Short communication Appraisal of GABA and PABA as linker: Design and synthesis of novel benzamide based histone deacetylase inhibitors Harish Rajak a, * , Pramod Kumar a , Poonam Parmar a , Bhupendra Singh Thakur a , Ravichandran Veerasamy b , Prabodh Chander Sharma c , Ajay Kumar Sharma d , Arun Kumar Gupta e , Jawahar Singh Dangi a a Medicinal Chemistry Research Laboratory, SLT Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur 495 009, CG, India b Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia c Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra 136119, Haryana, India d Department of Pharmacy, G.S.V.M., Medical College, Kanpur 208002, UP, India e B.P.S. Mahila Vishwavidyalaya, Khapur-Kalan, Sonepat 131 001, Haryana, India article info Article history: Received 15 December 2011 Received in revised form 5 March 2012 Accepted 31 March 2012 Available online 11 April 2012 Keywords: GABA PABA Anticancer activity Histone deacetylase inhibitors abstract Histone deacetylase inhibitors have been actively explored as a new generation of chemotherapeutics for cancers, generally known as epigenetic therapeutics. Two novel series of N-(2-amino-phenyl)-4-{[(2/3/4- substituted-phenylcarbamoyl)-methyl]-amino}-butyramide and N-(2-amino-phenyl)-4-{[(2/3/4- substituted-phenylcarbamoyl)-methyl]-amino}benzamide were designed and synthesized as novel histone deacetylase inhibitors. The anticancer potential of the compounds were determined in-vitro using MTTassay against HCT-116 and U251 (glioma) cell lines and histone deacetylase inhibitory assay. The synthesized compounds were investigated for anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice. The efforts were also made to ascertain structureeactivity relationships among test compounds. The results of the present studying represents appraisal of g-aminobutyric acid (GABA) and para-aminobenzoic acid (PABA) as linker moiety for development of newer benzamide based histone deacetylase inhibitor. Ó 2012 Elsevier Masson SAS. All rights reserved. 1. Introduction The epigenetic changes play a vital role in tumorigenesis. The acetylation and deacetylation of histones have been found to support to a substantial degree to epigenetic regulation of gene expression [1,2]. Histone deacetylase inhibitors (HDACi) are a novel class of chemotherapeutic agent that control gene expression by increasing the acetylation of histones, leading to induction of chromatin relaxation and alteration of gene expression [3,4]. Recent findings indicate that HDACi selectively induce growth arrest, differentiation and apoptosis in tumor cells via transcrip- tional activation of a small set of genes that control cell prolifera- tion and cell cycle development like p21 [5,6]. Entinostat (MS-275, SNDX-275) is a moderately potent benza- mide based HDACi, which is in phase II clinical trial. MS-275 was found to be an inhibitor of class I HDACs with a high affinity for HDAC1 (IC 50 ¼ 0.368 mM) and HDAC3 (IC 50 ¼ 0.501 mM) but rela- tively weak inhibition of HDAC8 (IC 50 ¼ 63.4 mM). MS-275 inhibits class II HDAC4, HDAC6 and HDAC10 with IC 50 of 10.7 mM, >100 mM and 50.1 mM, respectively. The IC 50 value of MS-275 toward Class HDACIII SIRT1 was found more than 100 mM [7]. The mechanism inducing cell death in cell lines appears to involve generation of Reactive Oxygen Species (ROS). MS-275 has demonstrated anti- proliferative action in an array of in-vitro human cancer cell lines including breast, ovary, colon, myeloma, pancrease and leukemia. It has also exhibited in vivo anti-tumor activity in a quite of adult and pediatric orthotopic tumor xenograft models following oral administration. Various reports of clinical trials in patients with refractory solid tumors or refractory hematologic malignancies have indicated that MS-275 is well tolerated and exhibited poten- tial anti-tumor activity. MGCD-0103 and CS-055 are other benza- mide based HDACi, which are in phase II clinical trial. WO2004035525-Ii is an example of patented benzamide based HDACi with potent biological activity [8e11].(Fig. 1). HDACi generally conform to a broadly accepted pharmacophore. The crystallographic studies for the design of valuable HDACi have pointed out three structural requirements: a cap group (A) that provides interaction with the pocket entrance, a terminal group (B) that can bind to the zinc ion at the bottom of the active site, also * Corresponding author. Tel.: þ91 9827911824; fax: þ91 7752260140. E-mail address: harishdops@yahoo.co.in (H. Rajak). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2012.03.058 European Journal of Medicinal Chemistry 53 (2012) 390e397