Chinese Journal of Natural Medicines 2013, 11(5): 0538−0545 Chinese Journal of Natural Medicines Synthesis and β- adrenergic blocking activity of oxime ether hybrids derived from a natural isochroman-4-one BAI Ren-Ren 1, 2, 4† , XU Sheng-Tao 1, 2† , LIU Jie 1, 2 , HONG Wen 3 , TANG Yi-Qun 3 , WU Xiao-Ming 1, 2 , XIE Wei-Jia 1, 2* , YAO He-Quan 1, 2 , XU Jin-Yi 1, 2* 1 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China； 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China； 3 Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China； 4 Jiangsu Honghui Medical Co., Ltd., Nanjing 210008, China Available online 20 Sept. 2013 [ABSTRACT] AIM: In a search for new cardiovascular drug candidates, a series of novel oxime ethers derived from a natural isochroman-4-one were synthesized. METHOD: Compounds 3 and 6, derived from the natural antihypertensive compound 7, 8-dihydroxy-3-methyl-isochroman-4-one (XJP), were designed and synthesized. Subsequently, a series of novel isochroman-4-one oxime ether hybrids were prepared by hybridizing various N-substituted isopropanolamine functionalities to isochroman-4-one oxime. Furthermore, β 1 -adrenergic blocking activities of the synthesized compounds were assayed using the isolated rat left atria. RESULTS: Twenty target compounds were obtained, and the preliminary structure-activity relationships were deduced. The most promising com- pound Ic exhibited β 1 -adrenoceptor blocking activity (inhibition: 52.2%) at 10 −7 mol·L −1 , which was superior to that of propranolol (inhibition: 49.7%). CONCLUSION: The results suggested that natural product XJP/isopropanolamine moiety hybrids may provide a promising approach for the discovery of novel cardiovascular drug candidates. [KEY WORDS] Isochroman-4-one derivatives; Oxime ethers; Hybrids; β-Adrenergic blocking activity; Antihypertensive activity [CLC Number] R284.3 [Document code] A [Article ID] 1672-3651(2013)05-0538-08 1 Introduction Cardiovascular disease affects millions of people around the world, causing loss of lives, and a heavy economic bur- den [1] . During the past few decades, enormous effects have been made in the development of new antihypertensive agents. Antihypertensive products from plants are an impor- [Received on] 28-Jan.-2013 [Research funding] This project was supported by a grant from “Eleventh Five-Year” Major Innovation Projects for New Drug Can- didates (No. 2009ZX09103-128), a grant from National Natural Science Foundation of China (No. 81302635), the Project for Re- search and Innovation of Graduates in Colleges and Universities of Jiangsu Province (No. CXZZ11-0798) and the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. JKGQ201115). [ * Corresponding author] XU Jin-Yi: Prof., E-mail: jinyixu@china. com; XIE Wei-Jia: E-mail: henry1202x@hotmail.com, Tel: 86-25- 83271299, Fax: 86-25-83302827 † These authors contributed equally to this work. These authors have no conflict of interest to declare. Published by Elsevier B.V. All rights reserved tant resource to find new leads for further structure modification [2-4] . The banana peel has been widely used as a folk medicine for the treatment of hypertension, ulceration, etc [5] . 7, 8-Dihydroxy-3-methyl-isochroman-4-one (XJP, Fig. 1), isolated from the banana, Musa sapientum L. peel extract, is a structurally unique polyphenolic compound possessing potent antihypertensive and antioxidant activities [6-8] . In previous studies from our laboratory, XJP significantly de- creased blood pressure in a dose-dependent manner. In both acute and therapeutic antihypertensive tests of conscious renal hypertensive rats (RHRs), the maximum antihyperten- sive effect of XJP at the dose of 100 mg·kg −1 was comparable to that of captopril at the dose of 25 mg·kg −1 [9] . In the further structure modification studies, XJP-B (Fig. 1), an analogue of XJP, was synthesized which was more active than XJP in spontaneously hypertensive rats (SHRs) [10] . Searching for new isochroman-4-one derivatives and analogues with potential cardiovascular protection properties has remained an interest for a long time. In order to overcome the instability and to enhance the bioavailability of these polyphenols [11] , the hydroxymethylated products of XJP and