Chalcone based azacarboline analogues as novel antitubulin agents

Design, synthesis, biological evaluation and molecular modelling studies

Sahil Sharma, Charanjit Kaur, Abhishek Budhiraja, Kunal Nepali, Manish K. Gupta, A. K. Saxena, P. M.S. Bedi

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The present study involves the design of a series of 3-aryl-9-acetyl- pyridazino[3,4-b]indoles as constrained chalcone analogues. A retrosynthetic route was proposed for the synthesis of target compounds. All the synthesized compounds were evaluated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. The results indicated that 2a, 3a, 5a and 6a possessed significant cytotoxic potential with an IC50 value ranging from 1.13 to 5.76 μM. Structure activity relationship revealed that the nature of both Ring A and Ring B influences the activity. Substitution of methoxy groups on the phenyl ring (Ring A) and unsubstituted phenyl ring (Ring B) were found to be the preferred structural features. The most potent compound 2a was further tested for tubulin inhibition. Compound 2a was found to significantly inhibit the tubulin polymerization (IC50 value - 2.41 μM against THP-1). Compound 2a also caused disruption of microtubule assembly as evidenced by Immunoflourescence technique. The significant cytotoxicity and tubulin inhibition by 2a was rationalized by molecular modelling studies. The most potent structure was docked at colchicine binding site (PDB ID-1SA0) and was found to be stabilized in the cavity via various hydrophobic and hydrogen bonding interactions.

Original languageEnglish
Pages (from-to)648-660
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume85
DOIs
Publication statusPublished - Oct 6 2014
Externally publishedYes

Fingerprint

Chalcone
Molecular modeling
Tubulin
Cytotoxicity
Inhibitory Concentration 50
Indoles
Colchicine
Hydrogen Bonding
Structure-Activity Relationship
Microtubules
Polymerization
Hydrogen bonds
Substitution reactions
Binding Sites
Cells
Cell Line
Neoplasms

Keywords

  • Carboline
  • Cell line
  • Chalcone
  • Constrained
  • Cytotoxic
  • Molecular modelling studies
  • Tubulin

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Chalcone based azacarboline analogues as novel antitubulin agents : Design, synthesis, biological evaluation and molecular modelling studies. / Sharma, Sahil; Kaur, Charanjit; Budhiraja, Abhishek; Nepali, Kunal; Gupta, Manish K.; Saxena, A. K.; Bedi, P. M.S.

In: European Journal of Medicinal Chemistry, Vol. 85, 06.10.2014, p. 648-660.

Research output: Contribution to journalArticle

Sharma, Sahil ; Kaur, Charanjit ; Budhiraja, Abhishek ; Nepali, Kunal ; Gupta, Manish K. ; Saxena, A. K. ; Bedi, P. M.S. / Chalcone based azacarboline analogues as novel antitubulin agents : Design, synthesis, biological evaluation and molecular modelling studies. In: European Journal of Medicinal Chemistry. 2014 ; Vol. 85. pp. 648-660.
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