Design, synthesis, and biological evaluation of novel 2,3-Di-O-Aryl/Alkyl sulfonate derivatives of l-ascorbic acid: Efficient access to novel anticancer agents via in vitro screening, tubulin polymerization inhibition, molecular docking study and ADME predictions

• Published in: Bioorganic chemistry 2024-06, Vol.147, p.107402-107402, Article 107402
• Main Authors: Deshmukh, Santosh R., Nalkar, Archana S., Sarkate, Aniket P., Tiwari, Shailee V., Lokwani, Deepak K., Thopate, Shankar R.
• Format: Article
• Language: English
• Subjects: ADMET study; Anti-cancer agent; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Ascorbic Acid - chemistry; Ascorbic Acid - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Colchicine; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; l-Ascorbic acid; Molecular docking; Molecular Docking Simulation; Molecular Structure; Polymerization - drug effects; Structure-Activity Relationship; Sulfonic Acids - antagonists & inhibitors; Sulfonic Acids - chemistry; Sulfonic Acids - pharmacology; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tubulin Polymerization Inhibition
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107402

[Display omitted] •A series of novel 2,3-di-O- and 3-O-sulfonate derivatives of 5,6-O-isopropylidene-l-ascorbic acid were synthesized, characterized, and evaluated for their anticancer activity.•Compounds 2b and 2c exhibited potent anticancer activity against MCF-7 (IC50 = 0.04 μM and 0.81 μM, respectively) and A-549 (IC50 = 0.1 μM and 0.9 μM, respectively) cancer cell lines. Notably, compound 2b displayed 89-fold selectivity for MCF-7 breast cancer over MCF-10A normal breast cells.•Compounds 2b and 2c exhibited remarkable inhibition of tubulin polymerization, with 73.12 % and 62.09 % inhibition, respectively, against A-549 lung cancer cells.•Molecular docking results revealed that all compounds were bound into the hydrophobic pocket of tubulin consisting of amino acid residues, and the interactions, pocket fit, and binding affinity resulted in higher docking scores compared to Colchicine.•In-silico ADMET predictions indicated favorable drug-like properties, with 2b exhibiting the highest binding affinity. A series of novel l-ascorbic acid derivatives bearing aryl and alkyl sulfonate substituents were synthesized and characterized. In vitro anticancer evaluation against MCF-7 (breast) and A-549 (lung) cancer cell lines revealed potent activity for most of the compounds, with 2b being equipotent to the standard drug colchicine against MCF-7 (IC50 = 0.04 μM). Notably, compound 2b displayed 89-fold selectivity for MCF-7 breast cancer over MCF-10A normal breast cells. Derivatives with two sulfonate groups (2a-g, 3a-g) exhibited superior potency over those with one sulfonate (4a-c,5g, 6b). Compounds 2b and 2c potently inhibited tubulin polymerization in A-549 cancer cells (73.12 % and 62.09 % inhibition, respectively), substantiating their anticancer potential through microtubule disruption. Molecular docking studies showed higher binding scores and affinities for these compounds at the colchicine-binding site of α, β-tubulin compared to colchicine itself. In-silico ADMET predictions indicated favourable drug-like properties, with 2b exhibiting the highest binding affinity. These sulfonate derivatives of l-ascorbic acid represents promising lead scaffolds for anticancer drug development.