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1.
J Nat Prod ; 84(8): 2129-2137, 2021 08 27.
Article in English | MEDLINE | ID: mdl-34283598

ABSTRACT

The phloeodictine-based 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a]pyrimidinium structural moiety with an n-tetradecyl side chain at C-6 has been demonstrated to be a new antifungal template. Thirty-four new synthetic analogues with modifications of the bicyclic tetrahydropyrrolopyrimidinium skeleton and the N-1 side chain have been prepared and evaluated for in vitro antifungal activities against the clinically important fungal pathogens including Cryptococcus neoformans ATCC 90113, Candida albicans ATCC 90028, Candida glabrata ATCC 90030, Candida krusei ATCC 6258, and Aspergillus fumigatus ATCC 90906. Nineteen compounds (5, 21-31, 34-38, 44, and 48) showed antifungal activities against the aforementioned five fungal pathogens with minimum inhibitory concentrations (MICs) in the range 0.88-10 µM, and all were fungicidal with minimum fungicidal concentrations (MFCs) similar to the respective MIC values. Compounds 24, 36, and 48 were especially active against C. neoformans ATCC 90113 with MIC/MFC values of 1.0/1.0, 1.6/1.6, and 1.3/2.0 µM but exhibited low cytotoxicity with an IC50 > 40 µM against the mammalian Vero cells. The structure and antifungal activity relationship indicates that synthetic modifications of the phloeodictines can afford analogues with potent antifungal activity and reduced cytotoxicity, necessitating further preclinical studies of this new class of antifungal compounds.


Subject(s)
Antifungal Agents/pharmacology , Pyridinium Compounds/pharmacology , Animals , Antifungal Agents/chemical synthesis , Aspergillus fumigatus/drug effects , Candida/drug effects , Chlorocebus aethiops , Cryptococcus neoformans/drug effects , Microbial Sensitivity Tests , Molecular Structure , Pyridinium Compounds/chemical synthesis , Vero Cells
2.
mSphere ; 5(1)2020 01 08.
Article in English | MEDLINE | ID: mdl-31915228

ABSTRACT

The cell wall-targeting echinocandin antifungals, although potent and well tolerated, are inadequate in treating fungal infections due to their narrow spectrum of activity and their propensity to induce pathogen resistance. A promising strategy to overcome these drawbacks is to combine echinocandins with a molecule that improves their activity and also disrupts drug adaptation pathways. In this study, we show that puupehenone (PUUP), a marine-sponge-derived sesquiterpene quinone, potentiates the echinocandin drug caspofungin (CAS) in CAS-resistant fungal pathogens. We have conducted RNA sequencing (RNA-seq) analysis, followed by genetic and molecular studies, to elucidate PUUP's CAS-potentiating mechanism. We found that the combination of CAS and PUUP blocked the induction of CAS-responding genes required for the adaptation to cell wall stress through the cell wall integrity (CWI) pathway. Further analysis showed that PUUP inhibited the activation of Slt2 (Mpk1), the terminal mitogen-activated protein (MAP) kinase in this pathway. We also found that PUUP induced heat shock response genes and inhibited the activity of heat shock protein 90 (Hsp90). Molecular docking studies predicted that PUUP occupies a binding site on Hsp90 required for the interaction between Hsp90 and its cochaperone Cdc37. Thus, we show that PUUP potentiates CAS activity by a previously undescribed mechanism which involves a disruption of Hsp90 activity and the CWI pathway. Given the requirement of the Hsp90-Cdc37 complex in Slt2 activation, we suggest that inhibitors of this complex would disrupt the CWI pathway and synergize with echinocandins. Therefore, the identification of PUUP's CAS-potentiating mechanism has important implications in the development of new antifungal combination therapies.IMPORTANCE Fungal infections cause more fatalities worldwide each year than malaria or tuberculosis. Currently available antifungal drugs have various limitations, including host toxicity, narrow spectrum of activity, and pathogen resistance. Combining these drugs with small molecules that can overcome these limitations is a useful strategy for extending their clinical use. We have investigated the molecular mechanism by which a marine-derived compound potentiates the activity of the antifungal echinocandin caspofungin. Our findings revealed a mechanism, different from previously reported caspofungin potentiators, in which potentiation is achieved by the disruption of Hsp90 activity and signaling through the cell wall integrity pathway, processes that play important roles in the adaptation to caspofungin in fungal pathogens. Given the importance of stress adaptation in the development of echinocandin resistance, this work will serve as a starting point in the development of new combination therapies that will likely be more effective and less prone to pathogen resistance.


Subject(s)
Caspofungin/pharmacology , Cell Wall/drug effects , Drug Resistance, Fungal/genetics , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Saccharomyces cerevisiae/genetics , Sesquiterpenes/pharmacology , Xanthones/pharmacology , Antifungal Agents/pharmacology , Cell Wall/metabolism , Fungal Proteins/genetics , Molecular Docking Simulation , Saccharomyces cerevisiae/drug effects , Sequence Analysis, RNA
3.
Molecules ; 24(3)2019 Feb 07.
Article in English | MEDLINE | ID: mdl-30736401

ABSTRACT

This Special Issue is dedicated to the late Dr. Charles (Charlie) D. Hufford, former Professor of Pharmacognosy and Associate Dean for Research and Graduate Studies at the University of Mississippi [...].


Subject(s)
Famous Persons , Pharmacognosy , History, 20th Century , History, 21st Century , Humans , Pharmacognosy/history , United States
4.
J Biol Chem ; 292(40): 16578-16593, 2017 10 06.
Article in English | MEDLINE | ID: mdl-28821607

ABSTRACT

Eupolauridine and liriodenine are plant-derived aporphinoid alkaloids that exhibit potent inhibitory activity against the opportunistic fungal pathogens Candida albicans and Cryptococcus neoformans However, the molecular mechanism of this antifungal activity is unknown. In this study, we show that eupolauridine 9591 (E9591), a synthetic analog of eupolauridine, and liriodenine methiodide (LMT), a methiodide salt of liriodenine, mediate their antifungal activities by disrupting mitochondrial iron-sulfur (Fe-S) cluster synthesis. Several lines of evidence supported this conclusion. First, both E9591 and LMT elicited a transcriptional response indicative of iron imbalance, causing the induction of genes that are required for iron uptake and for the maintenance of cellular iron homeostasis. Second, a genome-wide fitness profile analysis showed that yeast mutants with deletions in iron homeostasis-related genes were hypersensitive to E9591 and LMT. Third, treatment of wild-type yeast cells with E9591 or LMT generated cellular defects that mimicked deficiencies in mitochondrial Fe-S cluster synthesis including an increase in mitochondrial iron levels, a decrease in the activities of Fe-S cluster enzymes, a decrease in respiratory function, and an increase in oxidative stress. Collectively, our results demonstrate that E9591 and LMT perturb mitochondrial Fe-S cluster biosynthesis; thus, these two compounds target a cellular pathway that is distinct from the pathways commonly targeted by clinically used antifungal drugs. Therefore, the identification of this pathway as a target for antifungal compounds has potential applications in the development of new antifungal therapies.


Subject(s)
Antifungal Agents/pharmacology , Aporphines/pharmacology , Candida albicans , Fungal Proteins , Indenes/pharmacology , Iron-Sulfur Proteins , Mitochondrial Proteins , Naphthyridines/pharmacology , Antifungal Agents/chemistry , Aporphines/chemistry , Candida albicans/genetics , Candida albicans/growth & development , Cryptococcus neoformans/genetics , Cryptococcus neoformans/growth & development , Fungal Proteins/genetics , Fungal Proteins/metabolism , Genome-Wide Association Study , Indenes/chemistry , Iron-Sulfur Proteins/genetics , Iron-Sulfur Proteins/metabolism , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Naphthyridines/chemistry , Oxidative Stress/drug effects , Oxidative Stress/genetics , Oxygen Consumption/drug effects , Oxygen Consumption/genetics , Saccharomyces cerevisiae
5.
Bioorg Med Chem ; 24(23): 6119-6130, 2016 12 01.
Article in English | MEDLINE | ID: mdl-27769668

ABSTRACT

Eupolauridine, an indenonaphthyridine alkaloid, has been previously reported by us to exhibit antifungal activity. This study describes the synthesis of new alkyl and benzyl naphthyridinium/pyridinium analogs of eupolauridine as potential antifungal agents. A majority of the analogs exhibited antifungal activity against opportunistic pathogens such as Candida albicans and Cryptococcus neoformans. Several of them were also effective against bacteria (Staphylococcus aureus, MRS, Pseudomonas and Mycobacterium) and the malaria parasite (Plasmodium falciparum) to variable extents. A number of analogs were also cytotoxic to human cancer cell lines.


Subject(s)
Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Naphthyridines/pharmacology , Amphotericin B/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/chemical synthesis , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Antineoplastic Agents/chemical synthesis , Aspergillus fumigatus/drug effects , Candida albicans/drug effects , Cell Line, Tumor , Chlorocebus aethiops , Cryptococcus neoformans/drug effects , DNA Topoisomerases, Type I/metabolism , Humans , Indenes/chemical synthesis , Indenes/pharmacology , Naphthyridines/chemical synthesis , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Vero Cells
6.
J Nat Prod ; 78(9): 2255-9, 2015 Sep 25.
Article in English | MEDLINE | ID: mdl-26371504

ABSTRACT

Antifungal screening of small-molecule natural product libraries showed that a column fraction (CF) derived from the plant extract of Sagittaria latifolia was active against the fungal pathogen Cryptococcus neoformans. Dereplication analysis by liquid chromatography-mass spectrometry (LC-MS) and proton nuclear magnetic resonance spectroscopy ((1)H NMR) indicated the presence of new compounds in this CF. Subsequent fractionation of the plant extract resulted in the identification of two new isopimaradiene-type diterpenoids, 1 and 2. The structures of 1 and 2 were determined by chemical methods and spectroscopic analysis as isopimara-7,15-dien-19-ol 19-O-α-l-arabinofuranoside and isopimara-7,15-dien-19-ol 19-O-α-l-(5'-acetoxy)arabinofuranoside, respectively. Compound 1 exhibited IC50 values of 3.7 and 1.8 µg/mL, respectively, against C. neoformans and C. gattii. Its aglycone, isopimara-7,15-dien-19-ol (3), resulting from acid hydrolysis of 1, was also active against the two fungal pathogens, with IC50 values of 9.2 and 6.8 µg/mL, respectively. This study demonstrates that utilization of the combined LC-MS and (1)H NMR analytical tools is an improved chemical screening approach for hit prioritization in natural product drug discovery.


Subject(s)
Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Diterpenes/isolation & purification , Diterpenes/pharmacology , Glycosides/isolation & purification , Glycosides/pharmacology , Nuclear Magnetic Resonance, Biomolecular/methods , Sagittaria/chemistry , Antifungal Agents/chemistry , Cryptococcus/drug effects , Diterpenes/chemistry , Drug Discovery , Glycosides/chemistry , Inhibitory Concentration 50 , Molecular Structure , Pyridones , Small Molecule Libraries , Wisconsin
7.
Bioorg Med Chem Lett ; 23(17): 4828-31, 2013 Sep 01.
Article in English | MEDLINE | ID: mdl-23891181

ABSTRACT

Miltefosine is an alkylphosphocholine that shows broad-spectrum in vitro antifungal activities and limited in vivo efficacy in mouse models of cryptococcosis. To further explore the potential of this class of compounds for the treatment of systemic mycoses, nine analogs (3a-3i) were synthesized by modifying the choline structural moiety and the alkyl chain length of miltefosine. In vitro testing of these compounds against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Cryptococcus neoformans revealed that N-benzyl-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3a), N,N-dimethyl-N-(4-nitrobenzyl)-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3d), and N-(4-methoxybenzyl)-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3e) exhibited minimum inhibitory concentrations (MIC) of 2.5-5.0 µg/mL against all tested pathogens, when compared to miltefosine with MICs of 2.5-3.3 µg/mL. Compound 3a showed low in vitro cytotoxicity against three mammalian cell lines similar to miltefosine. In vivo testing of 3a and miltefosine against C. albicans in a mouse model of systemic infection did not demonstrate efficacy. The results of this study indicate that further investigation will be required to determine the potential usefulness of the alkylphosphocholines in the treatment of invasive fungal infections.


Subject(s)
Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Fungi/drug effects , Mycoses/drug therapy , Phosphorylcholine/analogs & derivatives , Animals , Aspergillosis/drug therapy , Aspergillus fumigatus/drug effects , Candida/drug effects , Candidiasis/drug therapy , Cell Line , Cryptococcosis/drug therapy , Cryptococcus neoformans/drug effects , Humans , Mice , Phosphorylcholine/chemistry , Phosphorylcholine/pharmacology
8.
Front Microbiol ; 3: 115, 2012.
Article in English | MEDLINE | ID: mdl-22470373

ABSTRACT

Drug resistance poses a significant challenge in antifungal therapy since resistance has been found for all known classes of antifungal drugs. The discovery of compounds that can act synergistically with antifungal drugs is an important strategy to overcome resistance. For such combination therapies to be effective, it is critical to understand the molecular basis for the synergism by examining the cellular effects exerted by the combined drugs. Genomic profiling technologies developed in the model yeast Saccharomyces cerevisiae have been successfully used to investigate antifungal combinations. This review discusses how these technologies have been used not only to identify synergistic mechanisms but also to predict drug synergies. It also discusses how genome-wide genetic interaction studies have been combined with drug-target information to differentiate between antifungal drug synergies that are target-specific versus those that are non-specific. The investigation of the mechanism of action of antifungal synergies will undoubtedly advance the development of optimal and safe combination therapies for the treatment of drug-resistant fungal infections.

9.
Antimicrob Agents Chemother ; 56(6): 2894-907, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22430960

ABSTRACT

6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model yeast Saccharomyces cerevisiae to investigate its mechanism of action. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes that are required for yeast growth in the presence of oleate. Mutants of S. cerevisiae lacking transcription factors that regulate fatty acid ß-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted in C. albicans. The transcriptional response and fatty acid profile of C. albicans were comparable to those obtained in S. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed in C. albicans. In a fluconazole-resistant clinical isolate of C. albicans, a fungicidal effect was produced when fluconazole was combined with 6-NDA. In hyphal growth assays, 6-NDA inhibited the formation of long hyphal filaments in C. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis and that 6-NDA has potential utility in the treatment of superficial Candida infections.


Subject(s)
Antifungal Agents/pharmacology , Fatty Acids/metabolism , Alkynes/pharmacology , Candida albicans/drug effects , Candida albicans/genetics , Candida albicans/metabolism , Fatty Acids, Monounsaturated/pharmacology , Fatty Acids, Unsaturated/pharmacology , Fluconazole/pharmacology , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism
10.
Res Rep Med Chem ; 2: 7-14, 2012 May 22.
Article in English | MEDLINE | ID: mdl-23936761

ABSTRACT

Screening natural product extracts from the National Cancer Institute Open Repository for antifungal discovery afforded hits for bioassay-guided fractionation. Using LC-MS analysis to generate chemical structure information on potentially active compounds, two new cyclic hexapeptides, microsclerodermins J (1) and K (2), were isolated from the deep-water sponge Microscleroderma herdmani, along with microsclerodermins A (3) and B (4), previously isolated from an unidentified Microscleroderma species. The structures of the new compounds were elucidated by spectroscopic analysis and chemical methods. In vitro antifungal testing showed that the four compounds possessed strong activities against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, and Aspergillus fumigatus.

11.
Eukaryot Cell ; 10(11): 1536-44, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21908598

ABSTRACT

The azaoxoaporphine alkaloid sampangine exhibits strong antiproliferation activity in various organisms. Previous studies suggested that it somehow affects heme metabolism and stimulates production of reactive oxygen species (ROS). In this study, we show that inhibition of heme biosynthesis is the primary mechanism of action by sampangine and that increases in the levels of reactive oxygen species are secondary to heme deficiency. We directly demonstrate that sampangine inhibits heme synthesis in the yeast Saccharomyces cerevisiae. It also causes accumulation of uroporphyrinogen and its decarboxylated derivatives, intermediate products of the heme biosynthesis pathway. Our results also suggest that sampangine likely works through an unusual mechanism-by hyperactivating uroporhyrinogen III synthase-to inhibit heme biosynthesis. We also show that the inhibitory effect of sampangine on heme synthesis is conserved in human cells. This study also reveals a surprising essential role for the interaction between the mitochondrial ATP synthase and the electron transport chain.


Subject(s)
Alkaloids/pharmacology , Heme/biosynthesis , Saccharomyces cerevisiae/drug effects , ATP-Dependent Proteases/genetics , ATP-Dependent Proteases/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Jurkat Cells , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Mitochondrial Proton-Translocating ATPases/genetics , Mitochondrial Proton-Translocating ATPases/metabolism , Naphthyridines , Plant Extracts/pharmacology , Protoporphyrinogen Oxidase/genetics , Protoporphyrinogen Oxidase/metabolism , Reactive Oxygen Species/metabolism , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Uroporphyrinogen III Synthetase/biosynthesis , Uroporphyrinogen III Synthetase/metabolism , Uroporphyrinogens/metabolism
12.
J Nat Prod ; 74(9): 2023-6, 2011 Sep 23.
Article in English | MEDLINE | ID: mdl-21905650

ABSTRACT

Seven 6-alkyl-2,3,4,5-tetrahydropyridines (5a-5g) that mimic the natural piperideines that were recently identified in fire ant venom have been synthesized. Compounds 5c-5g with C-6 alkyl chain lengths from C14 to C18 showed varying degrees of antifungal activities, with 5e (6-hexadecyl-2,3,4,5-tetrahydropyridine) and 5f (6-heptadecyl-2,3,4,5-tetrahydropyridine) being the most active. Compound 5e exhibited minimum fungicidal concentrations of 3.8, 15.0, 7.5, and 7.5 µg/mL against Cryptococcus neoformans, Candida albicans, Candida glabrata, and Candida krusei, respectively. The antifungal activities of these compounds appear to be associated with the C-6 side chain length. This study represents the first effort to evaluate antifungal activities of synthetic analogues of the newly identified fire ant venom alkaloids.


Subject(s)
Ant Venoms/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Antifungal Agents/chemistry , Ants , Candida/drug effects , Cryptococcus neoformans/drug effects , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Pyridines/chemistry
13.
ACS Med Chem Lett ; 2(5): 391-395, 2011 May 12.
Article in English | MEDLINE | ID: mdl-21743827

ABSTRACT

Synthetic analogues of the marine-derived class of natural products phloeodictines have been prepared and exhibited potent in vitro fungicidal activities against a broad array of fungal pathogens including drug resistant strains. The 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a]pyrimidinium structural moiety with a C12 to C16 aliphatic side chain at C-6 has been shown to be the antifungal pharmacophore and may serve as a new antifungal template for further lead optimization.

14.
Antimicrob Agents Chemother ; 55(4): 1611-21, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21300833

ABSTRACT

Plakortide F acid (PFA), a marine-derived polyketide endoperoxide, exhibits strong inhibitory activity against the opportunistic fungal pathogens Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model organism Saccharomyces cerevisiae to investigate the mechanism of action of this compound. PFA elicited a transcriptome response indicative of a Ca(2+) imbalance, affecting the expression of genes known to be responsive to altered cellular calcium levels. Several additional lines of evidence obtained supported a role for Ca(2+) in PFA's activity. First, mutants lacking calcineurin and various Ca(2+) transporters, including pumps (Pmr1 and Pmc1) and channels (Cch1 and Mid1), showed increased sensitivity to PFA. In addition, the calcineurin inhibitors FK506 and cyclosporine strongly enhanced PFA activity in wild-type cells. Furthermore, PFA activated the transcription of a lacZ reporter gene driven by the calcineurin-dependent response element. Finally, elemental analysis indicated a significant increase in intracellular calcium levels in PFA-treated cells. Collectively, our results demonstrate that PFA mediates its antifungal activity by perturbing Ca(2+) homeostasis, thus representing a potentially novel mechanism distinct from that of currently used antifungal agents.


Subject(s)
Antifungal Agents/pharmacology , Calcium/metabolism , Dioxanes/pharmacology , Aspergillus fumigatus/drug effects , Aspergillus fumigatus/metabolism , Candida albicans/drug effects , Candida albicans/metabolism , Cryptococcus neoformans/drug effects , Cryptococcus neoformans/metabolism , Homeostasis/drug effects
16.
Bioorg Med Chem Lett ; 19(21): 6140-3, 2009 Nov 01.
Article in English | MEDLINE | ID: mdl-19783432

ABSTRACT

Puupehanol (1), a new sesquiterpene-dihydroquinone derivative, was isolated from the marine sponge Hyrtios sp., along with the known compounds puupehenone (2) and chloropuupehenone (3) that are responsible for the antifungal activity observed in the extract. The structure of 1 was established as (20R,21R)-21-hydroxy-20,21-dihydropuupehenone by extensive spectroscopic and computational methods. Compound 2 exhibited potent activity against Cryptococcus neoformans and Candida krusei with MFCs of 1.25 and 2.50 microg/mL, respectively.


Subject(s)
Antifungal Agents/chemistry , Benzopyrans/chemistry , Cyclohexanones/chemistry , Porifera/chemistry , Quinones/chemistry , Sesquiterpenes/chemistry , Animals , Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Benzopyrans/isolation & purification , Benzopyrans/pharmacology , Cyclohexanones/isolation & purification , Cyclohexanones/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/isolation & purification , Heterocyclic Compounds, 4 or More Rings/pharmacology , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Conformation , Pyrans/chemistry , Pyrans/isolation & purification , Pyrans/pharmacology , Quinones/isolation & purification , Quinones/pharmacology , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Xanthones/chemistry , Xanthones/isolation & purification , Xanthones/pharmacology
17.
J Nat Prod ; 72(8): 1524-8, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19653640

ABSTRACT

Bioassay-guided fractionation of the extract of Topsentia sp. led to the identification of two new sulfated sterols, geodisterol-3-O-sulfite (1) and 29-demethylgeodisterol-3-O-sulfite (2), the active constituents reversing efflux pump-mediated fluconazole resistance. Both compounds enhanced the activity of fluconazole in a Saccharomyces cerevisiae strain overexpressing the Candida albicans efflux pump MDR1, as well as in a fluconazole-resistant Candida albicans clinical isolate known to overexpress MDR1. These results provide insight into the clinical utility of combining efflux pump inhibitors with current antifungals to combat the resistance associated with opportunistic fungal infections caused by C. albicans.


Subject(s)
Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Drug Resistance, Fungal/drug effects , Fluconazole/pharmacology , Porifera/chemistry , Sterols/isolation & purification , Sterols/pharmacology , Sulfuric Acid Esters/isolation & purification , Sulfuric Acid Esters/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Antifungal Agents/chemistry , Antifungal Agents/pharmacokinetics , Candida albicans/drug effects , Candida albicans/genetics , Candida albicans/metabolism , Fluconazole/pharmacokinetics , Genes, MDR/drug effects , Marine Biology , Molecular Structure , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Sterols/chemistry , Sterols/pharmacokinetics , Sulfuric Acid Esters/chemistry , Sulfuric Acid Esters/pharmacokinetics
18.
J Nat Prod ; 72(6): 1022-7, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19485332

ABSTRACT

Verbesinosides A-F (1-6), six new 15,27-cyclooleanane-type triterpenoid saponins carrying different aromatic acyl moieties on the aglycon, were isolated from the leaves and flowers of Verbesina virginica. Their structures were established by interpretation of spectroscopic data and chemical methods. The representative major saponin, verbesinoside A (1), has the structure 21-trimethoxybenzoyl 15alpha,27-cycloolean-12-en-3beta,21beta-diol-28-oic acid 3-O-beta-D-xylopyranosyl(1-->4)-beta-D-xylopyranosyl(1-->2)-beta-D-glucopyranoside. This is the first report of triterpenoid saponins possessing the unique 15,27-cyclooleanane skeleton. The anisotropic effects of the aromatic acyl moieties on the triterpenoid skeleton are discussed.


Subject(s)
Oleanolic Acid/isolation & purification , Saponins/isolation & purification , Verbesina/chemistry , Flowers/chemistry , Missouri , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/chemistry , Plant Leaves/chemistry , Saponins/chemistry
19.
Heterocycles ; 78(10)2009 Jun 19.
Article in English | MEDLINE | ID: mdl-24371369

ABSTRACT

Phytochemical investigation of the native American plant Gaura longiflora led to the isolation of three new and eight known flavonol glycosides. The structures of the new compounds were established primarily by spectroscopic data as quercetin 3-O-(2″-O-α-l-rhamnopyranosyl-6″-O-E-p-coumaroyl)-ß-D-glucopyranoside (1), kaempferol 3-O-(2″-O-α-l-rhamnopyranosyl-6″-O-E-p-coumaroyl)-ß-d-gluco-pyranoside (2) and quercetin 3-O-(2″-O-α-l-rhamnopyranosyl-6″-O-Z-p-coumaroyl)-ß-D-glucopyrano-side (3).

20.
Antimicrob Agents Chemother ; 52(7): 2442-8, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18458131

ABSTRACT

Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.


Subject(s)
Alkynes/pharmacology , Antifungal Agents/pharmacology , Fatty Acids, Unsaturated/pharmacology , Alkynes/chemistry , Alkynes/toxicity , Animals , Antifungal Agents/chemistry , Antifungal Agents/toxicity , Candida albicans/drug effects , Cell Line , Fatty Acids, Unsaturated/chemistry , Fatty Acids, Unsaturated/toxicity , Fungi/drug effects , Humans , Mice , Microbial Sensitivity Tests , Molecular Structure , Plants, Medicinal/chemistry , Rubiaceae/chemistry , Trichophyton/drug effects
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