ABSTRACT
From both pharmaceutical and structural perspectives, the large family of prostaglandins represent a truly remarkable class of natural products. Prostaglandin A2 is a tissue hormone naturally found in human seminal plasma and in the sea whip Plexaura homomalla with yet poorly understood biological or therapeutic effects. Herein, a novel strategy for the stereoselective construction of both naturally occurring prostaglandin A2 epimers and first insights into their functional effects on the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) type A receptors (GABAAR) are provided. The synthesis of both epimers was achieved in only 11 steps starting from commercially available 2,5-dimethoxy-tetrahydrofuran employing an organocatalytic domino-aldol reaction, a Mizoroki-Heck reaction, a Wittig reaction as well as an oxidation-decarboxylation sequence. The (15R)-epimer significantly reduced GABA-induced currents through GABAA receptors while its (15S)-epimer did not show any significant effect. These data suggest that (15R)-PGA2 might serve as a novel scaffold for the development of selective GABAA receptor modulators.
ABSTRACT
Male sex represents one of the major risk factors for severe COVID-19 outcome. However, underlying mechanisms that mediate sex-dependent disease outcome are as yet unknown. Here, we identify the CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (also known as aromatase) as a host factor that contributes to worsened disease outcome in SARS-CoV-2-infected males. We analyzed exome sequencing data obtained from a human COVID-19 cohort (n = 2,866) using a machine-learning approach and identify a CYP19A1-activity-increasing mutation to be associated with the development of severe disease in men but not women. We further analyzed human autopsy-derived lungs (n = 86) and detect increased pulmonary CYP19A1 expression at the time point of death in men compared with women. In the golden hamster model, we show that SARS-CoV-2 infection causes increased CYP19A1 expression in the lung that is associated with dysregulated plasma sex hormone levels and reduced long-term pulmonary function in males but not females. Treatment of SARS-CoV-2-infected hamsters with a clinically approved CYP19A1 inhibitor (letrozole) improves impaired lung function and supports recovery of imbalanced sex hormones specifically in males. Our study identifies CYP19A1 as a contributor to sex-specific SARS-CoV-2 disease outcome in males. Furthermore, inhibition of CYP19A1 by the clinically approved drug letrozole may furnish a new therapeutic strategy for individualized patient management and treatment.
Subject(s)
Aromatase , COVID-19 , Female , Humans , Male , Aromatase/genetics , Letrozole , SARS-CoV-2 , COVID-19/genetics , Estradiol , TestosteroneABSTRACT
Due to their high stability towards enzymatic hydrolysis C-acyl glycosidic compounds are useful synthetic intermediates for potential candidates in drug discovery. Syntheses for C-acyl mannosides have remained scarce and usually employ donors obtained from lengthy syntheses. Furthermore, syntheses of unprotected C-acyl mannosides have not been reported so far, due to the incapability of the C-acyl mannoside motif with deprotection conditions for protective groups commonly used in carbohydrate chemistry. Herein, we report an efficient and highly α-selective four-step one-pot method for the synthesis of C-acyl α-d-manno-, l-rhamno- and d-lyxopyranosides from easily accessible persilylated monosaccharides and dithianes requiring only trace amounts of a copper source as catalyst and explain the crucial role of the catalyst by mechanistic studies. Furthermore, the C-acyl α-glycosides were easily isomerized to give rapid access to their ß-anomers.
Subject(s)
Copper , Mannosides , Glycosylation , Mannosides/chemistry , Catalysis , StereoisomerismABSTRACT
Stenotrophomonas maltophilia is a multidrug-resistant human opportunistic pathogen. S. maltophilia contributes to disease progression in cystic fibrosis patients and is found in wounds and infected tissues and on catheter surfaces. Due to its well-known multidrug resistance, it is difficult to treat S. maltophilia infections. Strain-specific susceptibility to antimicrobials has also been reported in several studies. Recently, three fungal diorcinols and 14 rubrolides were shown to reduce S. maltophilia K279a biofilm formation. Based on these initial findings, we were interested to extend this approach by testing a larger number of diorcinols and rubrolides and to understand the molecular mechanisms behind the observed antibiofilm effects. Of 52 tested compounds, 30 were able to significantly reduce the biofilm thickness by up to 85% ± 15% and had strong effects on mature biofilms. All compounds with antibiofilm activity also significantly affected the biofilm architecture. Additional RNA-sequencing data of diorcinol- and rubrolide-treated biofilm cells of two clinical isolates (454 and K279) identified a small set of shared genes that were affected by these potent antibiofilm compounds. Among these, genes for iron transport, general metabolism, and membrane biosynthesis were most strongly and differentially regulated. A further hierarchical clustering and detailed structural inspection of the diorcinols and rubrolides implied that a prenyl group as side chain of one of the phenyl groups of the diorcinols and an increasing degree of bromination of chlorinated rubrolides were possibly the cause of the strong antibiofilm effects. This study gives a deep insight into the effects of rubrolides and diorcinols on biofilms formed by the important global pathogen S. maltophilia. IMPORTANCE Combating Stenotrophomonas maltophilia biofilms in clinical and industrial settings has proven to be challenging. S. maltophilia is multidrug resistant, and occurrence of resistance to commonly used drugs as well as to antibiotic combinations, such as trimethoprim-sulfamethoxazole, is now frequently reported. It is therefore now necessary to look beyond conventional and already existing antimicrobial drugs when battling S. maltophilia biofilms. Our study contains comprehensive and detailed data sets for diorcinol and rubrolide-treated S. maltophilia biofilms. The study defines genes and pathways affected by treatment with these different compounds. These results, together with the identified structural elements that may be crucial for their antibiofilm activity, build a strong backbone for further research on diorcinols and rubrolides as novel and potent antibiofilm compounds.
Subject(s)
Gram-Negative Bacterial Infections , Stenotrophomonas maltophilia , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Biofilms , Gram-Negative Bacterial Infections/microbiology , HumansABSTRACT
Diorcinols and related prenylated diaryl ethers were reported to exhibit activity against methicillin-resistant clinical isolates of Staphylococcus aureus (MRSA). Within these lines, we report the first total synthesis of diorcinolâ D, I, J, the proposed structure of verticilatin and recently isolated antibacterial diaryl ether by using an efficient and highly divergent synthetic strategy. These total syntheses furnish the diaryl ethers in only five to seven steps employing a Pd-catalyzed diaryl ether coupling as the key step. The total synthesis led to the structural revision of the natural product verticilatin, which has been isolated from a plant pathogenic fungus. Furthermore, these structures were tested in order to determine their antibacterial activities against different MRSA strains as well as further Gram-positive and -negative bacteria.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Phenols/chemical synthesis , Phenols/pharmacology , Phenyl Ethers/chemical synthesis , Phenyl Ethers/pharmacology , Humans , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiologyABSTRACT
C-Glycosides are carbohydrates that bear a C-C bond to an aglycon at the anomeric center. Due to their high stability towards chemical and enzymatic hydrolysis, these compounds are widely used as carbohydrate mimics in drug development. Herein, we report a general and exclusively ß-selective method for the synthesis of a naturally abundant acyl-C-glycosidic structural motif first found in the scleropentaside natural product family. A Corey-Seebach umpolung reaction as the key step in the synthesis of scleropentasideâ A and analogues enables the ß-selective construction of the anomeric C-C bond starting from unprotected carbohydrates in only four steps. The one-pot approach is highly atom-efficient and avoids the use of toxic heavy metals.
Subject(s)
Glycosides/chemistry , Carbohydrate Conformation , Glycosylation , Santalaceae/chemistryABSTRACT
Re-investigation of the l-proline catalyzed double aldol cascade dimerization of succinaldehyde for the synthesis of a key bicyclic enal intermediate, pertinent in the field of stereoselective prostaglandin synthesis, is reported. The yield of this process has been more than doubled, from 14 % to a 29 % isolated yield on a multi-gram scale (32 % NMR yield), through conducting a detailed study of the reaction solvent, temperature, and concentration, as well as a catalyst screen. The synthetic utility of this enal intermediate has been further demonstrated through the total synthesis of Δ12 -prostaglandin J3 , a compound with known anti-leukemic properties.
Subject(s)
Aldehydes/chemistry , Fatty Acids, Omega-3/chemical synthesis , Proline/metabolism , Prostaglandins/chemical synthesis , Catalysis , Fatty Acids, Omega-3/chemistry , Molecular Structure , Proline/chemistry , Prostaglandins/chemistryABSTRACT
Two antiglaucoma drugs, bimatoprost and latanoprost, which are analogues of the prostaglandin, PGF2α, have been synthesized in just 7 and 8 steps, respectively. The syntheses employ an organocatalytic aldol reaction that converts succinaldehyde into a key bicyclic enal intermediate, which is primed for attachment of the required lower and upper side chains. By utilizing the crystalline lactone, the drug molecules were prepared in >99% ee.
Subject(s)
Amides/chemical synthesis , Cloprostenol/analogs & derivatives , Dinoprost/chemical synthesis , Prostaglandins F, Synthetic/chemical synthesis , Prostaglandins, Synthetic/chemical synthesis , Aldehydes/chemistry , Amides/chemistry , Bimatoprost , Cloprostenol/chemical synthesis , Cloprostenol/chemistry , Dinoprost/analogs & derivatives , Dinoprost/chemistry , Latanoprost , Molecular Structure , Prostaglandins F, Synthetic/chemistry , Prostaglandins, Synthetic/chemistryABSTRACT
Here we report the synthesis of all four stereoisomers of mefloquine. Mefloquine (Lariam) is an important anti-malaria drug that is applied as a racemate of the erythro form. However, the (-)-isomer induces psychosis, while the (+)-enantiomer does not have this undesired side effect. There are six syntheses of which five lead to the wrong enantiomer without the authors of these syntheses noting that they had synthesized the wrong compound. At the same time physical chemistry investigations had assigned the absolute configuration correctly and the last enantioselective synthesis that took these results into account delivered the correct absolute configuration. Since various synthetic approaches failed to provide the correct stereoisomers in previous syntheses, we submit here a synthetic approach with a domino Sonogashira-6π-electrocyclisation as key step that confirmed synthetically the correct absolute configuration of all four isomers.
Subject(s)
Antimalarials/chemical synthesis , Mefloquine/chemical synthesis , Antimalarials/chemistry , Drug Design , Mefloquine/chemistry , StereoisomerismABSTRACT
The controversy over the absolute configuration of (+)-erythro-mefloquine, the less psychosis-causing enantiomer of the anti-malarial drug Lariam, has been resolved by Mosher ester crystallization. The configuration determined previously by physical methods is correct, whereas the configuration determined by three enantioselective syntheses is wrong.
Subject(s)
Antimalarials/chemistry , Erythromycin/chemistry , Mefloquine/chemistry , StereoisomerismABSTRACT
An efficient de novo synthesis of uronic acid building blocks is described. The synthetic strategy relies on the stereoselective elongation of thioacetal protected dialdehydes 12 a and 17. The dialdehydes are prepared from D-xylose, a cheap and commercially available source. A highly stereoselective MgBr(2)OEt(2)-mediated Mukaiyama aldol addition to C4-aldehyde 12 a is performed to obtain D-glucuronic acid building block 16, whereas L-iduronic acid building block 22 is prepared by MgBr(2)OEt(2)-mediated cyanation of C5-aldehyde 17. Synthesis of a heparin disaccharide demonstrates the utility of the de novo strategy for the assembly of glycosaminoglycan oligosaccharides.