title: Novel Combretastatin-2-aminoimidazole Analogues as Potent Tubulin Assembly Inhibitors: Exploration of Unique Pharmacophoric Impact of Bridging Skeleton and Aryl Moiety.
abstract: Combretastatin A-4 (CA-4) in phosphate and serine pro-drug forms is under phase II clinical trials. With our interest of discovering CA-4 inspired new chemical entities, a novel series of 4,5-diaryl-2-aminoimidazole analogues of the compound was designed and synthesized by an efficient and diversity feasible route involving atom economical arene C-H bond arylation. Interestingly, four compounds showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, compound 12 inhibited the proliferation of several types of cancer cells much more efficiently than CA-4. It depolymerized microtubules, induced spindle defects, and stalled mitosis in cells. Compound 12 bound to tubulin and inhibited the polymerization of tubulin in vitro. In addition, podophyllotoxin and CA-4 inhibited the binding of compound 12 to tubulin. The distinctive pharmacophoric features of the bridging motif as well as quinoline nucleus were explored. We noted also a valuable quality of compound 12 as a potential probe in characterizing new CA-4 analogues.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Chaudhary
authors.affiliation: IITB-Monash Research Academy, Indian Institute of Technology Bombay , Mumbai 400076, India.
authors.forename: Jubina B
authors.initials: JB
authors.lastname: Venghateri
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Powai, Mumbai 400076, India.
authors.forename: Hemendra P S
authors.initials: HP
authors.lastname: Dhaked
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
authors.forename: Anil S
authors.initials: AS
authors.lastname: Bhoyar
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
authors.forename: Sankar K
authors.initials: SK
authors.lastname: Guchhait
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Powai, Mumbai 400076, India.
authors.forename: Dulal
authors.initials: D
authors.lastname: Panda
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001632:Bibenzyls / Q000737:chemistry*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D001632:Bibenzyls; D007093:Imidazoles; D011355:Prodrugs; D014404:Tubulin; D050257:Tubulin Modulators; C014973:2-aminoimidazole; C040105:combretastatin