ABSTRACT
An overview of marine natural products synthesis during 2005 is provided. In a similar vein to earlier installments in this series, the emphasis is on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure confirmation or stereochemical assignments.
Subject(s)
Biological Products/chemical synthesis , Macrolides/chemical synthesis , Marine Biology , Alkaloids/chemical synthesis , Alkanes/chemical synthesis , Biological Products/chemistry , Carbamates/chemical synthesis , Ethers/chemical synthesis , Guanidine/analogs & derivatives , Guanidine/chemical synthesis , Guanidines/chemical synthesis , Lactones/chemical synthesis , Molecular Structure , Pyrones/chemical synthesis , Spiro Compounds/chemical synthesisABSTRACT
An overview of marine natural products synthesis during 2004 is provided. As with the previous installment of this series, the emphasis is on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure confirmation or stereochemical assignments.
Subject(s)
Biological Products/chemical synthesis , Marine Biology , Alkaloids/chemical synthesis , Biological Products/chemistry , Ethers/chemical synthesis , Guanidines/chemical synthesis , Lactones/chemical synthesis , Macrolides/chemical synthesis , Marine Toxins/chemical synthesis , Molecular Structure , Spiro Compounds/chemical synthesis , Tetrodotoxin/chemical synthesisABSTRACT
An overview of marine natural products synthesis during 2003 is provided. The emphasis on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure conformation or stereochemical assignments.
Subject(s)
Biological Products/chemical synthesis , Biological Products/chemistry , Ethers/chemical synthesis , Macrolides/chemical synthesis , Marine Biology , Molecular Structure , Oxazoles/chemical synthesis , Tetrodotoxin/chemical synthesisABSTRACT
seco-Hinokiol (1), a new abietane diterpenoid, has been isolated from the leaves of Rosmarinus officinalis. Its structure was elucidated on the basis of extensive spectroscopic analysis. To our knowledge, this is the fourth report of a seco-abietane having been isolated. In addition, methyl carnosate (4) was synthesized from carnosic acid (3), and detailed NMR spectroscopic data are provided to clarify previous literature reports.
Subject(s)
Abietanes/isolation & purification , Plants, Medicinal/chemistry , Rosmarinus/chemistry , Abietanes/chemistry , Mediterranean Region , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Plant Extracts/chemistry , Plant Leaves/chemistryABSTRACT
Mycothiol (MSH, 1-D-myo-inosityl 2-(N-acetyl-L-cysteinyl)amido-2-deoxy-alpha-D-glucopyranoside) is the principal low molecular weight thiol in actinomycetes. The enzyme 1-D-myo-inosityl 2-N-acetamido-2-deoxy-alpha-D-glucopyranoside deacetylase (AcGI deacetylase) is involved in the biosynthesis of MSH and forms the free amine 1-D-myo-inosityl 2-amino-2-deoxy-alpha-D-glucopyranoside, which is used in the third of four steps of MSH biosynthesis. Here, we report the synthesis of two isomers of AcGI, which contain either 1-L-myo-inositol or 1-D-myo-inositol. These synthetic products were used to investigate substrate specificity of the Mycobacterium tuberculosis enzyme AcGI deacetylase.
Subject(s)
Amidohydrolases/metabolism , Disaccharides/chemical synthesis , Mycobacterium tuberculosis/enzymology , Pyrazoles/chemical synthesis , Sulfhydryl Compounds/chemical synthesis , Bacterial Proteins , Cysteine , Disaccharides/metabolism , Glycopeptides , Inositol , Pyrazoles/metabolism , Recombinant Fusion Proteins/metabolism , Stereoisomerism , Substrate Specificity , Sulfhydryl Compounds/metabolismABSTRACT
Mycothiol is an abundant small molecular weight thiol found only in actinomycetes, which include mycobacteria. Mycothiol biosynthetic and detoxification enzymes are novel and unique to actinomycetes, thereby representing potential antimycobacterial targets. To better guide inhibitor design, we have determined by NMR the solution conformations of mycothiol bimane (MSmB) and the pseudodisaccharide 1-D-GlcNAc-alpha-(1 --> 1)-D-myo-Ins (D-GI), molecules that represent the natural substrates for the mycothiol-dependent detoxification enzyme mycothiol-S-conjugate amidase (MCA) and the mycothiol biosynthetic enzyme D-GlcNAc-alpha-(1 --> 1)-D-myo-Ins deacetylase (AcGI deacetylase), respectively. Comparison of the mean structure of MSmB and the energy-minimized structures of two competitive spiroisoxazoline-containing MCA inhibitors shows striking similarities between these molecules in the region of the scissile amide bond of MSmB and provides structural evidence that those inhibitors are substrate mimics. Owing to our earlier finding that AcGI deacetylase will not deacetylate the unnatural isomer 1-d-GlcNAc-alpha-(1 --> 1)-L-myo-Ins (L-GI), the solution conformation of L-GI was also determined. The interglycosidic bond angles for all three compounds are comparable. When considered together with the observation that a simplified cyclohexyl thioglycoside mycothiol analogue is a good substrate for MCA, it appears that the stereochemistry of the inositol ring is critical for deacetylase function, superceding the importance of the full complement of hydroxyl groups on the "nonreducing" ring.
Subject(s)
Actinomyces/chemistry , Actinomyces/metabolism , Amidohydrolases/metabolism , Disaccharides/chemistry , Pyrazoles/chemistry , Sulfhydryl Compounds/chemistry , Amidohydrolases/genetics , Cyclization , Cysteine , Glycopeptides , Inositol , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The current rise in mycobacterial-related infections and disease, coupled with drug resistance, underlines the continuing need for new antimycobacterials. To this end, we have screened approximately 1500 extracts derived from marine plants and invertebrates and terrestrial fungi for their ability to inhibit a newly described mycobacterial detoxification enzyme mycothiol-S-conjugate amidase (MCA). As described in this paper, our screening and chemistry efforts thus far have led to the identification of 13 natural product inhibitors that represent six different structural classes. By conducting enzyme inhibition assays using varied inhibitor and substrate concentrations, we have determined the mode of inhibition of Mycobacterium tuberculosis MCA for four of these compounds. We show that two types of bromotyrosine-derived natural products are competitive inhibitors of MCA; while oceanapiside, an alpha,omega-bis-aminohydroxy glycosphingolipid, and the fungal metabolite gliotoxin, a dithiadiketopiperazine, are simple and mixed non-competitive inhibitors, respectively. Correlation of these results with the chemical structures suggests that MCA is a metalloenzyme and that the oximinoamide and spiro-isoxazoline amide groups present in the competitive inhibitors are substrate mimics.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Infective Agents/pharmacology , Biological Factors/pharmacology , Enzyme Inhibitors/pharmacology , Mycobacterium smegmatis/enzymology , Mycobacterium tuberculosis/enzymology , Animals , Anti-Bacterial Agents , Aspergillus/chemistry , Drug Design , Fungi/chemistry , Kinetics , Magnetic Resonance Spectroscopy , Mass Spectrometry , Microbial Sensitivity Tests , Mycobacterium smegmatis/drug effects , Mycobacterium tuberculosis/drug effects , Porifera , Structure-Activity RelationshipABSTRACT
A series of bromotyrosine-derived compounds, including marine natural products and members of a psammaplin A-inspired combinatorial synthetic library, were screened for their ability to inhibit the Mycobacterium tuberculosis detoxification enzyme mycothiol-S-conjugate amidase (MCA). Correlations between the structures and their respective IC(50) values (which range from 3 microM to 2.7 mM) should prove valuable when optimizing more potent inhibitors of MCA.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Mycobacterium tuberculosis/enzymology , Structure-Activity Relationship , Tyrosine/analogs & derivatives , Tyrosine/chemistry , Tyrosine/pharmacologyABSTRACT
The in vitro antifungal activity of a series of alpha,omega-bifunctionalized aminoalcohols against Candida glabrata was measured. The dimeric bi-functionalized lipids exhibited activity about approximately 10-fold higher higher than D-sphingosine, which is a larger factor than expected from the simple additive effects of vicinal aminoalcohols groups.
Subject(s)
Amino Alcohols/chemistry , Amino Alcohols/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Sphingolipids/chemistry , Sphingolipids/pharmacology , Amino Alcohols/chemical synthesis , Antifungal Agents/chemical synthesis , Binding Sites , Candida glabrata/drug effects , Glycolipids/chemistry , Glycolipids/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Sphingolipids/chemical synthesisABSTRACT
Mycothiol is a low-molecular weight thiol produced by actinomycetes that serves to protect these organisms from oxidative stress and alkylating agents. We report the total synthesis of mycothiol bimane (1) which is a commonly isolated derivative of mycothiol. The synthesis confirms the original structure assignment and unambiguously establishes the absolute stereochemistry of mycothiol to be 1-d-myo-inosityl 2-deoxy-2-(N-acetamido-l-cysteinamido)-alpha-d-glucopyranoside.
