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

  • Bioorg Chem. 2024 Dec:153:107891. doi: 10.1016/j.bioorg.2024.107891.
Eram Fatima  1 ,  Yashveer Gautam  2 ,  Barsha Thapa  3 ,  Ranjana Das  3 ,  Amrita Singh  1 ,  Laxmikant Trivedi  1 ,  Palak Singh  1 ,  Kavita Singh  3 ,  Divya Bhatt  1 ,  Prema G Vasudev  1 ,  Atul Gupta  1 ,  Debabrata Chanda  1 ,  Dnyaneshwar U Bawankule  1 ,  Karuna Shanker  1 ,  Feroz Khan  1 ,  Arvind S Negi  4
Affiliations
  • 1. 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.
  • 2. 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.
  • 3. CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226015, India.
  • 4. 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: [email protected].
PMID: 39454495 DOI: 10.1016/j.bioorg.2024.107891
Abstract

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 IC50 < 10.75 µM. The best representative compound 21, exhibited IC50 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.

Keywords
Acute oral toxicity; Anticancer; Benzofluorenes; Microtubule destabilization; Reductive cyclization.
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