Elangovan Manivannan

Advances in Chalcones with Anticancer Activities

Chalcones are naturally occurring compounds exhibiting broad spectrum biological activities including anticancer activity through multiple mechanisms. Literature on anticancer chalcones highlights the employment of three pronged strategies, namely; structural manipulation of both aryl rings, replacement of aryl rings with heteroaryl scaffolds, molecular hybridization through conjugation with other pharmacologically interesting scaffolds for enhancement of anticancer properties. Methoxy substitutions on both the aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings appear to influence anticancer and other activities. Similarly, heterocyclic rings either as ring A or B in chalcones, also influence the anticancer activity shown by this class of compounds. Hybrid chalcones formulated by chemically linking chalcones to other prominent anticancer scaffolds such as pyrrol[2,1-c][1,4]benzodiazepines, benzothiazoles, imidazolones have demonstrated synergistic or additive pharmacological activities. The successful application of these three pronged strategies for discovering novel anticancer agents based on chalcone scaffold has resulted in many novel and chemically diverse chalcones with potential therapeutic application for many types of cancer. This review summarizes the concerted efforts expended on the design and development of anticancer chalcones recorded in recent literature and also provides an overview of the patents published in this area between 2007 and 2014 (WO2013022951, WO201201745 & US2012029489).

Quantitative structure–activity relationship analysis of 2,3-diaryl indoles as selective cyclooxygenase-2 inhibitors

Quantitative structure–activity relationship (QSAR) studies have been performed on a combined series of 2-sulfonylphenyl-3-phenyl-indoles and 2-phenyl-3-sulfonylphenyl-indoles with a common 2,3 vicinal diaryl indole scaffold, recently reported as selective COX-2 inhibitors. This study is aimed to throw light on this, special class of diaryl heterocyclic family of selective COX-2 inhibitors. A preliminary Fujita-Ban analysis on 32 compounds provided valuable insights about the role of different substituents R1 and R2 around the 2,3 vicinal diaryl rings and R3, at position-5 of the central indole moiety in explaining their in vitro COX-2 inhibitory activity. The contribution of R1, R2, R3 towards COX-2 inhibitory activity resulted in statistically significant linear multiple regression equation with r = 0.942, r2 = 0.888, s = 0.532 and F = 7.92, q2 = 0.516 for 29 compounds. Fujita-Ban model shows a negative contribution of SO2NH2 and SO2CH3 at the R1 position; a negative contribution of 4-Cl, 2-Cl, 3-Cl, 3-CH3, 4-SO2CH3, 4-Br and a positive contribution of 4-OCH3, 4-CH3 substituents at the R2 position. At the R3 position a negative contribution of F, Br and a positive contribution of Cl, CH3 is encountered. In the light of our preliminary investigation that electron donating groups at the para position of R2 are conducive for COX-2 inhibitory activity from the Fujita-Ban model, we attempted to correlate the COX-2 inhibitory activity with quantum chemical descriptors of semi-empirical AM1 optimized geometries of the title compounds. Correlation analysis showed the molecular electronic descriptor, MOPAC total energy as crucial in governing COX-2 inhibitory activity of all the reported 41 compounds.

HM015k, a Novel Silybin Derivative, Multi-Targets Metastatic Ovarian Cancer Cells and Is Safe in Zebrafish Toxicity Studies

This study was designed to determine the in vitro mechanisms by which the novel silybin derivative, (E)-3-(3-(benzyloxy) phenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one (HM015k or 15k), produces its anticancer efficacy in ovarian cancer cells. Compound 15k induced apoptosis in ovarian cancer cells in a time-dependent manner by significantly upregulating the expression of Bax and Bak and downregulating the expression of Bcl-2. Interestingly, 15k induced the cleavage of Bax p21 into its more efficacious cleaved form, Bax p18. In addition, caspase 3 and caspase 9 were cleaved to their active forms, inducing the cleavage of poly ADP ribose polymerase (PARP) and β-catenin. Furthermore, in OV2008 cells, 15k induced significant cleavage in nuclear β-catenin to primarily inactive fragments of lower molecular weight. Furthermore, 15k reversed the metastatic potential of OV2008 cells by inhibiting their migration and invasiveness. The mesenchymal phenotype in OV2008 was reversed by 15k, causing cells to be rounder with epithelial—like phenotypes. The 15k-induced reversal was further confirmed by significant upregulation of the E-cadherin expression, an epithelial marker, while N-cadherin, a mesenchymal marker, was downregulated in OV2008 cells. Compound 15k inhibited the expression of the oncogenic c-Myc protein, downregulated proteins DVL3 and DVL2 and significantly upregulated cyclin B1. Also, 15k significantly downregulated the expression levels of ABCG2 and ABCB1 transporters in resistant ABCG2 overexpressing H460/MX20 and resistant ABCB1 overexpressing MDCK/MDR1 cells, respectively. Finally, 15k was safe in zebrafish in vivo model at concentrations up to 10 μM and induced no major toxicities in cardiac, morphology and swimming position parameters. Overall, 15k is a multi-targeted inhibitor with efficacy against metastatic and resistant ovarian cancer. Future in vivo studies will be conducted to determine the efficacy of 15k in tumor-bearing animals.

Analysis of surface area features of structurally diverse molecules for Bcr/Abl kinase inhibitory activity and antiproliferative activity

In the present investigation, structurally different compounds possessing Bcr/Abl kinase inhibitory activity and antiproliferative activity against K562 cell lines were used for the structural analysis. The significant QSAR models developed were validated by internal and external validation techniques. The contributed descriptors explain that the hydrophobic and polar properties on the van der Waals surface of the molecules determine the activities of the molecules. The correlations developed between the TPSA, logP and activities showed that the compounds have increased TPSA values possessed better Bcr/Abl kinase inhibitory activity, while those compounds have moderate logP values. Higher logP values containing compounds have less Bcr/Abl kinase inhibitory activity and moderate antiproliferative activity on K562 cancer cell lines.

Bax/Tubulin/Epithelial-Mesenchymal Pathways Determine the Efficacy of Silybin Analog HM015k in Colorectal Cancer Cell Growth and Metastasis

The inhibition of apoptosis, disruption of cellular microtubule dynamics, and over-activation of the epithelial mesenchymal transition (EMT), are involved in the progression, metastasis, and resistance of colorectal cancer (CRC) to chemotherapy. Therefore, the design of a molecule that can target these pathways could be an effective strategy to reverse CRC progression and metastasis. In this study, twelve novel silybin derivatives, HM015a-HM015k (15a−15k) and compound 17, were screened for cytotoxicity in CRC cell lines. Compounds HM015j and HM015k (15k and 15j) significantly decreased cell proliferation, inhibited colony formation, and produced cell cycle arrest in CRC cells. Furthermore, 15k significantly induced the formation of reactive oxygen species and apoptosis. It induced the cleavage of the intrinsic apoptotic protein (Bax p21) to its more efficacious fragment, p18. Compound 15k also inhibited tubulin expression and disrupted its structure. Compound 15k significantly decreased metastatic LOVO cell migration and invasion. Furthermore, 15k reversed mesenchymal morphology in HCT116 and LOVO cells. Additionally, 15k significantly inhibited the expression of the mesenchymal marker N-cadherin and upregulated the expression of the epithelial marker, E-cadherin. Compound 15k inhibited the expression of key proteins known to induce EMT (i.e., DVL3, β-catenin, c-Myc) and upregulated the anti-metastatic protein, cyclin B1. Overall, in vitro, 15k significantly inhibited CRC progression and metastasis by inhibiting apoptosis, tubulin activity and the EMT pathways. Overall, these data suggest that compound 15k should be tested in vivo in a CRC animal model for further development.

Abstract 2238: Novel sylibin analogues target ovarian cancer EMT-Wnt/β-catenin resistance pathways

Ovarian cancer (OC) is one of most lethal malignancies in woman reproductive tract. The OC diagnosed in advanced stage (III-IV) patients is highly aggressive and relapses back in over 80% patient after initial response to chemotherapy. Currently used chemotherapies are limited due to significant adverse/toxic effects, a narrow therapeutic index, and development of multidrug resistance mediated by the epithelial-to-mesenchymal transition (EMT) and cancer cell membrane efflux transporters. It is presumed that an ideal anti-OC drug that has diverse mechanisms, would inhibit several key cell-survival signaling and resistance pathways when combined with conventional chemotherapy (paclitaxel and cisplatin). Silybin, a polyphenolic flavonoid, has previously shown to inhibit metastasis by inhibition of EMT pathways and bypass other drug resistance factors i.e. efflux transporters in ovarian cancer both in vitro and in vivo. However, clinical use of silybin is limited due to their poor absorption and low bioavailability and poor potency. To overcome this, we designed and synthesized 11 silybin derivatives using molecular modeling, computer aided drug design, structure activity relationship, natural product lead optimization and ring disjunction approaches. In our preliminary findings, we found the lead molecule (15k) to have a cytotoxicity (IC50l 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2238. doi:10.1158/1538-7445.AM2017-2238