DNA-binding affinity and anticancer activity of β-carboline-chalcone conjugates as potential DNA intercalators: Molecular modelling and synthesis

Nagula Shankaraiah; K P Siraj; Shalini Nekkanti; Vunnam Srinivasulu; Pankaj Sharma; Kishna Ram Senwar; Manda Sathish; M V P S Vishnuvardhan; Sistla Ramakrishna; Chetna Jadala; Narayana Nagesh; Ahmed Kamal

doi:10.1016/j.bioorg.2015.02.007

DNA-binding affinity and anticancer activity of β-carboline-chalcone conjugates as potential DNA intercalators: Molecular modelling and synthesis

Bioorg Chem. 2015 Apr:59:130-9. doi: 10.1016/j.bioorg.2015.02.007. Epub 2015 Mar 5.

Affiliations

¹ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: shankar@niperhyd.ac.in.
² Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
³ Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India.
⁴ Pharmacology Department, Indian Institute of Chemical Technology, Hyderabad 500 607, India.
⁵ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India; Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India.
⁶ CSIR-Centre for Cellular & Molecular Biology, Hyderabad 500 607, India.
⁷ Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India. Electronic address: ahmedkamal@iict.res.in.

PMID: 25771335
DOI: 10.1016/j.bioorg.2015.02.007

Abstract

A new series of DNA-interactive β-carboline-chalcone conjugates have been synthesized and evaluated for their in vitro cytotoxicity and DNA-binding affinity. It has been observed that most of these new hybrids have shown potent cytotoxic activities on A-549 (lung adenocarcinoma) cell lines with IC50 values lower than 10 μM. The hybrid 7b is more effective against some of the selected cancer cell lines with IC50 values less than 50 μM. In addition, compounds 7e, 7k, 7p-u has displayed significant elevation in ΔTm of DNA in comparison to Adriamycin, suggesting significant interaction and remarkable DNA stabilization. The DNA intercalation of these new hybrids has been investigated by fluorescence titration, DNA viscosity measurements, molecular docking as well as molecular dynamics and the results are in agreement with the thermal denaturation studies.

Keywords: Anticancer activity; Chalcone; Claisen–Schmidt condensation; DNA-binding ability; Molecular modelling; β-Carboline.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Carbolines / chemistry*
Carbolines / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Chalcone / chemistry*
Chalcone / pharmacology*
DNA / metabolism
Drug Screening Assays, Antitumor
Humans
Intercalating Agents / chemistry
Intercalating Agents / pharmacology
Models, Molecular
Neoplasms / drug therapy
Structure-Activity Relationship

Substances

Antineoplastic Agents
Carbolines
Intercalating Agents
Chalcone
DNA