Abstract
Novel 1,1-diaryl vinyl-sulfones analogues of combretastatin CA-4 were synthesized via Suzuki–Miyaura coupling method and screened for in-vitro antiproliferative activity against four human cancer cell lines: MDA-MB 231(breast cancer), HeLa (cervical cancer), A549 (lung cancer), and IMR-32 (neuroblast cancer), along with a normal cell line HEK-293 (human embryonic kidney cell) by employing 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The compounds synthesised had better cytotoxicity against the A549 and IMR-32 cell lines compared to HeLa and MDA-MB-231 cell lines. The synthesized compounds also showed significant activity on MDA-MB-231 cancer cell line with IC50 of 9.85–23.94 µM, and on HeLa cancer cell line with IC50 of 8.39–11.70 µM relative to doxorubicin having IC50 values 0.89 and 1.68 µM respectively for MDA-MB-231 and HeLa cell lines. All the synthesized compounds were not toxic to the growth of normal cells, HEK-293. They appear to have a higher binding affinity for the target protein, tubulin, PDB ID = 5LYJ (beta chain), relative to the reference compounds, CA4 (− 7.1 kcal/mol) and doxorubicin (− 7.2 kcal/mol) except for 4E, 4M, 4N and 4O. The high binding affinity for beta-tubulin did not translate into enhanced cytotoxicity but the compounds (4G, 4I, 4J, 4M, 4N, and 4R, all having halogen substituents) that have a higher cell permeability (as predicted in-silico) demonstrated an optimum cytotoxicity against the tested cell lines in an almost uniform manner for all tested cell lines. The in-silico study provided insight into the role that cell permeability plays in enhancing the cytotoxicity of this class of compounds and as potential antiproliferative agents.
Highlights
IntroductionNovel 1,1-diaryl vinyl-sulfones analogues of combretastatin Combretastatin A-4 (CA-4) were synthesized via Suzuki– Miyaura coupling method and screened for in-vitro antiproliferative activity against four human cancer cell lines: MDA-MB 231(breast cancer), HeLa (cervical cancer), A549 (lung cancer), and IMR-32 (neuroblast cancer), along with a normal cell line HEK-293 (human embryonic kidney cell) by employing 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay
Novel 1,1-diaryl vinyl-sulfones analogues of combretastatin Combretastatin A-4 (CA-4) were synthesized via Suzuki– Miyaura coupling method and screened for in-vitro antiproliferative activity against four human cancer cell lines: MDA-MB 231(breast cancer), HeLa, A549, and IMR-32, along with a normal cell line HEK-293 by employing 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay
A vast variety of drugs are able to bind to tubulin and modify its assembly properties, e.g. colchicine, vincristine, combretastatin, etc
Summary
Novel 1,1-diaryl vinyl-sulfones analogues of combretastatin CA-4 were synthesized via Suzuki– Miyaura coupling method and screened for in-vitro antiproliferative activity against four human cancer cell lines: MDA-MB 231(breast cancer), HeLa (cervical cancer), A549 (lung cancer), and IMR-32 (neuroblast cancer), along with a normal cell line HEK-293 (human embryonic kidney cell) by employing 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. All the synthesized compounds were not toxic to the growth of normal cells, HEK-293 They appear to have a higher binding affinity for the target protein, tubulin, PDB ID = 5LYJ (beta chain), relative to the reference compounds, CA4 (− 7.1 kcal/mol) and doxorubicin (− 7.2 kcal/ mol) except for 4E, 4M, 4N and 4O. The in-silico study provided insight into the role that cell permeability plays in enhancing the cytotoxicity of this class of compounds and as potential antiproliferative agents. Its occurrence annually and globally is in millions, especially in developed countries, resulting to well over 5 million mortality rates a nnually[2] This has necessitated the drive to find a lasting solution from both synthetic compounds[3–5] and several other therapeutic medicinal agents inspired from plants or aquatic organisms[6–11] to arrest the situation (Fig. 1a). To enhance the cytotoxicity of these isolates, a di-aromatic ring separated through a C=C bond along with a 3-OCH3 in one of the rings is essential (Fig. 1c)[27–29]
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