Synthetic a-(aminomethyl)-c-butyrolactones and their anti-pancreatic cancer activities P. Veeraraghavan Ramachandran a,⇑ , Daniel R. Nicponski a , Hari N. G. Nair a , Matthew A. Helppi a , Pravin D. Gagare a , C. Max Schmidt b,c , Michele T. Yip-Schneider b,c a Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, USA b Department of Surgery, Indiana University School of Medicine, 980 West Walnut Street, Indianapolis, IN 46202, USA c Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 980 West Walnut Street, Indianapolis, IN 46202, USA article info Article history: Received 26 March 2013 Revised 20 September 2013 Accepted 23 September 2013 Available online 30 September 2013 Keywords: Pancreatic cancer Parthenolide Amination Michael addition a-Methylene-c-butyrolactones abstract Aminated a-methylene-c-butyrolactones, which are readily synthesized with facile control of the diastereoisomerism, provide an economical and commercially-viable alternative to the use of aminated natural products. These aminoloactones, which exhibit excellent activity against three pancreatic cancer cell lines when measured at 10 lM—Panc-1, MIA PaCa-2, and BxPC-3—and are comparable to or better than parthenolide and dimethylaminoparthenolide (DMAPT, LC-1). It has also been shown that there is an effect on the biological activity depending on the identity of the amine. Ó 2013 Elsevier Ltd. All rights reserved. The nearly ubiquitous presence of a-methylene-c-butyrolac- tones (AMGBL’s) in nature is a testament to their biological and synthetic importance. Indeed, so prevalent and important is this scaffolding, that, despite the concerns associated with cytotoxicity, their consideration for potential use as actual and pro-drugs in medicinal chemistry is undergoing a recent revival, according to the number of reports being published in the literature. 1 Exemplifying this is the fact that some 3% of all known natural products are now reported to contain this Michael acceptor scaffolding, and that many scores of new natural and synthetic products are being reported each year. 1a The potential of these compounds for use in pharmaceutical applications is becoming more apparent, as these compounds, which have historically been reported to possess a wide range of biological activities, are now being further considered for or even undergoing clinical trials. 2 One such example is parthenolide (PT), which, when considered as an anti-cancer agent, has shown some very promising results. Indeed, it, along with some of its derivatives, or in combination with other drugs, 2,3 have been shown to possess anti-pancreatic, 4 anti-leukemic, 4 anti- pulmonary, 5 anti-bladder, 5 and anti-melanoma 6 activities. Making parthenolide and most of its derivatives even more attractive is the fact that they are considered viable drug candidates according to Lipinski’s rule of five. 7 Parthenolide, which is isolated from the plant Feverfew (Tanacetum parthenium) in the range of 0.3–0.35%, 8,9 is an interest- ing germacranolide sesquiterpene lactone that has been used in herbalism in past times. As there is currently no reported synthesis of parthenolide in the literature, all medical uses and chemical and biological studies must be conducted with commercially pur- chased samples, or be tediously extracted from Feverfew. Unfortu- nately, the exceedingly high cost of commercial parthenolide ($143.50/25 mg = $1.42 M/mole) 10 makes such studies and poten- tial uses prohibitively expensive or impractically tedious. While the exact biological mechanism of action of parthenolide is still under investigation, much effort has been devoted to under- standing its anti-cancer activities. There has been strong evidence gathered which suggests that it is covalently modified through the conjugate addition of both 12 and 22 kDa proteins containing free exo-facial thiols present on the exterior of cancer cells. 11 This recip- rocate covalent modification of the cancer cell exterior has been shown to alter the cell’s internal redox pathways, ultimately resulting in cell death. 12 In the case of Granta mantle lymphoma cells, wherein the NF-jB cycle has been specifically shown to be affected, 11 it can be reasonably expected that similar—if not iden- tical—biological mechanisms exist for the related anti-cancer activ- ities such as pancreatic or bladder. Fascinatingly, parthenolide and its derivatives have a remarkably high cytoselectivity in their 0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2013.09.065 ⇑ Corresponding author. E-mail address: chandran@purdue.edu (P.V. Ramachandran). Bioorganic & Medicinal Chemistry Letters 23 (2013) 6911–6914 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl