5H-benzo[c]fluorene derivative exhibits antiproliferative activity via microtubule destabilization.

Autor: Fatima E; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India., Gautam Y; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Department of Chemistry, Pandit Prithi Nath PG College, 96/12 Mahatma Gandhi Marg, Kanpur 208001, India., Thapa B; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India., Das R; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India., Singh A; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India., Trivedi L; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India., Singh P; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India., Singh K; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India., Bhatt D; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India., Vasudev PG; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India., Gupta A; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India., Chanda D; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India., Bawankule DU; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India., Shanker K; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India., Khan F; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India., Negi AS; CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, U.P. 201002, India. Electronic address: as.negi@cimap.res.in.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Dec; Vol. 153, pp. 107891. Date of Electronic Publication: 2024 Oct 18.
DOI: 10.1016/j.bioorg.2024.107891
Abstrakt: Present study aimed at a single component cyclization of 2-benzylidene-1-tetralones for the preparation of 5H-benzo[c]fluorenes and their antiproliferative activity. This ring closure reaction underwent via reductive cyclization in the presence of a sodium borohydride-aluminium chloride system. Ten diverse 5H-benzo[c]fluorene derivatives were prepared and evaluated for antiproliferative activity against three human cancer cell lines by SRB assay. Four of these benzofluorenes exhibited significant antiproliferative effect with an IC 50  < 10.75 µM. The best representative compound 21, exhibited IC 50 against K562 leukemic cells at 3.27 µM in SRB assay and 7.68 µM in Soft agar colony assay. It exhibited a microtubule destabilization effect in tubulin kinetics and inhibited 82.9 % microtubule polymer mass at 10 µM concentration in Protein Sedimentation assay (Microtubule). Compound 21 exerted G0/G1 phase arrest in cell division cycle analysis in K562 cells. It also induced apoptosis in K562 cells via activation of Caspase cascade pathway. Furthermore, compound 21 also possessed anti-inflammatory activity by inhibiting TNF-α and IL-6 moderately. It exhibited significant in vivo efficacy and reduced K562 tumour in xenograft mice by 47 % at an 80 mg/kg oral dose. Further, it was found to be safe and well tolerable up to 1000 mg/kg in Swiss albino mice. Compound 21 needs to be optimized for better in vivo efficacy in rodent models for further development.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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