Total synthesis and antihypertensive activity of (±)7,8- dihydroxy-3-methyl-isochromanone-4 Jie Liu a , Hao Ren a , Jinyi Xu a, * , Renren Bai a , Qi Yan a , Wenlong Huang b , Xiaoming Wu b, * , Jihua Fu c , Qiujuan Wang c , Qian Wu c , Rong Fu c a Department of Medicinal Chemistry, China Pharmaceutical University, Tongjia Xiang 24, Nanjing, Jiangsu 210009, China b Center of Drug Discovery, China Pharmaceutical University, Nanjing 210038, China c Department of Physiology, China Pharmaceutical University, Nanjing 210009, China article info Article history: Received 24 September 2008 Revised 4 December 2008 Accepted 26 December 2008 Available online 31 December 2008 Keywords: (±)7,8-Dihydroxy-3-methyl- isochromanone-4 Total synthesis Antihypertensive activity ACE inhibitors abstract This letter describes the total synthesis, preliminary biological evaluation and mechanism studies of a novel and structurally unique isochromanone, (±)7,8-dihydroxy-3-methyl-isochromanone-4 (1), a nature product contained in banana (Musa sapientum L.) peel. The bioassay showed that compound 1 displays potent antihypertensive activity in renal hypertensive rats and further mechanism studies revealed that it is an ACE inhibitor. Ó 2008 Elsevier Ltd. All rights reserved. Hypertension is a leading cause of the human angiocardiopathy death, approximately 1 billion individuals worldwide are esti- mated to have blood pressure (BP) levels that warrant treatment, and the prevalence of chronic heart disease and end-stage renal disease has increased in recent years. Therapeutic intervention is the most common method used to control hypertension and re- duce hypertension-related organ damage. During the last few decades, great progress has been made in finding new antihyper- tensive drugs and currently there are three main categories of anti- hypertensive drugs available: (1) diuretics, adrenergic receptor blockers; (2) calcium channel blockers and (3) inhibitors targeting the renin–angiotensin system (RAS), namely angiotensin-convert- ing enzyme (ACE) inhibitors and angiotensin type 1 (AT 1 ) receptor antagonists. Despite the development of antihypertensive drugs, effective BP control remains a major medical challenge and there has been a consistent demand for novel and more effective thera- pies. Antihypertensive product from plants is an important re- source to find new lead for further structure modification. 1 The peel of banana has a great resource in China, which has been widely used as a folk medicine for antihypertension, antiulceration, antibacterial and so on. 2 Recently, we first reported a novel and structurally unique isochromanone, (±)7,8-dihydroxy- 3-methyl-isochromanone-4 (1), isolated from banana (Musa sap- ientum L.) peel extract. 3 The structure of compound 1 has been identified by extensive spectra. A preliminary bioassay proved that compound 1 displays potent antihypertensive activity in a renal hypertensive rats (RHRs). However, the low abundance of this compound impeded the further biological tests both in vitro and in vivo. As our long-term interest, we initialized the project to- wards the study of total synthesis of compound 1 and its deriva- tives. In this letter, we wish to report the total syntheses of compound 1 as well as its biological evaluations. O HO OH O 1 2 3 4 5 6 7 8 9 10 11 1 In our recent study, a more efficient synthesis of compound 1 was found. The synthetic route is shown in Scheme 1. Metal- halogen exchange provided favourable conditions leading o-brom- ophenylalkanoic acid to self-condensation. 4 Treatment of o-brom- 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.12.102 * Corresponding authors. Tel.: +86 25 83271445, +86 25 83242366; fax: +86 25 83302827. E-mail addresses: jinyixu@china.com (J. Xu), xmwu@cpu.edu.cn (X. Wu). Bioorganic & Medicinal Chemistry Letters 19 (2009) 1822–1824 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl