Eight drimane sesquiterpenoids including (-)-drimenol and (+)albicanol were synthesized from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, (+)-albicanol, and (1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1carbaldehyde (4) showed strong activity against C. albicans. (-)-Drimenol, the strongest inhibitor of the three, (at concentrations of 8-64 µg/ml, causing 100% death of various fungi), acts not only against C. albicans in a fungicidal manner, but also inhibits other fungi such as Aspergillus, Cryptococcus, Pneumocystis, Blastomyces, Saksenaea and fluconazole resistant strains of C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. auris. These observations suggest that drimenol is a broad-spectrum antifungal agent. At a high concentration (100 μg/ml) drimenol caused rupture of the fungal cell wall/membrane. In a nematode model of C. albicans infection, drimenol rescued the worms from C. albicans-mediated death, indicating drimenol is tolerable and bioactive in metazoans. Genome-wide fitness profiling assays of both S. cerevisiae (nonessential homozygous and essential heterozygous) and C. albicans (Tn-insertion mutants) collections revealed putative genes and pathways affected by drimenol. Using a C. albicans mutant spot assay, the Crk1 kinase associated gene products, Ret2, Cdc37, and orf19.759, orf19.1672, and orf19.4382 were revealed to be involved in drimenol's mechanism of action. The three orfs identified in this study are novel and appear to be linked with Crk1 function. Further, computational modeling results suggest possible modifications of the structure of drimenol, including the A ring, for improving the antifungal activity.
Second-generation chiral-substituted poly-N-vinylpyrrolidinones (CSPVPs) (−)-1R and (+)-1S were synthesized by free-radical polymerization of (3aR,6aR)-and (3aS,6aS)-5-ethenyltetrahydro-2,2-dimethyl-4H-1,3-dioxolo [4,5-c]pyrrol-4-one, respectively, using thermal and photochemical reactions. They were produced from respective D-isoascorbic acid and D-ribose. In addition, chiral polymer (−)-2 was also synthesized from the polymerization of (S)-3-(methoxymethoxy)-1-vinylpyrrolidin-2one. Molecular weights of these chiral polymers were measured using HRMS, and the polymer chain tacticity was studied using 13 C NMR spectroscopy. Chiral polymers (−)-1R, (+)-1S, and (−)-2 along with poly-N-vinylpyrrolidinone (PVP, MW 40K) were separately used in the stabilization of Cu/Au or Pd/Au nanoclusters. CD spectra of the bimetallic nanoclusters stabilized by (−)-1R and (+)-1S showed close to mirror-imaged CD absorption bands at wavelengths 200−300 nm, revealing that bimetallic nanoclusters' chiroptical responses are derived from chiral polymer-encapsulated nanomaterials. Chemo-, regio-, and stereoselectivity was found in the catalytic C−H group oxidation reactions of complex bioactive natural products, such as ambroxide, menthofuran, boldine, estrone, dehydroabietylamine, 9-allogibberic acid, and sclareolide, and substituted adamantane molecules, when catalyst Cu/Au (3:1) or Pd/Au (3:1) stabilized by CSPVPs or PVP and oxidant H 2 O 2 or t-BuOOH were applied. Oxidation of (+)-boldine N-oxide 23 using NMO as an oxidant yielded 4,5-dehydroboldine 27, and oxidation of (−)-9-allogibberic acid yielded C6,15 lactone 47 and C6-ketone 48.
Catalytic oxidations of tricyclic endo-norbornene-fused tetrahydrofuran with bimetallic nanoclusters Cu/Au-PVP and H2O2 or t-BuOOH as an oxidant provided C-H bond oxidation adjacent to the ether function and 4-oxa-tricyclo[5.2.1.0]-8,9-exo-epoxydecane (4), however, oxidation with Pd/Au-PVP took place at the C=C function giving epoxide 4 and oxidative three-bond forming dimeric product, dodecahydro-1,4:6,9-dimethanodibenzofurano[2,3-b:7,8-b']bisoxolane (5). Formation of the latter suggests the involvement of a reactive Pd-C intermediate. Similarly, oxidative C-C bond forming reactions were found in cycloaddition reactions of N2-Boc-1,2,3,4-tetrahydro-γ-carbolines and 2,3-dihydroxybenzoic acid with 2 - 5 mol% Cu/Au-PVP and H2O2 at 25 oC, providing two-bond-forming [4+2] cycloadducts. Under similar reaction conditions, Pd/Au-PVP did not produce the cycloadduct, indicating a need of complexation between Cu with the carboxylic acid group of 2,3-dihydroxybenzoic acid and allylic amine function of γ-carbolines in the cyclization reaction. The reported intermolecular coupling reactions using Pd/Au-PVP or Cu/Au-PVP nanocluster catalysts under oxidative conditions at 25 oC are unprecedented.
25Eight drimane sesquiterpenoids including (-)-drimenol and (+)-albicanol were synthesized 26 from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, 27 (+)-albicanol, and (1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1-28 carbaldehyde (4) showed strong activity against C. albicans. (-)-Drimenol, the strongest inhibitor 29 of the three, (at concentrations of 8 -64 g/ml, causing 100% death of fungi), acts not only against 30 C. albicans as a fungicidal manner, but also inhibits other fungi such as Aspergillus, Cryptococcus, 31 Pneumocystis, Blastomyces, Fusarium, Rhizopus, Saksenaea and FLU resistant strains of C. 32 albicans, C. glabrata, C. krusei, C. parapsilosis and C. auris. These observations suggest drimenol 33 is a broad-spectrum antifungal agent. At high concentration (100 μg/ml), drimenol caused a 34 rupture of the fungal cell wall/membrane. In a nematode model of C. albicans infection, drimenol 35 rescued the worms from C. albicans-mediated death, indicating drimenol is tolerable and bioactive 36 in a metazoan. Genome-wide fitness profiling assays of both S. cerevisiae (nonessential 37 homozygous and essential heterozygous) and C. albicans (Tn-insertion mutants) collections 38 revealed putative genes and pathways affected by drimenol. Using a C. albicans mutants spot 39 assay, the Crk1 kinase associated gene products, Ret2, Cdc37, and novel putative targets 40 orf19.759, orf19.1672, and orf19.4382 were revealed to be the potential targets of drimenol. 41 Further, computational modeling results suggest possible modification of the structure of drimenol 42 including the A ring for improving antifungal activity. 43 44 45 46 47 48 Life-threatening fungal infections are an important cause of morbidity and mortality, 49 particularly for patients with immune deficiency and those who are undergoing chemotherapeutic 50 treatments. Some of the leading invasive fungal pathogens include Candida sp., Aspergillus sp. 51 and Cryptococcus sp. Currently, the antifungal therapeutic options are limited, especially when 52 compared to available antibacterial agents (1-4). Among the five classes of antifungals, azoles, 53 echiocandins, polyenes, allylamines, and pyrimidine derivatives, only three are used clinically; 54 azoles, echiocandins, and polyenes. Azole drugs, such as fluconazole (FLU), inhibit ergosterol 55 synthesis through inhibition of lanosterol 14--demethylase, impairing formation of the fungal 56 cell wall. Echocandins, such as caspofungin (CAS), block 1,3--glucan synthase and lead to 57 depletion of glucan in fungal cell wall. Polyenes, including amphotericin B (AMB), bind to 58 ergosterol in fungal cell membrane and change the cell membrane transition temperature, resulting 59 in leakage of ions and small organic molecules, and eventual cell death. Allylamines, such as 60 amorolfin, affect ergosterol synthesis by inhibition of squalene epoxidase. Pyrimidines, such as 61 flucytosine (or 5-fluorocytosine), block nucleic acid synthesis,...
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