G. M. Kamal B. Gunaherath

Geopyxins A-E, ent-kaurane diterpenoids from endolichenic fungal strains Geopyxis aff. majalis and Geopyxis sp. AZ0066: structure-activity relationships of geopyxins and their analogues.

Four new ent-kaurane diterpenoids, geopyxins A-D (1-4), were isolated from Geopyxis aff. majalis, a fungus occurring in the lichen Pseudevernia intensa, whereas Geopyxis sp. AZ0066 inhabiting the same host afforded two new ent-kaurane diterpenoids, geopyxins E and F (5 and 6), together with 1 and 3. The structures of 1-6 were established on the basis of their spectroscopic data, while the absolute configurations were assigned using modified Moshers ester method. Methylation of 1-3, 5, and 6 gave their corresponding methyl esters 7-11. On acetylation, 1 and 7 yielded their corresponding monoacetates 12 and 14 and diacetates 13 and 15. All compounds were evaluated for their cytotoxic and heat-shock induction activities. Compounds 2, 7-10, 12, 14, and 15 showed cytotoxic activity in the low micromolar range against all five cancer cell lines tested, but only compounds 7-9, 14, and 15 were found to activate the heat-shock response at similar concentrations. From a preliminary structure-activity perspective, the electrophilic α,β-unsaturated ketone carbonyl motif present in all compounds except 6 and 11 was found to be necessary but not sufficient for both cytotoxicity and heat-shock activation.

1,2(3)-Tetrahydro-3,3′-biplumbagin: A naphthalenone and other constituents from Plumbago zeylanica☆

Abstract The isolation of plumbagin, droserone, isoshinanolone and a new naphthalenone, 1,2(3)-tetrahydro-3,3′-biplumbagin is reported from the phenolic fract

Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. We establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug resistance, and renders resistant pathogens responsive to treatment in mammalian infection models. Harnessing genome sequencing of beauvericin-resistant mutants, affinity purification of a biotinylated beauvericin analog, and biochemical and genetic assays reveals that beauvericin blocks multidrug efflux and inhibits the global regulator TORC1 kinase, thereby activating protein kinase CK2 and inhibiting the molecular chaperone Hsp90. Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux, thereby impeding resistance to the drug combination. Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for fungal infectious disease that evades resistance.

Studies on terpenoids and steroids. Part 3. Structure and synthesis of a new phenolic D:A-friedo-24-noroleanane triterpenoid, zeylasterone, from kokoona zeylanica

Zeylasterone, the first of a novel series of natural phenolic nortriterpenes from Kokoona zeylanica(Celastraceae) and ‘ kokum soap ’ has been shown to be 29-methyl hydrogen 2,3-dihydroxy-6-oxo-D:A-friedo-24-noroleana-1,3,5(10),7-tetraene-23,29-dioate (3) on the basis of spectroscopic and chemical evidence. Trimethylzeylasterone (8) has been synthesized from pristimerin, a quinone methide present in K. zeylanica and ‘ kokum soap ’. The biosynthetic importance of some triterpenoids of K. zeylanica is discussed.

Structures of two new phenolic 24-nor-D:A-friedo-oleananes related to zeylasterone: A partial synthesis of trimethylzeylasterone

Abstract Zeylasteral and desmethylzeylasterone, two new triterpenes from Kokoona zeylanica have been shown to be 2,3-dihydroxy-6,23-dioxo-24-nor-D:A-friedo-oleana-1,3,5(10),7-tetraen-29-oic acid methyl ester (20α) and 2,3-dihydroxy-6-oxo-24-nor-D:A-friedo-oleana-1,3,5(10),7-tetraen23,29-dioic acid (20α), respectively, and have been related to trimethylzeylasterone. A partial synthesis of trimethylzeylasterone starting from pristimerin has been achieved.

Synthesis and biological evaluation of novobiocin analogues as potential heat shock protein 90 inhibitors.

Recent studies have shown that novobiocin (NB), a member of the coumermycin (CA) family of antibiotics with demonstrated DNA gyrase inhibitory activity, inhibits Heat shock protein 90 (HSP90) by binding weakly to a putative ATP-binding site within its C-terminus. To develop more potent HSP90 inhibitors that target this site and to define structure-activity relationships (SARs) for this class of compounds, we have synthesized twenty seven 3-amido-7-noviosylcoumarin analogues starting from NB and CA. These were evaluated for evidence of HSP90 inhibition using several biological assays including inhibition of cell proliferation and cell cycle arrest, induction of the heat shock response, inhibition of luciferase-refolding in vitro, and depletion of the HSP90 client protein c-erbB-2/HER-2/neu (HER2). This SAR study revealed that a substantial increase in biological activity can be achieved by introduction of an indole-2-carboxamide group in place of 4-hydroxy-isopentylbenzamido group at C-3 of NB in addition to removal/derivatization of the 4-hydroxyl group from the coumarin ring. Methylation of the 4-hydroxyl group in the coumarin moiety moderately increased biological activity as shown by compounds 11 and 13. Our most potent new analogue 19 demonstrated biological activities consistent with known HSP90-binding agents, but with greater potency than NB.

Studies on medicinal and related plants of Sri Lanka. Part 18. Structure of a new naphthoquinone from Plumbago zeylanica.

The isolation of chitranone (3), zeylanone (4), maritinone (5), 2-methylnaphthazarin (6), plumbazeylanone, and a new naphthoquinone, methylene-3,3′-diplumbagin (7) from the phenolic fraction of the light petroleum extract of the roots of Plumbago zeylanica(Plumbaginaceae) is reported. The dimethyl ether of the new quinone has been synthesized from plumbagin methyl ether.

Oxaspirol B with p97 Inhibitory Activity and Other Oxaspirols from Lecythophora sp. FL1375 and FL1031, Endolichenic Fungi Inhabiting Parmotrema tinctorum and Cladonia evansii.

A new metabolite, oxaspirol D (4), together with oxaspirols B (2) and C (3) were isolated from Lecythophora sp. FL1375, an endolichenic fungus isolated from Parmotrema tinctorum, whereas Lecythophora sp. FL1031 inhabiting the lichen Cladonia evansii afforded oxaspirols A (1), B (2), and C (3). Of these, oxaspirol B (2) showed moderate p97 ATPase inhibitory activity. A detailed characterization of all oxaspirols was undertaken because structures proposed for known oxaspirols have involved incomplete assignments of NMR spectroscopic data leading only to their planar structures. Thus, the naturally occurring isomeric mixture (2a and 2b) of oxaspirol B was separated as their diacetates (5a and 5b) and the structures and absolute configurations of 1, 2a, 2b, 3, and 4 were determined by the application of spectroscopic techniques including two-dimensional NMR and the modified Moshers ester method. Oxaspirol B (2) and its diacetates 5a and 5b were evaluated for their ATPase inhibitory activities of p97, p97 mutants, and other ATP-utilizing enzymes, and only 2 was found to be active, indicating the requirement of some structural features in oxaspirols for their activity. Additional biochemical and cellular assays suggested that 2 was a reversible, non-ATP competitive, and specific inhibitor of p97.

Functional chromatographic technique for natural product isolation

Natural product discovery arises through a unique interplay between chromatographic purification and biological assays. Currently, most techniques used for natural product purification deliver leads without a defined biological action. We now describe a technique, referred to herein as functional chromatography, that deploys biological affinity as the matrix for compound isolation.

Natural products chemistry. Part 124. Revised structure and synthesis of a new acridone alkaloid, hallacridone from Ruta graveolens tissue cultures

The synthesis of 6-hydroxy-2,1 2-dimethyl-3H-pyrano[2,3-c]acridine-3,7(12H)-dione (1) by two different routes revealed the previously proposed structure of hallacridone, to be incorrect. Careful examination of the spectral characteristics, of an authentic sample of hallacridone, led us to suggest a revised structure, 2-acetyl-5-hydroxy-11 -methylfuro[2,3-c]acridin-6(11H)-one (2), which we unambiguously confirmed by total synthesis. The biosynthetic significance of hallacridone (2) is discussed.