ABSTRACT
This review describes novel organocatalytic methods for the enantioselective construction of spiroindans and spirochromans and the application of the methods to the total synthesis of natural products. We developed an intramolecular Friedel-Craftstype 1,4-addition in which the substrates were a resorcinol derivative and 2-cyclohexenone linked by an alkyl chain. The reaction proceeded smoothly in the presence of a cinchonidine-based primary amine (30 mol%) with water and p-bromophenol as additives. A variety of spiroindanes were obtained with high enantioselectivity under these conditions. The reaction was applied in the first total synthesis of the unusual proaporphine alkaloid (-)-misramine, which included the key steps of enantioselective spirocyclization and double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. The total synthesis of misrametine was achieved by selective demethylation of the methoxy group from the precursor to misramine. Next, a method for highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. An intramolecular oxy-Michael addition was catalyzed by a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivity of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.
Subject(s)
Biological Products , Catalysis , Biological Products/chemical synthesis , Biological Products/chemistry , Stereoisomerism , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Cinchona Alkaloids/chemistry , Cyclohexanones/chemical synthesis , Cyclohexanones/chemistry , Organic Chemistry Phenomena , Pharmaceutical Preparations/chemical synthesis , Pharmaceutical Preparations/chemistry , Amines/chemistry , Amines/chemical synthesis , Thiourea/chemistry , Thiourea/chemical synthesis , Resorcinols/chemical synthesis , Resorcinols/chemistry , Indans/chemical synthesis , Indans/chemistryABSTRACT
Human Hsp90 chaperones are implicated in various aspects of cancer. Due to this, Hsp90 has been explored as potential target in cancer treatment. Initial attempts to use Hsp90 inhibitors in drug trials failed due to toxicity and inefficacy. The next generation of drugs were less toxic but still insufficiently effective in a clinical setting. Recently, a lot of effort is being put into understanding the consequences of Hsp90 isoform selective inhibition, expecting that this might hold the key in targeting Hsp90 for disease treatment. Here we investigate a series of compounds containing the aryl-resorcinol scaffold with a 5-membered ring as a promising class of new human Hsp90 inhibitors, reaching nanomolar affinity. We compare how the replacement of 5-membered ring, from thiadiazole to imidazole, as well as a variety of their substituents, influences the potency of these inhibitors for Hsp90 alpha and beta isoforms. To further elucidate the dissimilarity in ligand selectivity between the isoforms, a mutant protein was constructed and tested against the ligand library. In addition, we performed a series of molecular dynamics (MD) and docking simulations to further explain our experimental findings as well as evaluated key compounds in cell assays. Our results deepen the understanding of Hsp90 isoform ligand selectivity and serve as an informative base for further Hsp90 inhibitor optimization.
Subject(s)
Drug Design , HSP90 Heat-Shock Proteins , Imidazoles , Resorcinols , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/metabolism , Humans , Resorcinols/chemistry , Resorcinols/pharmacology , Resorcinols/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Imidazoles/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Dose-Response Relationship, Drug , Molecular Dynamics Simulation , Molecular Docking Simulation , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesisABSTRACT
Leishmaniasis is a vector-borne disease caused by the protozoan parasite Leishmania found in tropical and sub-tropical areas, affecting 12 million people around the world. Only few treatments are available against this disease and all of them present issues of toxicity and/or resistance. In this context, the development of new antileishmanial drugs specifically directed against a therapeutic target appears to be a promising strategy. The GDP-Mannose Pyrophosphorylase (GDP-MP) has been previously shown to be an attractive therapeutic target in Leishmania. In this study, a chemical library of 5000 compounds was screened on both L. infantum (LiGDP-MP) and human (hGDP-MP) GDP-MPs. From this screening, oncostemonol D was found to be active on both GDP-MPs at the micromolar level. Ten alkyl-resorcinol derivatives, of which oncostemonols E and J (2 and 3) were described for the first time from nature, were then evaluated on both enzymes as well as on L. infantum axenic and intramacrophage amastigotes. From this evaluation, compounds 1 and 3 inhibited both GDP-MPs at the micromolar level, and compound 9 displayed a three-times lower IC50 on LiGDP-MP, at 11 µM, than on hGDP-MP. As they displayed mild activities on the parasite, these compounds need to be further pharmacomodulated in order to improve their affinity and specificity to the target as well as their antileishmanial activity.
Subject(s)
Leishmaniasis/drug therapy , Nucleotidyltransferases/antagonists & inhibitors , Resorcinols/pharmacology , Animals , Antiprotozoal Agents/pharmacology , Humans , Leishmania/drug effects , Leishmania/pathogenicity , Mice , Nucleotidyltransferases/drug effects , Nucleotidyltransferases/metabolism , Pharmaceutical Preparations , RAW 264.7 Cells , Resorcinols/chemical synthesis , Resorcinols/chemistry , Small Molecule LibrariesABSTRACT
From the venerable Robinson annulation to the irreplaceable Diels-Alder cycloaddition, annulation reactions have fueled the progression of the field of natural product synthesis throughout the past century. In broader terms, the ability to form a cyclic molecule directly from two or more simpler fragments has transformed virtually every aspect of the chemical sciences from the synthesis of organic materials to bioconjugation chemistry and drug discovery. In this Account, we describe the evolution of our meroterpene synthetic program over the past five years, enabled largely by the development of a tailored anionic annulation process for the synthesis of hydroxylated 1,3-cyclohexanediones from lithium enolates and the reactive ß-lactone-containing feedstock chemical diketene.First, we provide details on short total syntheses of the prototypical polycyclic polyprenylated acylphloroglucinol (PPAP) natural products hyperforin and garsubellin A, which possess complex bicyclo[3.3.1]nonane architectures. Notably, these molecules have served as compelling synthetic targets for several decades and induce a number of biological effects of relevance to neuroscience and medicine. By merging our diketene annulation process with a hypervalent iodine-mediated oxidative ring expansion, bicyclo[3.3.1]nonane architectures can be easily prepared from simple 5,6-fused bicyclic diketones in only two chemical operations. Leveraging these two key chemical reactions in combination with various other stereoselective transformations allowed for these biologically active targets to be prepared in racemic form in only 10 steps.Next, we extend this strategy to the synthesis of complex fungal-derived meroterpenes generated biosynthetically from the coupling of 3,5-dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate. A Ti(III)-mediated radical cyclization of a terminal epoxide was used to rapidly prepare a 6,6,5-fused tricyclic ketone which served as an input for our annulation/rearrangement process, ultimately enabling a total synthesis of protoaustinoid A, an important biosynthetic intermediate in DMOA-derived meroterpene synthesis, and its oxidation product berkeleyone A. Through a radical-based, abiotic rearrangement process, the bicyclo[3.3.1]nonane cores of these natural products could again be isomerized, resulting in the 6,5-fused ring systems of the andrastin family and ultimately delivering a total synthesis of andrastin D and preterrenoid. Notably, these isomerization transformations proved challenging when employing classic, acid-induced conditions for carbocation generation, thus highlighting the power of radical biomimicry in total synthesis. Finally, further oxidation and rearrangement allowed for access to terrenoid and the lactone-containing metabolite terretonin L.Overall, the merger of annulative diketene methodology with an oxidative rearrangement transformation has proven to be a broadly applicable strategy to synthesize bicyclo[3.3.1]nonane-containing natural products, a class of small molecules with over 1000 known members.
Subject(s)
Biological Products/chemical synthesis , Terpenes/chemical synthesis , Biological Products/chemistry , Bridged Bicyclo Compounds/chemistry , Cyclization , Cycloaddition Reaction , Molecular Conformation , Oxidation-Reduction , Phloroglucinol/analogs & derivatives , Phloroglucinol/chemical synthesis , Phloroglucinol/chemistry , Resorcinols/chemical synthesis , Resorcinols/chemistry , Stereoisomerism , Terpenes/chemistryABSTRACT
Dialkylresorcinols are a class of antimicrobial natural products produced by a range of bacterial species. Semi-synthetic derivatization of two microbial dialkylresorcinols isolated from a Pseudomonas aurantiaca strain has yielded 21 derivatives, which were tested for antimicrobial activity, revealing several trends in their activity. The presence of aromatic and phenolic hydrogen atoms was crucial for activity, with all derivatives lacking these features possessing greatly reduced activity. On the other hand, derivatives with shorter alkyl chains at C-5 possessed lower MIC values, while one mono-fluorosulfated derivative showed significantly improved activity against several of the test strains.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Resorcinols/chemical synthesis , Resorcinols/pharmacology , Anti-Bacterial Agents/chemistry , Bacteria/ultrastructure , Drug Design , Microbial Sensitivity Tests , Molecular Structure , Resorcinols/chemistryABSTRACT
The synthesis of three phenolic natural products has been accomplished with unprecedented efficiency using a new alumina-promoted regioselective aromatic allylation reaction. Cannabigerol and grifolin were prepared in one step from the inexpensive 5-alkyl-resorcinols olivetol and orcinol. Piperogalin was synthesized, for the first time, via two sequential allylations of orcinol with geraniol and prenol.
Subject(s)
Aluminum Oxide/chemistry , Cannabinoids/chemical synthesis , Resorcinols/chemical synthesis , Cannabis/chemistry , Catalysis , Molecular Structure , Terpenes/chemical synthesisABSTRACT
In this study, the synthesis and structure of 4-aminocoumarin derivatives of resorcin[4]arene were investigated. Spectroscopic analysis and quantum mechanical calculations showed that this molecule undertakes a crown-in conformation in chloroform. The conformations of the aminocoumarin derivative of resorcin[4]arene were compared with a hydroxycoumarin derivative of resorcin[4]arene, and the effect of the substituent on the conformational selectivity of the coumarin derivatives of resorcin[4]arene was demonstrated. Both UV-VIS and fluorescence spectroscopy for the coumarin derivative of resorcin[4]arene (3) were performed, and a strong fluorescence quenching of derivative 3 compared to 4-aminocoumarin was observed.
Subject(s)
Aminocoumarins/chemistry , Chloroform/chemistry , Resorcinols/chemical synthesis , Density Functional Theory , Hydrogen Bonding , Molecular Conformation , Molecular Structure , Quantum Dots , Resorcinols/chemistry , Spectrometry, FluorescenceABSTRACT
Novel resorcinol diphenyl ether-based PROTACs (PROteolysis TArgeting Chimeras) were designed and evaluated for their inhibitory activity against the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway and their ability to degrade PD-L1 protein. Most of the compounds displayed excellent inhibitory activities against PD-1/PD-L1, as assessed by the homogenous time-resolved fluorescence (HTRF) binding assay, with IC50 values ranging from 25 nM to 200 nM. Among them, compound P22 is one of the best with an IC50 value of 39.2 nM. In addition to inhibiting PD-1/PD-L1 interaction, P22 also significantly restored the immunity repressed in a co-culture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, flow cytometry (FCM) and western-blot data demonstrated that P22 could moderately reduce the protein levels of PD-L1 in a lysosome-dependent manner, which may contribute to its immune effects. Preliminary FCM and western-blot data suggest that it is possible to build PD-L1-targeting PROTAC-like molecules based on PD-1/PD-L1 small molecule inhibitors, though these compounds showed only modest degradation efficiencies. Collectively, this work suggests that P22 may serve as a starting point for exploring the degradation of PD-L1 by PROTAC-like strategy.
Subject(s)
B7-H1 Antigen/antagonists & inhibitors , Drug Discovery , Immune Checkpoint Inhibitors/pharmacology , Phenyl Ethers/pharmacology , Proteolysis/drug effects , Resorcinols/pharmacology , B7-H1 Antigen/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Coculture Techniques , Dose-Response Relationship, Drug , Humans , Immune Checkpoint Inhibitors/chemical synthesis , Immune Checkpoint Inhibitors/chemistry , Molecular Structure , Phenyl Ethers/chemical synthesis , Phenyl Ethers/chemistry , Resorcinols/chemical synthesis , Resorcinols/chemistry , Structure-Activity RelationshipABSTRACT
A series of isosteric surrogates of the 4-phenyl group in luminespib were investigated as new scaffolds of the Hsp90 inhibitor for the discovery of novel antitumor agents. Among the synthesized surrogates of isoxazole and pyrazole, compounds 4a, 5e and 12b exhibited potent Hsp90 inhibition in ATPase activity and Her2 degradation assays and significant antitumor activity in A2780 and HCT116 cell lines. Animal studies indicated that compared to luminespib, their activities were superior in A2780 or NCI-H1975 tumor xenograft models. A molecular modeling study demonstrated that compound 4a could fit nicely into the N-terminal ATP binding pocket.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Isoxazoles/pharmacology , Resorcinols/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HSP90 Heat-Shock Proteins/metabolism , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Resorcinols/chemical synthesis , Resorcinols/chemistry , Structure-Activity RelationshipABSTRACT
Macrocyclic hosts have long been the workhorses of molecular recognition. Despite the widespread use of container-shaped molecules as synthetic receptors, an efficient preparation of cavitands bearing multiple functional groups has not been realized. This Letter describes a new cavitand derived from a sequence-defined oligoamide foldamer scaffold. A solid-phase synthesis approach is reported, which enables the display of multiple chemically diverse functional groups on the cavitand rim.
Subject(s)
Ethers, Cyclic/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Resorcinols/chemical synthesis , Cyclization , Ethers, Cyclic/chemistry , Macrocyclic Compounds/chemistry , Molecular Structure , Resorcinols/chemistry , Solid-Phase Synthesis TechniquesABSTRACT
The Friedel-Crafts alkylation is commonly used in organic synthesis to form aryl-alkyl C-C linkages. However, this reaction lacks the stereospecificity and regiocontrol of enzymatic catalysis. Here, we describe a stereospecific, biocatalytic Friedel-Crafts alkylation of the 2-position of resorcinol rings using the cylindrocyclophane biosynthetic enzyme CylK. This regioselectivity is distinct from that of the classical Friedel-Crafts reaction. Numerous secondary alkyl halides are accepted by this enzyme, as are resorcinol rings with a variety of substitution patterns. Finally, we have been able to use this transformation to access novel analogues of the clinical drug candidate benvitimod that are challenging to construct with existing synthetic methods. These findings highlight the promise of enzymatic catalysis for enabling mild and selective C-C bond-forming synthetic methodology.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Resorcinols/chemistry , Stilbenes/chemistry , Alkylation , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Biocatalysis , Models, Molecular , Resorcinols/chemical synthesis , Stereoisomerism , Stilbenes/chemical synthesisABSTRACT
Sixteen novel orsellinic esters (6a-l, 7a-d) along with four lecanoric acid related depsides (3a-c, 4) were synthesized and confirmed their structures by spectroscopic data (1H, 13C & HRMS). The synthesized compounds were evaluated for their in vitro α-glucosidase (Saccharomyces cerevisiae) inhibitory potential. Among the tested compounds, 3c (IC50: 140.9 µM) and 6c (IC50: 203.9 µM) displayed potent α-glucosidase inhibitory activity and found more active than the standard drug acarbose (IC50: 686.6 µM). Both the test compounds were subjected to in vivo antihyperglycemic activity using sucrose loaded model in Wistar rats and found compound 3c exhibited significant reduction in glucose levels.
Subject(s)
Depsides/chemical synthesis , Depsides/pharmacology , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/pharmacology , Resorcinols/chemical synthesis , Resorcinols/pharmacology , Salicylates/chemical synthesis , Salicylates/pharmacology , Animals , Blood Glucose/metabolism , Hyperglycemia/chemically induced , Hyperglycemia/drug therapy , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Male , Molecular Docking Simulation , Rats , Rats, Wistar , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/enzymology , Structure-Activity Relationship , SucroseABSTRACT
Resorcinol alkyl glucosides 7-12 were developed as novel tyrosinase inhibitors based on the structure of rhododendrin. These were synthesized from 2,4-dibenzyloxybenzaldehyde using either the Wittig or the Horner-Wadsworth-Emmons reaction with Koenigs-Knorr glycosylation as key steps. The tyrosinase inhibitory activity of 7-12 increased with the length of the alkyl spacer between resorcinol and glucose. The 50% inhibitory concentration (IC50) of tetradecyl derivative 12 was 0.39⯵M, making it the most potent of the compounds synthesized. The IC50 of 8 (3.62⯵M) with a propyl spacer was ca 10â¯times that of 7 (35.9⯵M) with an ethyl spacer. This significant activity difference suggests that an interaction between resorcinol alkyl glucoside and tyrosinase may increase remarkably if the length of the alkyl spacer exceeds C3.
Subject(s)
Enzyme Inhibitors/pharmacology , Glucosides/pharmacology , Monophenol Monooxygenase/antagonists & inhibitors , Resorcinols/pharmacology , Alkylation , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glucosides/chemical synthesis , Glucosides/chemistry , Molecular Structure , Monophenol Monooxygenase/metabolism , Resorcinols/chemical synthesis , Resorcinols/chemistry , Structure-Activity RelationshipABSTRACT
In this study, porous magnetic resin grafted chitosan (R-g-Ch) beads were prepared for removal of 4-chlorophenol and phenol from aqueous solutions. The R-g-Ch beads were characterized by vibrating sample magnetometer, Fourier-transform infrared spectroscopy, scanning electron microscopy and thermogravimetry methods. The removal of the phenolic compounds was optimized by varying the experimental conditions. Results herein are well fitted to the pseudo-second order kinetic and Langmuir isotherm. The maximum adsorption capacity of phenol and 4-chlorophenol were found to be 188.6 and 99â¯mg/g, respectively. The thermodynamic studies suggested that the adsorption process was exothermic, irreversible and feasible within the range of 298-318â¯K.
Subject(s)
Chitosan/chemistry , Magnetics , Microspheres , Phenols/isolation & purification , Resins, Synthetic/chemistry , Adsorption , Chitosan/chemical synthesis , Chlorophenols/isolation & purification , Differential Thermal Analysis , Formaldehyde/chemical synthesis , Formaldehyde/chemistry , Hydrogen-Ion Concentration , Kinetics , Porosity , Resorcinols/chemical synthesis , Resorcinols/chemistry , Solutions , Temperature , Thermogravimetry , Time Factors , Triazines/chemical synthesis , Triazines/chemistryABSTRACT
Chemical investigation of the extracts of Aspergillus terreus resulted in the identification of terreusterpenes A-D (1-4), four new 3,5-dimethylorsellinic acid-based meroterpenoids. The structures and absolute configurations of 1-4 were elucidated by spectroscopic analyses including HRESIMS and 1D- and 2D-NMR, chemical conversion, and single crystal X-ray diffraction. Terreusterpenes A (1) and B (2) featured 2,3,5-trimethyl-4-oxo-5-carboxy tetrahydrofuran moieties. Terreusterpene D (4) was characterized by a 4-hydroxy-3-methyl gamma lactone fragment that was generated by accident from the rearrangement of 3 in a mixed tetrahydrofuran-H2O-MeOH solvent. All these compounds were evaluated for the ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and acetylcholinesterase (AchE) inhibitory activities. Among them, compounds 1 and 2 showed potentially significant BACE1 inhibitory activity, with IC50 values of 5.98 and 11.42 µM, respectively. Interestingly, compound 4 exhibited promising BACE1 and AchE inhibitory activities, with IC50 values of 1.91 and 8.86 µM, respectively, while 3 showed no such activity. Taken together, terreusterpenes A and B could be of great importance for the development of new BACE1 inhibitors, while terreusterpene D could serve as the first dual-targeted 3,5-dimethylorsellinic acid-based meroterpenoid for the treatment of Alzheimer's disease.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspergillus/chemistry , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Resorcinols/chemistry , Resorcinols/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Cholinesterase Inhibitors/chemical synthesis , Crystallography, X-Ray , GPI-Linked Proteins/antagonists & inhibitors , GPI-Linked Proteins/metabolism , Humans , Models, Molecular , Molecular Docking Simulation , Resorcinols/chemical synthesisABSTRACT
The protecting group manoeuvring as a strategy was applied for tuning the stability and reactivity of 4-(2,2-dibromovinyl)benzene-1,3-diol (12a) and 6-(2,2-dibromovinyl)-2,2-dimethylchroman-7-ol (22) in the domino synthesis of benzofuran-based natural products (1-8). The functional group demands and their impact on the reactivity driven by electronic effects were successfully managed by varying the protecting groups with substituted gem-dibromovinylphenols in domino couplings and triarylbismuth reagents under palladium-catalyzed conditions. This approach paved the way for the synthesis of moracin M (1) and cicerfuran (2), and the first time synthesis of moracin D (3) and moracin E (4) along with chromene-fused benzofuran-based natural products (5-8) in overall good yields.
Subject(s)
Benzofurans/chemistry , Benzofurans/chemical synthesis , Benzopyrans/chemistry , Biological Products/chemistry , Biological Products/chemical synthesis , Chemistry Techniques, Synthetic , Drug Stability , Resorcinols/chemical synthesis , Resorcinols/chemistryABSTRACT
Peptide-based cavitands (resorcin[4]arenes substituted with histidine and glutamine hydrazides) exist as monomeric species in polar solvents (DMSO and methanol). Upon complexation of fullerenes, the cavitands wrap around the hydrophobic guests forming dimeric capsular shells (as evidenced by DOSY). The self-assembly of the cavitands is based on the formation of beta-sheet-like binding motifs around the hydrophobic core. In a polar environment, these hydrogen bonded structures are kinetically stable and highly ordered as manifested by a 100-fold increase of intensity of circular dichroism bands, as well as a separate set of signals and substantial differences in chemical shifts in NMR spectra. This behavior resembles a protein folding process at the molten globule stage with non-specific hydrophobic interactions creating a protective and favourable local environment for the formation of secondary structures of proteins.
Subject(s)
Ethers, Cyclic/chemical synthesis , Peptides/chemistry , Resorcinols/chemical synthesis , Ethers, Cyclic/chemistry , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Molecular Structure , Resorcinols/chemistryABSTRACT
Total synthesis of the proposed structure of baulamycin A was performed. The spectral properties of the synthetic compound differ from those reported for the natural product. On the basis of comprehensive NMR study, we proposed two other possible structures for natural baulamycin A. Total syntheses of these two substances were performed, which enabled assignment of the correct structure of baulamycin A. Key features of the convergent and fully stereocontrolled route include Evans Aldol and Brown allylation reactions to construct the left fragment, a prolinol amide-derived alkylation/desymmetrization to install the methyl-substituted centers in the right fragment, and finally, a Carreira alkynylation to join both fragments. In addition, we have determined the inhibitory activities of novel baulamycin A derivatives against the enzyme SbnE. This SAR study provides useful insight into the design of novel SbnE inhibitors that overcome the drug resistance of pathogens, which cause life-threatening infections.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Fatty Alcohols/chemical synthesis , Resorcinols/chemical synthesis , Alkylation , Drug Resistance, Bacterial/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fatty Alcohols/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Resorcinols/chemistry , Structure-Activity RelationshipABSTRACT
Small-molecule, biologically active natural products continue to be our most rewarding source of, and inspiration for, new medicines. Sometimes we happen upon such molecules in minute quantities in unique, difficult-to-reach, and often fleeting environments, perhaps never to be discovered again. In these cases, determining the structure of a molecule-including assigning its relative and absolute configurations-is paramount, enabling one to understand its biological activity. Molecules that comprise stereochemically complex acyclic and conformationally flexible carbon chains make such a task extremely challenging. The baulamycins (A and B) serve as a contemporary example. Isolated in small quantities and shown to have promising antimicrobial activity, the structure of the conformationally flexible molecules was determined largely through J-based configurational analysis, but has been found to be incorrect. Our subsequent campaign to identify the true structures of the baulamycins has revealed a powerful method for the rapid structural elucidation of such molecules. Specifically, the prediction of nuclear magnetic resonance (NMR) parameters through density functional theory-combined with an efficient sequence of boron-based synthetic transformations, which allowed an encoded (labelled) mixture of natural-product diastereomers to be prepared-enabled us rapidly to pinpoint and synthesize the correct structures.
Subject(s)
Fatty Alcohols/chemistry , Fatty Alcohols/chemical synthesis , Magnetic Resonance Spectroscopy , Molecular Structure , Resorcinols/chemistry , Resorcinols/chemical synthesis , Chemistry Techniques, Synthetic , Models, Molecular , StereoisomerismABSTRACT
We investigated the influence of bronchodilating ß2-agonists on the activity of human acetylcholinesterase (AChE) and usual, atypical and fluoride-resistant butyrylcholinesterase (BChE). We determined the inhibition potency of racemate and enantiomers of fenoterol as a resorcinol derivative, isoetharine and epinephrine as catechol derivatives and salbutamol and salmeterol as saligenin derivatives. All of the tested compounds reversibly inhibited cholinesterases with Ki constants ranging from 9.4 µM to 6.4 mM and had the highest inhibition potency towards usual BChE, but generally none of the cholinesterases displayed any stereoselectivity. Kinetic and docking results revealed that the inhibition potency of the studied compounds could be related to the size of the hydroxyaminoethyl chain on the benzene ring. The additional π-π interaction of salmeterol's benzene ring and Trp286 and hydrogen bond with His447 probably enhanced inhibition by salmeterol which was singled out as the most potent inhibitor of all the cholinesterases.