title: Synthesis and biological evaluation of curcumin inspired indole analogues as tubulin polymerization inhibitors.
abstract: In our endeavour towards the development of potent cytotoxic agents, a series of some new curcumin inspired indole analogues, in which indole and phenyl moieties are linked on either sides of 1,5-diaryl-1,4-pentadien-3-one system have been synthesized and characterized by spectral data. All the newly synthesized analogues were tested for their cytotoxic potential against a panel of eight cancer cell lines namely, lung (A549), breast (MDA-MB-231, BT549 and 4T1), prostate (PC-3, DU145), gastric (HGC-27) and cervical (HeLa). Notably, among all the compounds tested, compounds 11c, 11d and 11f showed potent growth inhibition on PC-3 and BT549 with IC50values in the range of 3.12-6.34 μM and 4.69-8.72 μM respectively. The most active compound (11c) was also tested on RWPE-1 (normal prostate) cells and was found to be safe compared to the PC-3 cells. In tubulin polymerization assay, compounds 11c and 11f effectively inhibited microtubule assembly with IC50values of 10.21 ± 0.10 and 8.83 ± 0.06 μM respectively. The results from molecular modelling studies revealed that these compounds bind at the colchicine binding site of the tubulin. Moreover, DAPI and acridine orange/ethidium bromide staining studies indicated that compounds 11c and 11f can induce apoptosis in PC-3 cells. Further flow-cytometry analysis revealed that compound 11c arrests PC-3 cells in G2/M phase of the cell cycle while compound 11f treatment resulted in moderate increase in the G2/M population. Additionally, the treatment by these compounds led to the impairment of mitochondrial membrane potential (DΨm) in PC-3 cells.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
authors.forename: P V
authors.initials: PV
authors.lastname: Sri Ramya
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Angapelly
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
authors.forename: Lalita
authors.initials: L
authors.lastname: Guntuku
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
authors.forename: Chander
authors.initials: C
authors.lastname: Singh Digwal
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
authors.forename: Bathini
authors.initials: B
authors.lastname: Nagendra Babu
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
authors.forename: V G M
authors.initials: VGM
authors.lastname: Naidu
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India. Electronic address: ahmedkamal@iict.res.in.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003474:Curcumin / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008958:Models, Molecular; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007211:Indoles; D014404:Tubulin; D050257:Tubulin Modulators; D003474:Curcumin
keywords: Apoptosis; Cell cycle; Claisen-Schmidt condensation; Curcumin mimics; Cytotoxic; Indole