Month 2018 Synthesis of New Heterocyclic Amino Derivatives of Alantolactone and Their Cytotoxic Activity Ashish Kumar, a,b Dharmesh Kumar, c Antim K. Maurya, a,b Yogendra S. Padwad, c and Vijai K. Agnihotri a,b * a Academy of Scientific and Innovative Research, CSIR—Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176061, India b Natural Product Chemistry and Process Development Division, CSIR—Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176061, India c Pharmacology and Toxicology Lab, Food and Nutraceuticals Division, CSIR—Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176061, India *E-mail: kantvijai@yahoo.com; vijai@ihbt.res.in Received July 30, 2018 DOI 10.1002/jhet.3328 Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com). In this study, a series of new alantolactone (AL) amino scaffolds (AL1–AL13) had been synthesized and evaluated for in vitro cytotoxicity against three human cancer cell lines: human cervical cancer (SiHa), hu- man epidermoid carcinoma (KB), and human lung cancer (A549). The compounds AL 2, 4, 5, 7, and 13 were found to be nearly as equally active as AL against three tested cell lines, whereas AL 1 and 12 against SiHa cells. This study also provides a correlation on the structure activity relationship of AL and derivatized analogues against tested cells. The retention of cytotoxicity with enhanced water solubility in derivatized amino adducts including AL 1, 2, 4, 5, 7, 12, and 13 indicates that these adducts can further be tested for the detailed in vivo safety and anticancer studies. J. Heterocyclic Chem., 00, 00 (2018). INTRODUCTION Over the past decades, extensive pharmacological studies had provided convincing evidences of the anticancer property of sesquiterpene lactones against various human cancer cells [1]. Diverse studies had been accomplished on the development of selective methods for modification of sesquiterpene lactones with conservation of α-methylene-γ-lactone fragment. Aza-Michael addition of biologically active sesquiterpene lactones recently represents an emerging field for medicinal chemistry [2–4]. These Michael adducts of sesquiterpene lactones are potentially prodrugs of bioactive molecules. Sesquiterpene lactones had been well known to exhibit excellent antitumor activity. However, due to the nonselective binding with undesired targets and very poor aqueous solubility, clinical translation of these molecules has been hampered. To overcome these problem, scientific community has developed an amino- prodrug strategy to enhance aqueous solubility, improve the pharmacokinetic profile, and maintain or even enhance the biological activity of the parent molecule [3]. Alantolactone (AL) is a sesquiterpene lactone (SL) originally purified from the roots of Inula racemosa and Saussurea lappa [5]. Alantolactone (AL) had demonstrated diverse in vitro and in vivo studies [5–7]. There are several published reports in literature regarding its significant anticancer potential. However, due to its very poor water solubility, its therapeutic potential and had been hampered. Literature studies also revealed that addition of amines to α-methylene-γ- butyrolactone of AL enhances its water solubility and biological activity [2,3]. In continuation to our previous work on semisynthetic modification of natural compounds especially sesquiterpene lactones [8], in the present study, we had synthesized new polar functionalized analogues of AL with heterocyclic amines and their substituted derivatives using well accepted aza-Michael addition reaction and evaluated the cytotoxicity of semi- synthesized analogues against some tested cancer cells. To the best of our knowledge, this is the first report on cytotoxic effect of heterocyclic amine derivatives of alantolactone. © 2018 Wiley Periodicals, Inc.