Exploring novel capping framework: high substituent pyridine-hydroxamic acid derivatives as potential
Fernando Hernández-Borja1, Itzel Mercado-Sánchez1, Yolanda Alcaraz2
1Departamento de Química, Universidad de Guanajuato, Guanajuato, Gto, 36050, México.
Summary
Novel pyridine compounds were synthesized and tested as anticancer agents. Compounds 15j and 15k demonstrated significant antiproliferative activity against breast and prostate cancer cells by modulating key gene expressions.
Area of Science:
- Medicinal Chemistry
- Epigenetics
- Cancer Biology
Background:
- Histone deacetylases (HDACs) are crucial for epigenetic regulation and are overexpressed in various cancers, making them a promising drug target.
- Inhibitors of HDACs are actively researched, with the capping group being critical for biological activity through interactions at the active site entrance.
Purpose of the Study:
- To synthesize novel pyridine derivatives with high substitution.
- To evaluate the antiproliferative activity of these compounds against cancer cell lines.
- To investigate the binding interactions of these compounds with HDAC isoforms using docking studies.
Main Methods:
- Synthesis of pyridine derivatives (15a-k) through a four-step reaction.
- Assessment of antiproliferative effects using the sulphorhodamine B (SRB) assay.
- Quantitative real-time PCR to analyze gene expression of p21, cyclin D1, and p53.
- Molecular docking simulations with HDAC1, HDAC6, and HDAC8 isoforms.
Main Results:
- Compounds 15j (2-thiophene pyridine) and 15k (2-furan pyridine) exhibited potent antiproliferative activity against breast and prostate cancer cell lines at 10 µM.
- These active compounds modulated gene expression by increasing p21 mRNA and decreasing cyclin D1 and p53 expression.
- Docking studies revealed enhanced interactions (van der Waals, π-stacking, hydrogen bonds) of the capping moiety in compounds 15j and 15k compared to SAHA.
Conclusions:
- The synthesized pyridine derivatives, particularly 15j and 15k, effectively inhibit cancer cell growth and regulate cell cycle-related genes in highly metastatic cancer cell lines.
- Molecular docking confirmed that the capping groups of 15j and 15k form stronger interactions with HDAC1, HDAC6, and HDAC8, correlating with their observed biological activity.
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