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.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Ashraf M,Shaik TB,Malik MS,Syed R,Mallipeddi PL,Vardhan MVPSV,Kamal Adoi
10.1016/j.bmcl.2016.06.044subject
Has Abstractpub_date
2016-09-15 00:00:00pages
4527-4535issue
18eissn
0960-894Xissn
1464-3405pii
S0960-894X(16)30655-2journal_volume
26pub_type
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