Synthesis and biological evaluation of curcumin inspired imidazo[1,2-a]pyridine analogues as tubulin polymerization inhibitors

• Published in: European journal of medicinal chemistry Vol. 143; pp. 216 - 231
• Main Authors: Ramya, P.V. Sri, Guntuku, Lalita, Angapelly, Srinivas, Digwal, Chander Singh, Lakshmi, Uppu Jaya, Sigalapalli, Dilep Kumar, Babu, Bathini Nagendra, Naidu, V.G.M., Kamal, Ahmed
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.01.2018; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Cell Proliferation - drug effects; Chemistry, Medicinal; Claisen-Schmidt condensation; Curcumin - chemistry; Curcumin - pharmacology; Curcumin inspired analogues; Cytotoxic; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Imidazo[1,2-a]pyridine; Life Sciences & Biomedicine; Molecular Docking Simulation; Molecular Structure; Pharmacology & Pharmacy; Polymerization - drug effects; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Science & Technology; Structure-Activity Relationship; Tubulin - metabolism; Tumor Cells, Cultured; Curcumin inspired analogues; Claisen-Schmidt condensation; Cytotoxic; Imidazo[1,2-a]pyridine; Apoptosis; ANTIOXIDANT ACTIVITY; CANCER-CELLS; DESIGN; MOLECULAR DOCKING; ANTITUMOR; DISCOVERY; POTENTIAL ANTICANCER AGENTS; ANTIINFLAMMATORY ACTIVITIES; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.11.010

With an aim to develop new curcumin inspired analogues as potent anticancer agents, we synthesized a series of (1E,4E)-1-phenyl-5-(3-phenylimidazo[1,2-a]pyridin-2-yl)penta-1,4-dien-3-ones (12a–t) as tubulin polymerization inhibitors. An initial screening was carried out to evaluate their cytotoxic potential on a panel of six cancer cell lines namely, cervical (HeLa), gastric (HGC-27), lung (NCI-H460), prostate (DU-145 and PC-3) and breast (4T1), using MTT assay. Among the compounds tested, compounds 12e, 12r and 12t showed potent growth inhibition and 12t {(1E,4E)-1-(3-(3,4-difluorophenyl)imidazo[1,2-a]pyridin-2-yl)-5-(2,4,6-trimethoxyphenyl)penta-1,4-dien-3-one} being the most active member of the series inhibited the growth of all the tested cell lines with IC50 values varying from 1.7 – 2.97 μM. Moreover, 12t showed promising cytotoxicity on PC-3, HGC-27 and HeLa cell lines with IC50 values of 2.11 ± 0.27 μM, 2.21 ± 0.25 μM and 2.53 ± 0.01 μM respectively. The results from aqueous solubility test showed that compounds 12e and 12t have 1.7 and 2.8 times more aqueous solubility than curcumin. Interestingly, the most active compound 12t was found to be nearly 2 times more selective on PC-3 cells as well as safe on normal human prostate (RWPE-1) cells. In addition, compound 12t efficiently inhibited tubulin polymerization with IC50 value of 8.44 ± 0.13 μM and molecular modelling studies disclosed that 12t binds at the colchicine binding site of the tubulin. Cell cycle analysis revealed that 12t arrests PC-3 cells in G2/M phase in a dose dependant manner. Further, treatment of PC-3 cells with 12t showed typical apoptotic morphology, also led to the impairment of mitochondrial membrane potential (DΨm) and increased levels of reactive oxygen species (ROS). Altogether, the results from acridine orange/ethidium bromide (AO-EB) and DAPI staining studies, annexin V-FITC/propidium iodide staining assay, analysis of mitochondrial membrane potential (DΨm) and reactive oxygen species (ROS) levels undoubtedly demonstrated the induction of apoptosis in PC-3 cells by compound 12t. [Display omitted] •New series of curcumin inspired imidazo[1,2-a]pyridine analogues were synthesized.•Anticancer activity was tested on six cancer cell lines and one normal cell line.•Compound 12t effectively inhibited polymerization of tubulin in a cell-free assay.•12t induced apoptosis and cell cycle arrest in G2/M phase in PC-3 cells.•12t was almost 2 times more selective on PC-3 cells compared to RWPE-1 cells.