Inhibition of prostaglandin E 2 production by synthetic minor prenylated chalcones and flavonoids: Synthesis, biological activity, crystal structure, and in silico evaluation Kamal Rullah a,f , Mohd Fadhlizil Fasihi Mohd Aluwi a , Bohari M. Yamin b , Mohd Nazri Abdul Bahari c , Leong Sze Wei d , Syahida Ahmad c , Faridah Abas d , Nor Hadiani Ismail e , Ibrahim Jantan a , Lam Kok Wai a,⇑ a Drugs and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia b School of Chemical Sciences and Food Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia c Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia d Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia e Faculty of Science, Universiti Teknologi MARA, 50400 Shah Alam, Selangor, Malaysia f Sekolah Tinggi Ilmu Farmasi Riau, Universitas Riau, Kampus Bina Widya Km 12.5, Simpang baru-Pekanbaru, Indonesia article info Article history: Received 25 April 2014 Revised 11 June 2014 Accepted 20 June 2014 Available online 27 June 2014 Keywords: Prenylated chalcone Minor flavonoids Single-crystal XRD Prostaglandin E 2 COX-2 inhibitor ADMET prediction abstract The discovery of potent inhibitors of prostaglandin E 2 (PGE 2 ) synthesis in recent years has been proven to be an important game changer in pharmaceutical industry. It is known that excessive production of PGE 2 triggers a vast array of biological signals and physiological events that contributes to inflammatory dis- eases such as rheumatoid arthritis, atherosclerosis, cancer, and pain. In this Letter, we report the synthe- sis of a series of minor prenylated chalcones and flavonoids which was found to be significantly active in suppressing the PGE 2 production secreted by lipopolysaccharide-induced mouse macrophage cells (RAW 264.7). Among the compounds tested, 14b showed a dose-response inhibition of PGE 2 production with an IC 50 value of 2.1 lM. The suppression upon PGE 2 secretion was not due to cell death since 14b did not reduce the cell viability in close proximity to the PGE 2 inhibition concentration. The obtained atomic coordinates for the single-crystal XRD of 14b was then applied in the docking simulation to determine the potential important binding interactions with murine COX-2 and mPGES-1 putative binding sites. Ó 2014 Elsevier Ltd. All rights reserved. Prostaglandin E 2 (PGE 2 ), a product of the cyclooxygenase (COX) pathway is well identified as the lipid mediator that contributes to inflammatory diseases such as cancer, rheumatoid arthritis, ath- erosclerosis, and pain. 1 The conversion of arachidonic acid into prostaglandin H 2 (PGH 2 ) is tightly regulated by cyclooxygenases and subsequently transformed to PGE 2 by either of the PGE synthases including microsomal prostaglandin E synthase-1 (mPGES-1), microsomal prostaglandin E synthase-2 (mPGES-2), and cytosolic prostaglandin E synthase (cPGES). Both cPGES and mPGES-2 are constitutively expressed in various organs/tissues, whilst mPGES-1, like COX-2, is up-regulated in response to various inflammatory stimuli (Fig. 1). 2–5 Dihydrochalcones, prenylated chalcones, prenylated flavones, aurones, and prenylated aurones are categorised into the group of minor flavonoids. 6 These compounds have a unique and defined chemical structure, which are commonly found in the plant king- dom and possess many interesting biological activities. Addition- ally, the presence of prenyl group in the flavonoid ring system increases lipophilicity and bestows to the molecule a strong affin- ity for biological membranes. It also improves the pharmacokinetic profile of a compound leading to a broader range of interesting pharmacological activities. 7 As an example, xanthohumol (1), a prenylated chalcone, was found to be active in a wide range of anti-inflammatory activities. 8,9 Furthermore, a prenylated flavo- noid namely sophoraflavanone G (2) inhibited prostaglandin E 2 (PGE 2 ) production from lipopolysaccharide (LPS)-treated RAW cells by down-regulating the COX-2 expression at 1–50 lM (IC 50 = 2.7 lM). 10 Some of the aurones such as sulfuretin (3) derivatives have been synthesized and displayed remarkable inhibition results on PGE 2 production in LPS-induced RAW 264.7 cells to reveal the SAR of the compounds. 11 On the other hand, artocarpaurone (4), a newly isolated prenylated aurone from the methanol extract of Artocarpus altilis was found to exhibit NO radical scavenging activ- ity (Fig. 2). 12 http://dx.doi.org/10.1016/j.bmcl.2014.06.061 0960-894X/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +60 3 9289 7031. E-mail address: david_lam_98@yahoo.com (L.K. Wai). Bioorganic & Medicinal Chemistry Letters 24 (2014) 3826–3834 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl