title: Exploration of Pharmacophore in Chrysosplenol C as Activator in Ventricular Myocyte Contraction.
abstract: Chrysosplenol C (4',5,6-trihydroxy-3,3',7-trimethoxyflavone) isolated from Miliusa balansae has unique structural features as a reversible inotropic agent independent of β-adrenergic signaling and with selective activation of cardiac myosin ATPase. Hence, a series of chrysosplenol analogues were synthesized and explored for identification of pharmacophore that is essential for the increasing contractility in rat ventricular myocytes. Analogue 7-chloro-2-(3-hydroxyphenyl)-3-methoxy-4H-chromen-4-one showed highly potent contractility (54.8% at 10 μM) through activating cardiac myosin ATPase (38.7% at 10 μM). Our systematic structure-activity relationship study revealed that flavonoid nucleus of chrososplenol C appears to be an essential basic skeleton and hydrophobic substituent at position 7 of chromenone such as methoxy or chloro enhances the activity. Additionally, our ATPase study suggested that these chrysosplenol analogues have selectivity toward cardiac myosin activation. Thus, the novel flavonone with 3-/7-hydrophobic substituent and 3'-hydrogen bonding donor function is a novel scaffold for discovery of a new positive inotropic agent.
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University , Daejeon 305-764, South Korea.
authors.forename: Eeda
authors.initials: E
authors.lastname: Venkateswararao
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University , Daejeon 305-764, South Korea.
authors.forename: Min-Jeong
authors.initials: MJ
authors.lastname: Son
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University , Daejeon 305-764, South Korea.
authors.forename: Niti
authors.initials: N
authors.lastname: Sharma
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University , Daejeon 305-764, South Korea.
authors.forename: Manoj
authors.initials: M
authors.lastname: Manickam
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University , Daejeon 305-764, South Korea.
authors.forename: PullaReddy
authors.initials: P
authors.lastname: Boggu
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University , Daejeon 305-764, South Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University , Daejeon 305-764, South Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Woo
authors.affiliation: College of Pharmacy and Institute of Drug Research and Development, Chungnam National University , Daejeon 305-764, South Korea.
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Jung
keywords: Chrysosplenol C; contractility; myosin activation; positive inotrope