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Design and Synthesis of C3‐Pyrazole/Chalcone‐Linked Beta‐Carboline Hybrids: Antitopoisomerase I, DNA‐Interactive, and Apoptosis‐Inducing Anticancer Agents
Author(s) -
Kamal Ahmed,
Srinivasulu Vunnam,
Nayak V. Lakshma,
Sathish Manda,
Shankaraiah Nagula,
Bagul Chandrakant,
Reddy N. V. Subba,
Rangaraj Nandini,
Nagesh Narayana
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300406
Subject(s) - chalcone , pyrazole , dna , chemistry , stereochemistry , dna fragmentation , moiety , topoisomerase , apoptosis , hybrid , biochemistry , biology , programmed cell death , botany
A series of β‐carboline hybrids bearing a substituted phenyl and a chalcone/( N‐ acetyl)‐pyrazole moiety at the C1 and C3 positions, respectively, was designed, synthesized, and evaluated for anticancer activity. These new hybrid molecules showed significant cytotoxic activity, with IC 50 values ranging from <2.0 μ M to 80 μ M , and the structure–activity relationships (SAR) associated with substitutions at positions 1 and 3 of these hybrids was clearly addressed. Further, induction of apoptosis was confirmed by Annexin V‐FITC, Hoechst staining, and DNA fragmentation analysis. In addition, DNA photocleavage studies proved that two of the hybrids, ( E )‐1‐(furan‐2‐yl)‐3‐(1‐(4‐(trifluoromethyl)phenyl)‐9 H ‐pyrido[3,4‐ b ]indol‐3‐yl)prop‐2‐en‐1‐one ( 7 d ) and 1‐(3‐(furan‐2‐yl)‐5‐(1‐(4‐(trifluoromethyl)phenyl)‐9 H ‐pyrido[3,4‐ b ]indol‐3‐yl)‐4,5‐dihydro‐1 H ‐pyrazol‐1‐yl)ethanone ( 8 d ) could effectively cleave pBR322 plasmid DNA upon irradiation with UV light. Active hybrid 8 d inhibited DNA topoisomerase I activity efficiently and preserved DNA in the supercoiled form. To further corroborate the biological activities, as well as to understand the nature of the interaction of these hybrids with DNA, spectroscopic studies were also performed. Unlike simple β‐carboline alkaloids, the binding mode of these new hybrid molecules with DNA was not similar, and both biophysical as well as molecular docking studies speculated a combilexin‐type of interaction with DNA. Further, an in silico study of these β‐carboline hybrids revealed their drug‐like properties.