1259 Special Issue on "Medicinal Chemistry" J. Indian Chem. Soc., Vol. 97, August 2020, pp. 1259-1264 Synthesis, biological evaluation, and enzyme assay of some 5-N-substituted-2-N- (arylsulphonyl)-L(+)glutamines as potential anticancer agents Tarun Jha* a , Soma Samanta a , Amit Kumar Halder a , Nilanjan Adhikari a , Sk. Abdul Amin a , Arpita Sanyal b and Tanmoy Mukherjee b a Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata-700 032, India b Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata-700 032, India E- mail: tjupharm@yahoo.com Manuscript received online 03 July 2020, accepted 30 July 2020 Thirty 5- N-substituted-2- N-(arylsulphonyl)- L(+)glutamines were synthesized and evaluated biologically for their anticancer ac- tivities. The best active compound of this series showed 92.92% inhibition of tumor weight against Ehrlich Ascites Carcinoma cells. The most active compound was proved to be a competitive inhibitor of glutaminase in the enzyme assay. The best ac- tive compound may be a starting point to generate ‘lead’ for further exploration. Keywords: Anticancer agent, glutamine derivative, glutaminase inhibition, inhibition assay. Introduction Glutamine is one of the important nutrients for the rapid growing cells 1–3 . Notably, neoplastic cells also utilize glutamine 4,5 . Hence, glutamine is involved in the cancer cell growth. It supplies its nitrogen atom (amide) in the biosyn- thesis of nucleic acid bases (e.g. purine, pyrimidine), other amino acids, and amino sugar as well as coenzymes via different amidotransferases with versatile mechanisms. As far as the cellular growth is concerned, glutamine plays piv- otal role in the metabolisms of protein and nucleic acid bases. Moreover, glutamine takes part in the transportation of few amino acids. It also serves as the pivotal carrier of nitrogen from the skeletal muscle to visceral organs. Glutamine lev- els are undetectable in malignant strain of Earlich ascite tu- mor cells (EATC). Additionally, literature reports suggested that glutamine modulates gene expression on various tis- sues. Glutamine stimulates antiapoptotic Bcl-2 and also in- hibits proapoptotic CD95, thus, may aid in malignancy 6 . Fur- thermore, the increase of glutamine catabolism by the en- zyme glutaminase has been reported recently. In conse- quence, an increased glutaminase activity is found to be the highest during the exponential stage of many cancer cell growth 7 . Overexpression of kidney type glutaminase (KGA) isoform was observed in rapidly proliferating cells of rodent and human hepatoma, EATCs, breast cancer cells as well as in leukemia. Moreover, inhibition of KGA in EATCs may activate apoptosis leading to the sensitization of these cells to hydrogen peroxide (H 2 O 2 ) as well as methotrexate (MTX) toxicity. Therefore, glutaminase may be potential target for anticancer drug development 8,9 . Considering these, it can be anticipated that chemotypes those successfully lower down the glutamine uptake, utilization, and also may inter- rupt the glutaminase enzyme in cancer cells may exhibit antiproliferative properties. Herein, we report some new 5- N-substituted-2-N-(arylsulphonyl)-L(+)glutamines (Fig. 1) with antiproliferative potential and the affect of these compounds on glutaminase enzyme activity. Experimental Chemistry: The synthesis of the titled compounds was carried out as depicted in Scheme 1. The synthetic work was initiated by the chloro-sulphonylation of substituted benzenes (1-5) to get compounds 6-10 10 . These (6-10) were condensed with L(+) glutamic acid under alkaline medium (2 N NaOH) to ob- tain the compounds 11-15. Next, the cyclization reaction of