2. Academic Validation
  3. Synthesis and in vitro cytotoxicity evaluation of β-carboline-combretastatin carboxamides as apoptosis inducing agents: DNA intercalation and topoisomerase-II inhibition

Synthesis and in vitro cytotoxicity evaluation of β-carboline-combretastatin carboxamides as apoptosis inducing agents: DNA intercalation and topoisomerase-II inhibition

  • Bioorg Med Chem. 2019 Aug 1;27(15):3285-3298. doi: 10.1016/j.bmc.2019.06.007.
Chetna Jadala 1,  Manda Sathish 2,  T Srinivasa Reddy 3,  Velma Ganga Reddy 4,  Ramya Tokala 1,  Suresh K Bhargava 3,  Nagula Shankaraiah 5,  Narayana Nagesh 6,  Ahmed Kamal 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
  • 2 Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
  • 3 Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT-University, GPO BOX 2476, Melbourne 3001, Australia.
  • 4 Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT-University, GPO BOX 2476, Melbourne 3001, Australia.
  • 5 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: shankar.niperhyd@gov.in.
  • 6 CSIR-CCMB, Medical Biotechnology Division, Annexure-II, Hyderabad 500007, India. Electronic address: nagesh@ccmb.res.ac.in.
  • 7 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India; Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110 062, India. Electronic address: ahmedkamal@iict.res.in.
PMID: 31227365 DOI: 10.1016/j.bmc.2019.06.007
Abstract

To explore a new set of cytotoxic agents, β-carboline-combretastatin carboxamide conjugates were designed, synthesized and evaluated for their in vitro cytotoxicity potential, DNA binding affinity and Topoisomerase-II (topo-II) inhibition activity. Among the designed hybrids, 10v and 10af have shown significant cytotoxic effect against A549 (lung Cancer) cell line having IC50 value 1.01 µM and 1.17 µM respectively. Further, it was speculated that treatment with compound 10v may induce Apoptosis among A549 cells, which was supported by Hoechst staining, DCFDA, Annexin V-FITC and morphological assays. Flow cytometric analysis revealed that the hybrid 10v arrests A549 cells in G2/M phase of cell cycle in a dose dependent manner. Amongst the active hybrids, most potent hybrid 10v was tested for DNA topo-II inhibition activity. Moreover, to further support the biological activity and to infer the mode of interaction between ligands and DNA, spectroscopy and molecular docking studies were carried out. The docking and spectroscopy results showed that the ligands exhibited an intercalative mode of binding with DNA and could efficiently bind to DNA and form topo-II ternary complex. Based on these experiments, the hybrids 10v and 10af were identified as proficient new scaffolds which need to be developed as hit molecules for therapeutic interest.

Keywords

Combretastatin-A4; Cytotoxicity; DNA binding studies; Molecular modeling; Topoisomerase-II inhibition; β-Carboline.

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