DNA-binding affinity and anticancer activity of b-carboline–chalcone conjugates as potential DNA intercalators: Molecular modelling and synthesis Nagula Shankaraiah a,⇑ , K.P. Siraj a , Shalini Nekkanti a , Vunnam Srinivasulu b , Pankaj Sharma a , Kishna Ram Senwar a , Manda Sathish b , M.V.P.S. Vishnuvardhan c , Sistla Ramakrishna c , Chetna Jadala a,b , Narayana Nagesh d , Ahmed Kamal b,⇑ a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India b Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India c Pharmacology Department, Indian Institute of Chemical Technology, Hyderabad 500 607, India d CSIR-Centre for Cellular & Molecular Biology, Hyderabad 500 607, India article info Article history: Received 18 September 2014 Available online 5 March 2015 Keywords: b-Carboline Chalcone Claisen–Schmidt condensation Anticancer activity DNA-binding ability Molecular modelling abstract A new series of DNA-interactive b-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 IC 50 val- ues lower than 10 lM. The hybrid 7b is more effective against some of the selected cancer cell lines with IC 50 values less than 50 lM. In addition, compounds 7e, 7k, 7p–u has displayed significant elevation in DT m of DNA in comparison to Adriamycin, suggesting significant interaction and remarkable DNA stabi- lization. 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. Ó 2015 Elsevier Inc. All rights reserved. 1. Introduction The b-carboline alkaloids possess a tricyclic pyrido[3,4-b]indole ring system and represent a large group of natural and synthetic indole alkaloids. This class of compounds were originally isolated from Peganum harmala and exert their antitumor activity through multiple mechanisms, such as intercalating into DNA [1], inhibiting topoisomerase I and II [2], CDK [3], MAPKAP-K2 [4], MK-2 [5] and kinesin [6]. Intercalation of b-carboline alkaloids into DNA leads to conformational changes in the double helix, which disrupts the normal mechanism of DNA replication, transcription, and repair [7]. Representative member of b-carbolines can induce apoptosis in HepG2 cells, down-regulate the expression of Bcl-2 and up-reg- ulate the expression of the death receptor Fas [8]. DNA-binding studies have revealed that b-carbolines and their derivatives display high selectivity to the G–C base pairs by inter- calation [9]. An important aspect in the design of DNA targeting anticancer drugs is the influence of the structural features of small molecules on their binding characteristics with DNA. The efficacy of DNA-interacting antitumor agents (groove binders, alkylating agents and intercalating agents) depends upon their property of DNA recognition. The antitumor activities of several clinically used drugs including anthracyclines, acridines, and anthraquinones have been attributed to DNA intercalation [10]. The drug discovery for cancer therapy has focused on the development of new DNA intercalating scaffolds like b-carbolines and its derivatives [11].A simple structural alteration of these biologically active scaffolds reinforce the development of new drugs with improved therapeu- tic properties. Previous Structure-Activity Relationship (SAR) analysis revealed that the incorporation of suitable groups at the C1 and C3-positions of the b-carboline nucleus potentiated antitumor activity as well as DNA-binding ability [12]. In recent studies indicating that the b-carboline derivatives with substituted phenyl group at C1-posi- tion and different heterocyclics at C3-position have displayed significant antitumor properties [13]. In addition, some of the b-carboline derivatives with a flexible amino side chain and their dimers, have also been found to possess significant antitumor activity as well as DNA interacting ability [14]. http://dx.doi.org/10.1016/j.bioorg.2015.02.007 0045-2068/Ó 2015 Elsevier Inc. All rights reserved. ⇑ Corresponding authors. Fax: +91 40 23073751 (N. Shankaraiah), +91 40 27193189 (A. Kamal). E-mail addresses: shankar@niperhyd.ac.in (N. Shankaraiah), ahmedkamal@iict. res.in (A. Kamal). Bioorganic Chemistry 59 (2015) 130–139 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg