Synthesis, Molecular Modeling, and Biological Evaluation of Novel Chiral Thiosemicarbazone Derivatives as Potent Anticancer Agents DEMET TAS ¸ DEMIR, 1 * AYS ¸ EGÜL KARAKÜÇÜK-I ˙ YIDOG ˘ AN, 1 MUSTAFA ULAS ¸ LI, 2 TUG ˘ BA TAS ¸ KIN-TOK, 1 EMI ˙ NE ELÇI ˙ N ORUÇ-EMRE, 1 AND HASAN BAYRAM 3 1 Gaziantep University, Faculty of Science and Arts, Department of Chemistry, Gaziantep, Turkey 2 Gaziantep University, Faculty of Medicine, Department of Medical Biology, Sehitkamil, Gaziantep, Turkey 3 Gaziantep University, Faculty of Medicine, Department of Pulmonary Diseases, Sehitkamil, Gaziantep, Turkey ABSTRACT A series of new chiral thiosemicarbazones derived from homochiral amines in both enantiomeric forms were synthesized and evaluated for their in vitro antiproliferative activity against A549 (human alveolar adenocarcinoma), MCF-7 (human breast adenocarcinoma), HeLa (human cervi- cal adenocarcinoma), and HGC-27 (human stomach carcinoma) cell lines. Some of compounds showed inhibitory activities on the growth of cancer cell lines. Especially, compound 17b exhibited the most potent activity (IC 50 4.6 μM) against HGC-27 as compared with the reference compound, sindaxel (IC 50 10.3 μM), and could be used as a lead compound to search new chiral thiosemicarbazone derivatives as antiproliferative agents. Chirality 27:177–188, 2015. © 2014 Wiley Periodicals, Inc. KEY WORDS: chiral amine; hydrazinecarbothioamide; cytotoxicity; HipHop; pharmacophore model INTRODUCTION Cancer is a significant cause of mortality and morbidity worldwide and current chemotherapeutic agents are not suffi- ciently effective. Delivery of anticancer drugs to specific tumor tissues is a complex process involving various biochemical, mechanical, and biophysical factors. Designing specific che- motherapeutic drugs may be challenging for treatment but using many advanced technologies such as next-generation sequencing, microarray protein expression profiles, and signal- ing pathways have supported the discovery of treatment targets and personalized treatments. 1 Recently, the majority of drugs used for cancer treatment are not "cancer cell- specific" and these drugs are cytotoxic for normal cells. There- fore, pharmaceutical research has depended on the discovery of new drugs for cancer treatment. 2 Thiosemicarbazones are an important class of imine derivatives that have very different kinds of pharmacological activities, especially as anticancer agents. 3 Their anticancer activity is attributed to the ability to inhibit three target points on which research is focused. First, thiosemicarbazone deriv- atives inhibit the iron-containing ribonucleotide reductase, which is involved in the biosynthesis of DNA by metal chela- tion. 4–6 Second, these compounds inhibit topoisomerase II by stabilization of the cleavable complex between this enzyme and DNA through a thiol alkylation. 7–9 Third, recently thiosemicarbazones were found to be inhibitors of ATP- binding cassette (ABC) transporters, which are known to play a critical role in the development of multidrug resistance. 10,11 Biological systems (proteins, sugars, enzymes, etc.) recog- nize an enantiomer pair as different substances and so two enantiomers of a chiral drug molecule bind differently to tar- get receptors. Consequently, an enantiomer may act as an ef- ficient therapeutic drug while the other enantiomer is inactive or highly toxic. 12–14 Approximately 56% of the drugs currently in use are chiral compounds, and about 88% of these chiral synthetic drugs are used therapeutically as racemates. Unfor- tunately, there are many racemic drugs where the stereospec- ificity of the metabolism and/or the pharmacodynamic effects of the enantiomers is not known. 15 Therefore, the synthesis of chiral drugs in enantiopure form is very important in synthetic organic chemistry, medicinal chemistry, natural product chemistry, and the pharmaceutical industry. 16,17 When a chiral compound is synthesized in several steps, it can be important for practical and economic reasons to intro- duce the proper stereochemistry at an early stage. This can be achieved starting from chiral building blocks that are enantiomerically pure and have functionalities that allow them to be transformed into the desired product. 18 According to this approach, chiral amines can be considered convenient starting materials in the synthesis of chiral thiosemicar- bazones because they are commercially available, and gener- ally accessible in two enantiomeric forms. In continuation of our research on compounds endowed with anticancer activity, we designed and synthesized enantiopure thiosemicarbazones derived from homochiral amines as chiral building blocks. Our previous results have shown that the reaction in basic media between amines and CS 2 in CHCl 3 is a very efficient procedure to synthesize the chiral isothiocyanate derivatives. Furthermore, this process retains the stereochemistry of the starting chiral amine. In the present work, we prepared chiral thiosemicarbazones with good yield and high enantiopurity and evaluated their cytotoxic activity against human alveolar adenocarcinoma (A549), human breast adenocarcinoma (MCF-7), human cervical adenocarcinoma (HeLa), and human stomach carci- noma (HGC-27) cell lines. In addition, a virtual screening of the mentioned chiral thiosemicarbazone (17b) was per- formed to illustrate its SAR (structure–activity relationships) of active sites of protein–ligand interactions and possible conformations by generating a pharmaphore hypothesis to increase knowledge of the structure and mechanism. *Correspondence to: Demet Taşdemir, Gaziantep University, Faculty of Science and Arts, Department of Chemistry, 27310, Gaziantep, Turkey. E-mail: demettasdemir@gmail.com Received for publication 2 September 2014; Accepted 13 October 2014 DOI: 10.1002/chir.22408 Published online 14 November 2014 in Wiley Online Library (wileyonlinelibrary.com). © 2014 Wiley Periodicals, Inc. CHIRALITY 27:177–188 (2015)