RESUMO
Recent discoveries have demonstrated that the physiological function of bile acids extends to the regulation of diverse signaling processes through interactions with nuclear and G protein-coupled receptors, most notably the Farnesoid-X nuclear receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Targeting such signaling pathways pharmacologically, i.e. with bile acid-derived therapeutics, presents great potential for the treatment of various metabolic, inflammatory immune, liver, and neurodegenerative diseases. Here we report the discovery of two potent and selective TGR5 agonists (NZP196 and 917). These compounds are the taurine conjugates of 6α-ethyl-substituted 12ß-methyl-18-nor-bile acids with the side chain being located on the α-face of the steroid scaffold. The compounds emerged from a screening effort of a diverse library of 12ß-methyl-18-nor-bile acids that were synthesized from 12ß-methyl-18-nor-chenodeoxycholic acid and its C17-epimer. Upon testing for FXR activity, both compounds were found to be inactive, thus revealing selectivity for TGR5.
Assuntos
Ácidos e Sais Biliares , Receptores Acoplados a Proteínas G , Ácidos e Sais Biliares/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Transdução de Sinais , Fígado/metabolismo , Ácido QuenodesoxicólicoRESUMO
Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure-activity relationships and define compounds that activate these receptors selectively. Towards this, access to large quantities of a chenodeoxycholic acid derivative bearing a C-12 methyl and a C-13 to C-14 double bond provided an interesting scaffold to investigate the chemical manipulation of the C/D ring junction in bile acids. The reactivity of this alkene substrate with various zinc carbenoid species showed that those generated using the Furukawa methodology achieved selective α-cyclopropanation, whereas those generated using the Shi methodology reacted in an unexpected manner giving rise to a rearranged skeleton whereby the C ring has undergone contraction to form a novel spiro-furan ring system. Further derivatization of the cyclopropanated steroid included O-7 oxidation and epimerization to afford new bile acid derivatives for biological evaluation.
Assuntos
Ácidos e Sais Biliares , Ácido Quenodesoxicólico , Ácido Quenodesoxicólico/química , Oxirredução , Esteroides , Relação Estrutura-AtividadeRESUMO
In the quest for new modulators of the Farnesoid-X (FXR) and Takeda G-protein-coupled (TGR5) receptors, bile acids are a popular candidate for drug development. Recently, bile acids endowed with a C16-hydroxy group emerged as ligands of FXR and TGR5 with remarkable agonistic efficacies. Inspired by these findings, we synthesised a series of C16-hydroxylated 12ß-methyl-18-nor-bile acid analogues from a Δ13(17)-12ß-methyl-18-nor-chenodeoxycholic acid intermediate (16), the synthesis of which we reported previously. The preparation of these aptly named 12ß-methyl-18-nor-avicholic acids (17, 18, 41 and 42) was accomplished via allylic oxidation at C16, hydrogenation of the C13âC17 double bond and selective reduction of the C16-carbonyl group. Described also are various side products which were isolated during the evaluation of methods to affect the initial allylic oxidation. In addition, C23-methyl modified 12ß-methyl-18-nor-bile acids with (48, 49, 51 and 52) and without a C16-hydroxy group (45, 46 and 55), were synthesized to enable comparison of biological activities between these compounds and their un-methylated counterparts. As a result of our investigations we identified (23R)-12ß,23-dimethyl-18-nor-chenodeoxycholic acid (46) and 12ß-methyl-17-epi-18-nor-chenodeoxycholic acid 53 as TGR5 ligands with EC50 values of 25 µM.
Assuntos
Ácidos e Sais Biliares , Ácido Quenodesoxicólico , Ácidos e Sais Biliares/farmacologia , Ácido Quenodesoxicólico/análogos & derivados , Hidrogenação , LigantesRESUMO
Hypermethylation of CpG regions by human DNA methyltransferase 1 (DNMT1) silences tumor-suppression genes, and inhibition of DNMT1 can reactivate silenced genes. The 5-azacytidines are approved inhibitors of DNMT1, but their mutagenic mechanism limits their utility. A synthon approach from the analogues of S-adenosylhomocysteine, methionine, and deoxycytidine recapitulated the chemical features of the DNMT1 transition state in the synthesis of 16 chemically stable transition-state mimics. Inhibitors causing both full and partial inhibition of purified DNMT1 were characterized. The inhibitors show modest selectivity for DNMT1 versus DNMT3b. Active-site docking predicts inhibitor interactions with S-adenosyl-l-methionine and deoxycytidine regions of the catalytic site, validated by direct binding analysis. Inhibitor action with purified DNMT1 is not reflected in cultured cells. A partial inhibitor activated cellular DNA methylation, and a full inhibitor had no effect on cellular DNA methylation. These compounds provide chemical access to a new family of noncovalent DNMT chemical scaffolds for use in DNA methyltransferases.
Assuntos
DNA (Citosina-5-)-Metiltransferases , Metilação de DNA , Linhagem Celular , DNA/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilases de Modificação do DNA/metabolismo , Desoxicitidina/metabolismo , HumanosRESUMO
The quest for isoform-selective and specific ATP-competitive protein kinase inhibitors is of great interest, as inhibitors with these qualities will come with reduced toxicity and improved efficacy. However, creating such inhibitors is very challenging due to the high molecular similarity of kinases ATP active sites. To achieve selectivity for our casein kinase (CK) 1 inhibitor series, we elected to endow our previous CK1δ-hit, 3-(4-fluorophenyl)-5-isopropyl-4-(pyridin-4-yl)isoxazole (1), with chiral iminosugar scaffolds. These scaffolds were attached to C5 of the isoxazole ring, a position deemed favorable to facilitate binding interactions with the ribose pocket/solvent-open area of the ATP binding pocket of CK1δ. Here, we describe the synthesis of analogs of 1 ((-)-/(+)-34, (-)-/(+)-48), which were prepared in 13 steps from enantiomerically pure ethyl (3R,4S)- and ethyl (3S,4R)-1-benzyl-4-[(tert-butyldimethylsilyl)oxy]-5-oxopyrrolidine-3-carboxylate ((-)-11 and (+)-11), respectively. The synthesis involved the coupling of Weinreb amide-activated chiral pyrrolidine scaffolds with 4- and 2-fluoro-4-picoline and reaction of the resulting 4-picolyl ketone intermediates ((-)-/(+)-40 and (-)-/(+)-44) with 4-fluoro-N-hydroxybenzenecarboximidoyl chloride to form the desired isoxazole ring. The activity of the compounds against human CK1δ, -ε, and -α was assessed in recently optimized in vitro assays. Compound (-)-34 was the most active compound with IC50 values (CK1δ/ε) of 1/8 µM and displayed enhanced selectivity toward CK1δ.
Assuntos
Caseína Quinase Idelta , Trifosfato de Adenosina/metabolismo , Caseína Quinase Idelta/química , Caseína Quinase Idelta/metabolismo , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Inibidores de Proteínas Quinases , Relação Estrutura-AtividadeRESUMO
Parkinson's Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson's Disease. Furthermore, ursodeoxycholic acid (UDCA) has been identified as a bile acid which leads to increased mitochondrial function in multiple in vitro and in vivo models of Parkinson's Disease. Here, we describe the synthesis of novel C-nor-D-homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid (7) and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson's Disease. These compounds boost mitochondrial function to a similar level or above that of UDCA in many assays; notable, however, is their ability to boost mitochondrial function to a higher level and at lower concentrations than UDCA specifically in the fibroblasts from LRRK2 patients. Our study indicates that novel bile acid chemistry could lead to the development of more efficacious bile acids which increase mitochondrial function and ultimately cellular health at lower concentrations proving attractive potential novel therapeutics for Parkinson's Disease.
Assuntos
Doença de Parkinson , Humanos , Ácidos e Sais Biliares , Doença de Parkinson/tratamento farmacológico , Ácido Ursodesoxicólico/farmacologia , Colanos/químicaRESUMO
Diffuse gastric cancer and lobular breast cancer are aggressive malignancies that are frequently associated with inactivating mutations in the tumor suppressor gene CDH1. Synthetic lethal (SL) vulnerabilities arising from CDH1 dysfunction represent attractive targets for drug development. Recently, SLEC-11 (1) emerged as a SL lead in E-cadherin-deficient cells. Here, we describe our efforts to optimize 1. Overall, 63 analogues were synthesized and tested for their SL activity toward isogenic mammary epithelial CDH1-deficient cells (MCF10A-CDH1-/-). Among the 26 compounds with greater cytotoxicity, AL-GDa62 (3) was four-times more potent and more selective than 1 with an EC50 ratio of 1.6. Furthermore, 3 preferentially induced apoptosis in CDH1-/- cells, and Cdh1-/- mammary and gastric organoids were significantly more sensitive to 3 at low micromolar concentrations. Thermal proteome profiling of treated MCF10A-CDH1-/- cell protein lysates revealed that 3 specifically inhibits TCOF1, ARPC5, and UBC9. In vitro, 3 inhibited SUMOylation at low micromolar concentrations.
Assuntos
Antineoplásicos/uso terapêutico , Descoberta de Drogas , Neoplasias Gástricas/tratamento farmacológico , Antígenos CD/genética , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caderinas/genética , Linhagem Celular Tumoral , Humanos , Mutação , Neoplasias Gástricas/patologiaRESUMO
Decoupling the roles of the farnesoid X nuclear receptor and Takeda G-protein-coupled bile acid receptor 5 is essential for the development of novel bile acid therapeutics targeting metabolic and neurodegenerative diseases. Herein, we describe the synthesis of 12ß-methyl-18-nor-bile acids which may serve as probes in the search for new bile acid analogues with clinical applicability. A Nametkin-type rearrangement was applied to protected cholic acid derivatives, giving rise to tetra-substituted Δ13,14- and Δ13,17-unsaturated 12ß-methyl-18-nor-bile acid intermediates (24a and 25a). Subsequent catalytic hydrogenation and deprotection yielded 12ß-methyl-18-nor-chenodeoxycholic acid (27a) and its 17-epi-epimer (28a) as the two major reaction products. Optimization of the synthetic sequence enabled a chromatography-free route to prepare these bile acids at a multi-gram scale. In addition, the first cis-C-D ring-junctured bile acid and a new 14(13 â 12)-abeo-bile acid are described. Furthermore, deuteration experiments were performed to provide mechanistic insights into the formation of the formal anti-hydrogenation product 12ß-methyl-18-nor-chenodeoxycholic acid (27a).
RESUMO
The cell-cell adhesion protein E-cadherin (CDH1) is a tumor suppressor that is required to maintain cell adhesion, cell polarity and cell survival signalling. Somatic mutations in CDH1 are common in diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In addition, germline mutations in CDH1 predispose to the autosomal dominant cancer syndrome Hereditary Diffuse Gastric Cancer (HDGC). One approach to target cells with mutations in specific tumor suppressor genes is synthetic lethality. To identify novel synthetic lethal compounds for the treatment of cancers associated with E-cadherin loss, we have undertaken a high-throughput screening campaign of ~114,000 lead-like compounds on an isogenic pair of human mammary epithelial cell lines - with and without CDH1 expression. This unbiased approach identified 12 novel compounds that preferentially harmed E-cadherin-deficient cells. Validation of these compounds using both real-time and end-point viability assays identified two novel compounds with significant synthetic lethal activity, thereby demonstrating that E-cadherin loss creates druggable vulnerabilities within tumor cells. In summary, we have identified novel synthetic lethal compounds that may provide a new strategy for the prevention and treatment of both sporadic and hereditary LBC and DGC.
Assuntos
Antígenos CD/genética , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Caderinas/genética , Neoplasias Gástricas/genética , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Caderinas/deficiência , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Mutação em Linhagem Germinativa , Humanos , Neoplasias Gástricas/metabolismoRESUMO
In this study, we report on the modification of a 3,4-diaryl-isoxazole-based CK1 inhibitor with chiral pyrrolidine scaffolds to develop potent and selective CK1 inhibitors. The pharmacophore of the lead structure was extended towards the ribose pocket of the adenosine triphosphate (ATP) binding site driven by structure-based drug design. For an upscale compatible multigram synthesis of the functionalized pyrrolidine scaffolds, we used a chiral pool synthetic route starting from methionine. Biological evaluation of key compounds in kinase and cellular assays revealed significant effects of the scaffolds towards activity and selectivity, however, the absolute configuration of the chiral moieties only exhibited a limited effect on inhibitory activity. X-ray crystallographic analysis of ligand-CK1δ complexes confirmed the expected binding mode of the 3,4-diaryl-isoxazole inhibitors. Surprisingly, the original compounds underwent spontaneous Pictet-Spengler cyclization with traces of formaldehyde during the co-crystallization process to form highly potent new ligands. Our data suggests chiral "ribose-like" pyrrolidine scaffolds have interesting potential for modifications of pharmacologically active compounds.
Assuntos
Caseína Quinase Idelta/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Isoxazóis/química , Trifosfato de Adenosina/química , Sítios de Ligação , Caseína Quinase Idelta/química , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Ligantes , Complexos Multiproteicos/química , Pirrolidinas/química , Relação Estrutura-AtividadeRESUMO
The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1δ inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38α MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1δ with compounds 11b (IC50 CK1δ = 4 nM, IC50 CK1ε = 25 nM), 12a (IC50 CK1δ = 19 nM, IC50 CK1ε = 227 nM), and 16b (IC50 CK1δ = 8 nM, IC50 CK1ε = 81 nM) being among the most potent CK1δ-targeting agents published to date. Inhibitor compound 11b, displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC50 = 3.5 µM) and Panc89 (EC50 = 1.5 µM). SAR is substantiated by X-ray crystallographic analysis of 16b in CK1δ and 11b in p38α.
Assuntos
Caseína Quinase Idelta/antagonistas & inibidores , Imidazóis/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/química , Inibidores de Proteínas Quinases/farmacologia , Trifosfato de Adenosina/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Imidazóis/síntese química , Imidazóis/química , Concentração Inibidora 50 , Modelos Moleculares , Filogenia , Inibidores de Proteínas Quinases/químicaRESUMO
MTDIA is a picomolar transition state analogue inhibitor of human methylthioadenosine phosphorylase and a femtomolar inhibitor of Escherichia coli methylthioadenosine nucleosidase. MTDIA has proven to be a non-toxic, orally available pre-clinical drug candidate with remarkable anti-tumour activity against a variety of human cancers in mouse xenografts. The structurally similar compound MTDIH is a potent inhibitor of human and malarial purine nucleoside phosphorylase (PNP) as well as the newly discovered enzyme, methylthioinosine phosphorylase, isolated from Pseudomonas aeruginosa. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the enantiomers of MTDIH and MTDIA, compounds 1 and 2, respectively, were prepared and their enzyme binding properties studied. Despite binding less tightly to their target enzymes than their enantiomers compounds 1 and 2 are nanomolar inhibitors.
Assuntos
Adenina/análogos & derivados , Escherichia coli/enzimologia , Plasmodium falciparum/enzimologia , Pseudomonas aeruginosa/enzimologia , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Pirrolidinas/química , Pirrolidinas/farmacologia , Adenina/química , Adenina/farmacologia , Descoberta de Drogas , Escherichia coli/efeitos dos fármacos , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Plasmodium falciparum/efeitos dos fármacos , Ligação Proteica , Pseudomonas aeruginosa/efeitos dos fármacos , Purina-Núcleosídeo Fosforilase/metabolismo , EstereoisomerismoRESUMO
The title compound, C(29)H(35)NO(6).0.334C(3)H(8)O, a novel chiral N-(fluoren-9-yl-methyl-oxyxcarbon-yl) precursor, crystallizes with two independent carbamate (M) mol-ecules and propan-2-ol solvent mol-ecules in the unit cell. Its crystal structure has been determined from barely adequate data obtained from a multi-fragment needle crystal. In the crystal, N-Hâ¯O hydrogen bonds link M mol-ecules related by translation along the a axis into two independent chains. The ordered solvent mol-ecule, having a partial occupancy of 0.334, is attached to one independent M mol-ecule through O-Hâ¯O hydrogen bonds. The crystal packing exhibits weak inter-molecular C-Hâ¯O inter-actions and voids of 270â Å(3) filled with randomly disordered solvent mol-ecules which were handled using the SQUEEZE methodology.
RESUMO
Ethyl- (7), benzyl- (8), tert-butyl- (9), and fluorenylmethyl-4-chlorobenzoyloxycarbamates (10) have been prepared as storable and easy-to-prepare nitrogen sources for use in the intermolecular Sharpless aminohydroxylation reaction and its asymmetric variant. These reagents were found to be effective under base-free reaction conditions. The scope and limitations of these methods have been explored using a variety of alkenes, among which, trans-cinnamates, in particular, proved to be good substrates.
Assuntos
Alcanos/química , Carbamatos/química , Indicadores e Reagentes/química , Nitrogênio/química , Catálise , Cromatografia Líquida de Alta Pressão , Hidroxilação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Estereoisomerismo , Raios UltravioletaRESUMO
The absolute configuration of the title cis-(1R,3R,4S)-pyrrolidine-borane complex, C(18)H(34)BNO(2)Si, was confirmed. Together with the related trans isomers (3S,4S) and (3R,4R), it was obtained unexpectedly from the BH(3) x SMe(2) reduction of the corresponding chiral (3R,4R)-lactam precursor. The phenyl ring is disordered over two conformations in the ratio 0.65:0.35. The crystallographic packing is dominated by the rarely found donor-acceptor hydroxy-borane O-H...H-B hydrogen bonds.
Assuntos
Boranos/química , Lactamas/química , Pirrolidinas/química , Cristalografia por Raios X , Ligação de Hidrogênio , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The title compound, C(29)H(31)N(3)O(5)S, forms needle-shaped ;segmented' crystals, thereby inhibiting successful single-crystal data collection using conventional laboratory facilities. One crystallite of dimensions 0.15 x 0.03 x 0.01 mm yielded sufficent single-crystal diffraction data on the Australian Synchrotron PX1 beamline. The two independent molecules in the asymmetric unit are nearly superimposable and show only minor conformational deviations from closely related compounds. The molecules pack using one N-H...O hydrogen bond and several phenyl C-H...O(=S), phenyl C-H...O(=C) and methylene C-H...O(=C) hydrogen bonds and weak C-H...pi interactions.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Pirróis/química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura MolecularRESUMO
The title compound, C(27)H(36)N(2)O(7)S, (I), is isomorphous by addition with the dimethyl ester analogue [Garner, Dogan, Youngs, Kennedy, Protasiewicz & Zaniewski (2001). Tetrahedron, 57, 71-85], (II), by replacing two methyl ester H atoms with two methyl groups. With the exception of the conformation of one of the ester groups, the molecules are almost superimposable. Likewise, apart from a slightly larger c axis in (I), few differences in the cell packing of (I) and (II) are found, with both dominated by the same C-H...O hydrogen bonds. Full synthetic and spectroscopic details of (I) are given. The molecular synthesis is important as an example of chiral auxiliary-assisted 1,3-dipolar cycloaddition of an azomethine ylid.
Assuntos
Ácidos Dicarboxílicos/química , Compostos Heterocíclicos com 3 Anéis/química , Pirrolidinas/química , Ácidos Dicarboxílicos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Ligação de Hidrogênio , Estrutura Molecular , Pirrolidinas/síntese química , EstereoisomerismoRESUMO
Mol-ecules of the title compound [systematic name: (2R,5S,7S)-2-phenyl-7-phenyl-sulfanyl-1-aza-3-oxa-bicyclo-[3.3.0]octan-8-one], C(18)H(17)NO(2)S, form high quality crystals even though they are only packed using C-Hâ¯O(carbon-yl) and weak C-Hâ¯S inter-actions. The dihedral angle between the aromatic rings is 85.53â (5)°. The fused rings adopt envelope and twist conformations.
RESUMO
Mycobacterium tuberculosis and many other members of the Actinomycetes family produce mycothiol, i.e., 1-d-myo-inosityl-2-(N-acetyl-l-cysteinyl)amido-2-deoxy-alpha-d-glucopyranoside (MSH or AcCys-GlcN-Ins), to act against oxidative and antibiotic stress. The biosynthesis of MSH is essential for cell growth and has been proposed to proceed via a biosynthetic pathway involving four key enzymes, MshA-MshD. The MSH biosynthetic enzymes present potential targets for inhibitor design. With this as a long-term goal, we have carried out a kinetic and mechanistic characterization, using steady-state and pre-steady-state approaches, of the recombinant Mycobacterium smegmatis MshC. MshC catalyzes the ATP-dependent condensation of GlcN-Ins and cysteine to form Cys-GlcN-Ins. Initial velocity and inhibition studies show that the steady-state kinetic mechanism of MshC is a Bi Uni Uni Bi Ping Pong mechanism, with ATP binding followed by cysteine binding, release of PPi, binding of GlcN-Ins, followed by the release of Cys-GlcN-Ins and AMP. The steady-state kinetic parameters were determined to be kcat equal to 3.15 s-1, and Km values of 1.8, 0.1, and 0.16 mM for ATP, cysteine, and GlcN-Ins, respectively. A stable bisubstrate analogue, 5'-O-[N-(l-cysteinyl)sulfamonyl]adenosine, exhibits competitive inhibition versus ATP and noncompetitive inhibition versus cysteine, with an inhibition constant of approximately 306 nM versus ATP. Single-turnover reactions of the first and second half reactions were determined using rapid-quench techniques, giving rates of approximately 9.4 and approximately 5.2 s-1, respectively, consistent with the cysteinyl adenylate being a kinetically competent intermediate in the reaction by MshC.
Assuntos
Cisteína/metabolismo , Ligases/metabolismo , Mycobacterium smegmatis/enzimologia , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Catálise , Cisteína/química , Difosfatos/química , Difosfatos/metabolismo , Glucosamina/química , Glucosamina/metabolismo , Glicopeptídeos/química , Glicopeptídeos/metabolismo , Concentração de Íons de Hidrogênio , Inositol/química , Inositol/metabolismo , Cinética , Ligases/química , Ligases/genética , Modelos Químicos , Estrutura MolecularRESUMO
A synthesis of the ABC framework of dumsin is described. The optically active intermediate 9b, which is expeditiously assembled from 5-oxobornyl pivalate by the sequential implementation of an oxy-Cope rearrangement and an intramolecular ene reaction, proved to be suitably functionalized for ultimate conversion to 5. The synthesis plan relies on two approaches to this targeted intermediate. In the first, the exocyclic double bond introduced during EtAlCl2-promoted closure of aldehyde 10b is cleaved to leave a carbonyl group that is amenable to hydride reduction and elimination of water. Cleavage of the resulting double bond with ruthenium tetroxide provided the seco ketoacid. The same advanced intermediate was obtained by initially positioning the double bond internal to the five-membered ring in advance of transient ring expansion via diketone formation and intramolecular aldolization. Both of these approaches bypass the complications arising from the substantial steric congestion prevailing in these structural networks. The task of covalently positioning an oxygen atom adjacent to the gem-dimethyl-substituted carbon in 5 was properly realized by oxidative decarboxylation. The stereochemical assignments to many of the intermediates were confirmed by an X-ray crystallographic analysis of 43.