Novel 3,5-bis(arylidiene)-4-piperidone based monocarbonyl analogs of curcumin: anticancer activity evaluation and mode of action study† Anuj Thakur, a Sunny Manohar, a Christian E. V ´ elez Gerena, b Beatriz Zayas, b Vineet Kumar, c Sanjay V. Malhotra * c and Diwan S. Rawat * a A series of eighteen novel 3,5-bis(arylidiene)-4-piperidone based symmetrical monocarbonyl analogs of curcumin were synthesised and a subset was screened by National Cancer Institute (NCI), USA for their anticancer activity. Dose–response studies and the mechanism of action investigation suggest that most active compounds are apoptosis inducers. Introduction Sequencing of genomes has revealed that the complexity in organisms at the molecular level is derived from many different interactions that proteins undergo. Also, the diversity of biolog- ical functions that a protein assumes depend on the molecular interactions that it makes. Such interactions are critical for practically all cellular, signaling and regulatory pathways. The dysfunction of these pathways is the cause of many diseases including cancer and neurological diseases. Therefore, control- ling the damages and alterations due to these protein interac- tions that cause or accelerate human diseases is a prime target for drug discovery. 1–5 Most of the efforts in recent decades have been made in the discovery and development of therapeutics that modulate individual disease-modifying targets. Though, such an approach has led to numerous successful drugs reaching the market, unfortunately few new drugs act at novel molecular targets. This is also because drugs designed to act against indi- vidual molecular targets cannot usually combat multi-genic diseases such as cancer, or diseases that affect multiple tissues. Successful development of rst-in-class drugs is challenging, in part because agents directed against individual molecular targets are oen found to be less effective at treating disease, and therefore, reach the market later than hoped. 6 Hence, to over- come these challenges, multi-targeting approaches such as combination therapy and design of multi-targeted hybrids could be promising strategies to surpass the existing one chemical for one target for one disease paradigm. However, an issue in a combination therapy is that the different solubilities of the two or more chemical species necessitate a ne-tuning of the formula- tion to ensure that their blood levels should be the same. On the other hand multi-targeted hybrids are generally incorporated by linking the framework of two target-selective ligands to provide a therapeutic benet greater than each ligand. 7,8 Given the importance of this approach and in continuation of our on-going effort to develop multifunctional drugs, 9 we decided to covalently hybridize curcumin with another known pharmacophore. The hope here is to nd new hybrid molecules, which could serve as useful ‘probes’ and help in developing new “molecular leads” for nding new drugs. Considering this approach of ‘hybrid mole- cules as potential drugs’ is still in its infancy, studies which provide data indicating inhibition of cancer cell growth are very valuable, give hope to the drug discovery community and should be taken seriously. Curcuma longa, a perennial herb of the ginger family (Zin- giberaceae), has been used extensively as an essential spice and a traditional medicine in India and China since ancient times. Turmeric, a yellow colouring powder derived from the rhizome of this herb, has been a source of curcumin (Fig. 1) and exhibits various pharmacological activities including anti-inamma- tory, 10 antioxidant, 11 antibacterial, 12 antimalarial, 13 anti-HIV 14 and anticancer. 15 Toxicological studies conducted in animal models and in humans proved that curcumin is extremely safe even at a dose level of 12 g per day. 16 However, inspite of its safe toxicological proles, curcumin itself is not a good candidate for further clinical development because of poor solubility, low systemic bioavailability, undesirable absorption and rapid metabolism when tested in vivo. 16 Detailed pharmacological studies conrmed that the central b-diketone functionality of curcumin is a substrate for liver aldoketo reductases and this may lead to rapid metabolism of curcumin. 17 a Department of Chemistry, University of Delhi, Delhi-110007, India. E-mail: dsrawat@ chemistry.du.ac.in; Fax: +91-11-27667501; Tel: +91-11-27662683 b School of Environmental Affairs, Universidad Metropolitana, San Juan, Puerto Rico, 00928, USA c Laboratory of Synthetic Chemistry, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. E-mail: malhotrasa@mail.nih.gov; Tel: +1-301-846-5141 † Electronic supplementary information (ESI) available: One dose mean graphs, drug–response curves, ve dose mean graphs, and GI 50 and LC 50 values of compounds 10, 14, 22 and 23. CCDC 971312. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3md00399j Cite this: Med. Chem. Commun. , 2014, 5, 576 Received 31st December 2013 Accepted 7th February 2014 DOI: 10.1039/c3md00399j www.rsc.org/medchemcomm 576 | Med. Chem. Commun. , 2014, 5, 576–586 This journal is © The Royal Society of Chemistry 2014 MedChemComm CONCISE ARTICLE Published on 11 February 2014. 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