Identification of gallic acid based glycoconjugates as a novel tubulin polymerization inhibitors

• Published in: Organic & biomolecular chemistry Vol. 14; no. 4; pp. 1338 - 1358
• Main Authors: Upadhyaya, Kapil, Hamidullah, Singh, Kartikey, Arun, Ashutosh, Shukla, Mahendra, Srivastava, Neetika, Ashraf, Raghib, Sharma, Abhisheak, Mahar, Rohit, Shukla, Sanjeev K., Sarkar, Jayanta, Ramachandran, Ravishankar, Lal, Jawahar, Konwar, Rituraj, Tripathi, Rama Pati
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 01.01.2016
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle - drug effects; Cell Proliferation - drug effects; Chemistry; Chemistry, Organic; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Gallic Acid - chemistry; Gallic Acid - pharmacology; Glycoconjugates - chemical synthesis; Glycoconjugates - chemistry; Glycoconjugates - pharmacology; Humans; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - pathology; Mice; Physical Sciences; Polymerization - drug effects; Rats; Reactive Oxygen Species - metabolism; Science & Technology; Structure-Activity Relationship; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tumor Cells, Cultured; CANCER-CELLS; GLYCOSYL AZIDES; APOPTOSIS; IN-VITRO; DESIGN; ANALOGS; CLICK CHEMISTRY; ANTIOXIDANT; AGENTS; RAPID SYNTHESIS
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c5ob02113h

A novel class of gallic acid based glycoconjugates were designed and synthesized as potential anticancer agents. Among all the compounds screened, compound 2a showed potent anticancer activity against breast cancer cells. The latter resulted in tubulin polymerization inhibition and induced G2/M cell cycle arrest, generation of reactive oxygen species, mitochondrial depolarization and subsequent apoptosis in breast cancer cells. In addition, ultraviolet-visible spectroscopy and fluorescence quenching studies of the compound with tubulin confirmed direct interaction of compounds with tubulin. Molecular modeling studies revealed that it binds at the colchicine binding site in tubulin. Further, 2a also exhibited potent in vivo anticancer activity in LA-7 syngeneic rat mammary tumor model. Current data projects its strong candidature to be developed as anticancer agent.