Bioactive 5,6-Dihydro-α-pyrone Derivatives from Hyptis brevipes

Abstract

Six new 5,6-dihydro-α-pyrone derivatives (1-6), namely, brevipolides A-F, together with seven known compounds, including a 5,6-dihydro-α-pyrone derivative (7), three flavonoids, a steroid glycoside, and two triterpenoids, were isolated from the entire plant of Hyptis brevipes. Compounds 1-7 were assigned with the absolute configuration, 5R, 6S, 7S, and 9S, as elucidated by analysis of data obtained from their CD spectra and by Mosher ester reactions. Compounds 2, 6, and 7 exhibited ED 50 values of 6.1, 6.7 and 3.6 μM against MCF-7 cells, and compounds 1, 2, 6, and 8 (the known 5,6,3′-trihydroxy-3,7,4′-trimethoxyflavone) gave ED 50 values of 5.8, 6.1 7.5, and 3.6 μM against HT-29 cells, respectively. However, no significant cytotoxicity was found against Lu1 cells for any of the compounds isolated. When these compounds were subjected to evaluation in a panel of mechanism-based in vitro assays, compound 7 were found to be active in an enzyme-based ELISA NF-κB assay, with an ED 50 value of 15.3 μM. In a mitochondrial transmembrane potential assay, compounds 3, 7, and 8 showed ED 50 values of 8.5, 75, and 310 nM, respectively. However, no potent activity was found in a proteasome inhibition assay for any of the isolated compounds.The genus Hyptis (Lamiaceae) is composed of approximately 350-400 species in the form of small herbs to large bushes, which are distributed in the tropics and warmer temperate regions all over the world. Previous studies on the constituents of species of the genus Hyptis have revealed diterpenoids, 1,2 flavonoids, 3,4 lignans, 4,5 and α-pyrone derivatives. 6,7 Hyptis brevipes Piot. originated from tropical America but is now widely distributed in other tropical regions of the world as an alien invasive species. Biological studies on crude extracts of this plant have shown inhibitory activities against bacterial and fungal growth, as well as DNA intercalation activity. 8,9 There has been no previous report on the phytochemical evaluation of this plant to date.* To whom correspondence should be addressed. Tel: .edu. † Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University. ‡ University of Illinois at Chicago. § Division of Pharmacy Practice and Administration, The Ohio State University. ⊥ Research Center for Indonesian Medicinal Plants, Tawangmangu, Indonesia. || Indonesian Institute of Science, Tangerang, Indonesia. ∇ Present address: College of Pharmacy, University of Hawaii-Hilo, Hilo, Hawaii 96720. Supporting Information Available: 1 H and 13 C NMR spectra of compounds 1 -6, DEPT and 2D NMR spectra including 1 H-1 H COSY, HSQC, HMBC, and NOESY of compound 1, as well as 1 H NMR spectra of R-and S-TPMA esters of compound 3. This material is available free-of-charge via the Internet at http://pubs.acs.org. As part of a collaborative, multi-disciplinary approach to the discovery of new naturally occurring anticancer drugs, 10,11 the entire plant of H. brevipes was selected for further investigation, following initial cytotoxicity screening using the MCF-7 human b...

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