title: Design and synthesis of cis-restricted benzimidazole and benzothiazole mimics of combretastatin A-4 as antimitotic agents with apoptosis inducing ability.
abstract: A series of colchicine site binding tubulin inhibitors were designed and synthesized by the modification of the combretastatin A-4 (CA4) pharmacophore. The ring B was replaced by the pharmacologically relevant benzimidazole or benzothiazole scaffolds, and the cis-configuration of the olefinic bond was restricted by the incorporation of a pyridine ring which is envisaged by the structural resemblance to a tubulin inhibitor like E7010. 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 (6c and 6l) demonstrated an antiproliferative effect comparable and superior to that of CA4 (GI50 up to 40nM). 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. The molecular docking studies suggested that the binding of these mimics at the colchicine site of the tubulin is similar to that of combretastatin A-4.
authors: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India.
authors: Md
authors: M
authors: Ashraf
authors: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India; Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, India.
authors: Thokhir B
authors: TB
authors: Shaik
authors: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India.
authors: M Shaheer
authors: MS
authors: Malik
authors: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India.
authors: Riyaz
authors: R
authors: Syed
authors: GVK Biosciences Pvt. Ltd, Plot No 79, IDA, Mallapur, Hyderabad 500076, Andhra Pradesh, India.
authors: Prema L
authors: PL
authors: Mallipeddi
authors: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India.
authors: M V P S Vishnu
authors: MVPSV
authors: Vardhan
authors: Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India. Electronic address: ahmedkamal@iict.res.in.
authors: Ahmed
authors: A
authors: Kamal
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D007150:Immunohistochemistry; D008938:Mitosis / Q000187:drug effects*; D062105:Molecular Docking Simulation; D018716:Molecular Mimicry; D058105:Polymerization; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D052160:Benzothiazoles; D013267:Stilbenes; C058728:fosbretabulin
keywords: Apoptosis; Benzimidazole; Benzothiazole; Combretastatin A-4; Tubulin inhibitor