title: Synthesis and biological evaluation of cis-restricted triazole/tetrazole mimics of combretastatin-benzothiazole hybrids as tubulin polymerization inhibitors and apoptosis inducers.
abstract: A series of colchicine site binding tubulin inhibitors were synthesized by the modification of the combretastatin pharmacophore. The ring B was replaced by the pharmacologically relevant benzothiazole scaffolds, and the cis configuration of the olefinic bond was restricted by the incorporation of a triazole and tetrazole rings which is envisaged by the structural resemblance to a tubulin inhibitor like combretastatin (CA-4). These compounds were evaluated for their antiproliferative activity on selected cancer cell lines and an insight in the structure activity relationship was developed. The most potent compounds (9a and 9b) demonstrated an antiproliferative effect comparable to that of CA-4. Mitotic cell cycle arrest in G2/M phase revealed the disruption of microtubule dynamics that was confirmed by tubulin polymerization assays and immunocytochemistry studies at the cellular level. Western blot analysis revealed that these compounds accumulate more tubulin in the soluble fraction. The colchicine competitive binding assay and the molecular docking studies suggested that the binding of these mimics at the colchicine site of the tubulin is similar to that of CA-4. Moreover, the triggering of apoptotic cell death after mitotic arrest was investigated by studying their effect by Hoechst staining, Annexin-V-FITC assay, mitochondrial membrane potential, ROS generation and caspase-3 activation.
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: A V
authors.initials: AV
authors.lastname: Subba Rao
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad 500 037, India.
authors.forename: Konderu
authors.initials: K
authors.lastname: Swapna
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: Siddiq Pasha
authors.initials: SP
authors.lastname: Shaik
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: V
authors.initials: V
authors.lastname: Lakshma Nayak
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad 500 037, India.
authors.forename: T
authors.initials: T
authors.lastname: Srinivasa Reddy
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: Satish
authors.initials: S
authors.lastname: Sunkari
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors.forename: Thokhir Basha
authors.initials: TB
authors.lastname: Shaik
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad 500 037, India.
authors.forename: Chandrakant
authors.initials: C
authors.lastname: Bagul
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad 500 037, India.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D058105:Polymerization / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D001632:Bibenzyls; D013777:Tetrazoles; D014230:Triazoles; D014404:Tubulin; C040105:combretastatin; C005465:benzothiazole
keywords: Antiproliferative activity; Apoptosis; Benzothiazole; Colchicine competition assay; Combretastatin A-4; Triazoles and tetrazoles; Tubulin polymerization