Showing papers by "John M. Pezzuto published in 2009"

Synthesis of Casimiroin and Optimization of Its Quinone Reductase 2 and Aromatase Inhibitory Activities

Abstract: An efficient method has been developed to synthesize casimiroin (1), a component of the edible fruit of Casimiroa edulis, on a multigram scale in good overall yield. The route was versatile enough to provide an array of compound 1 analogues that were evaluated as QR2 and aromatase inhibitors. In addition, X-ray crystallography studies of QR2 in complex with compound 1 and one of its more potent analogues has provided insight into the mechanism of action of this new series of QR2 inhibitors. The initial biological investigations suggest that compound 1 and its analogues merit further investigation as potential chemopreventive or chemotherapeutic agents.

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 ED50 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 ED50 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 was found to be active in an enzyme-based ELISA NF-κB assay, with an ED50 value of 15.3 μM. In a mitocho...

Cancer chemopreventive and anticancer evaluation of extracts and fractions from marine macro- and microorganisms collected from Twilight Zone waters around Guam.

Abstract: The cancer chemopreventive and cytotoxic properties of 50 extracts derived from Twilight Zone (50-150 m) sponges, gorgonians and associated bacteria, together with 15 extracts from shallow water hard corals, as well as 16 fractions derived from the methanol solubles of the Twilight Zone sponge Suberea sp, were assessed in a series of bioassays. These assays included: Induction of quinone reductase (QR), inhibition of TNF-alpha activated nuclear factor kappa B (NFkappaB), inhibition of aromatase, interaction with retinoid X receptor (RXR), inhibition of nitric oxide (NO) synthase, inhibition 2,2-diphenyl-1-picrylhydrazyl radical scavenging (DPPH), and inhibition of HL-60 and MCF-7 cell proliferation. The results of these assays showed that at least 10 extracts and five fractions inhibited NFkappaB by greater than 60%, two extracts and two fractions inhibited DPPH by more than 50%, nine extracts and two fractions affected the survival of HL-60 cells, no extracts or fractions affected RXR, three extracts and six fractions affected quinone reductase (QR), three extracts and 12 fractions significantly inhibited aromatase, four extracts and five fractions inhibited nitric oxide synthase, and one extract and no fractions inhibited the growth of MCF-7 cells by more than 95%. These data revealed the tested samples to have many and varied activities, making them, as shown with the extract of the Suberea species, useful starting points for further fractionation and purification. Moreover, the large number of samples demonstrating activity in only one or sometimes two assays accentuates the potential of the Twilight Zone, as a largely unexplored habitat, for the discovery of selectively bioactive compounds. The overall high hit rate in many of the employed assays is considered to be a significant finding in terms of "normal" hit rates associated with similar samples from shallower depths.

Unraveling the Relationship between Grapes and Health

Abstract: As described in this Supplement and elsewhere, consumption of grapes or grape products has been associated with various health benefits. Resveratrol is a unique component of grapes. Following our report on potential cancer chemopreventive activity, thousands of studies have been performed to characterize the mode of action of this substance. Nonetheless, scores of additional chemicals are known to be constituents of grapes, several of which are capable of mediating biological responses. Accordingly, when considering grapes and health, a holistic view appears to be more meaningful, taking into account all chemical components, metabolism, biological potential, biodistribution, absorption, processing, etc. To fathom such a massive amount of information, we propose the creation of focused ontologies. Grapes seem reasonable as a test bed for exploring this approach, especially because a fair amount of results are available with whole-grape powder. In essence, by utilizing a next generation intelligent system, attempts can be made to leverage the existing complexity. This approach involves bringing together all available information, together with expert judgment, and processing this information through a computational "engine" or engines to provide suggested solutions (or implicit functional relationships). Accomplishment of this task, employing grapes as a prototype, could lead to broader application by incorporating the myriad of features associated with other fruits and vegetables. The ability to correlate heretofore-uncharacterized "signatures" with biologic outcome could fundamentally transform copious amounts of disparate information into a coherent explanation of human disease prevention.

Evaluation of selected indigenous medicinal plants from the western Himalayas for cytotoxicity and as potential cancer chemopreventive agents

Abstract: The western Himalayas in the northern areas of Pakistan have significant potential for ethnomedicinal research. In the current study, indigenous informants were interviewed using open-ended questionnaires and a free-listing of knowledge related to native medicinal plants. Information patterns indicated that over 100 local plant species were in frequent medicinal use for a variety of conditions, including inflammation and cancer. Several field surveys were conducted in community forests and meadows, with the aim of exploration, collection, taxonomic identification, and finally, in vitro analysis. Organic extracts of eight species were tested for inhibition of nuclear factor-kappaB (NF-κB), activation of retinoic acid X receptor alpha (RXR), induction of quinone reductase (QR), and inhibition of aromatase, along with assessment of cytotoxicity with four human cancer cell lines. Mellia azedarach, Ajuga bractiosa, Figonia cretica and Swertia chirata inhibited both tetradecanoylphorbol-13-acetate (TPA) and tum...