTT assays against various cancer cell lines (MCF-7, A-549, MDA-MB-231) and a normal cell line (HEK-293).
• Mechanistic studies including apoptosis assays (Annexin V/PI), cell cycle analysis, ROS generation assays, HDAC inhibition assays, molecular docking, molecular dynamics simulations, DFT, and ADMET screening.

Main Results:

• Compound VI(i) exhibited significant antiproliferative activity (GI50 < 10 μg/mL) against MCF-7 and A-549 cells.
• VI(i) demonstrated potent cytotoxicity against breast cancer cell line MDA-MB-231 and MCF-7 (IC50 = 60 µg/mL), with minimal toxicity to normal HEK-293 cells.
• Mechanistic investigations revealed that VI(i) induces apoptosis, causes cell cycle arrest at S and G2/M phases, promotes ROS generation, and exhibits strong binding affinity to HDAC 1 and 6 isoforms.

Conclusions:

• The synthesized hydroxamate analogs, particularly compound VI(i), show promising anticancer properties, especially against breast cancer.
• Compound VI(i) acts through a dual mechanism involving apoptosis induction and cell cycle arrest, coupled with ROS generation.
• The in silico and in vitro data strongly support VI(i) as a potential lead candidate for targeted cancer therapy development.