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1.
J Org Chem ; 86(2): 1955-1963, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33400878

RESUMO

In this work, we report a novel and simple one-pot synthesis of substituted dibenzo[b,f]oxepines under transition-metal-free conditions. This cascade process involves nucleophilic aromatic substitution followed by Knoevanagel condensation, as evidenced by the isolated reaction intermediates. We have also achieved the synthesis of anticancer bauhinoxepin C in 7 steps with 5.1% overall yield using this synthetic approach.


Assuntos
Elementos de Transição , Estrutura Molecular
2.
J Antibiot (Tokyo) ; 72(6): 397-406, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30894676

RESUMO

The synthesis of functionalized pyroglutamates 15 and 16 could be achieved by the application of recently developed diastereodivergent asymmetric Michael addition reaction of iminoglycinate 7 to ethyl γ-silyloxycrotonate with >98:<2 diastereoselectivity followed by hydrolysis and lactamization. Formal syntheses of (-)-isoretronecanol and (+)-laburnine as well as a concise enantioselective synthesis of (+)-turneforcidine could be achieved from functionalized pyroglutamates 15 or 16.


Assuntos
Alcaloides de Pirrolizidina/síntese química , Catálise , Estrutura Molecular , Alcaloides de Pirrolizidina/química , Estereoisomerismo
3.
Angew Chem Int Ed Engl ; 57(47): 15572-15576, 2018 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-30284752

RESUMO

The first total synthesis of isopalhinine A, as well as unified syntheses of palhinine A and palhinine D, were successfully accomplished by means of a biomimetic strategy that proceeds through a bioinspired 5/6/6/9 tetracyclic intermediate, which mimics the amino ketone form of palhinine D. An early-stage direct SN 2 cyclization to construct the nine-membered azonane ring minimized the transannular strain that would otherwise be increased by the twisted nature of the isotwistane skeleton. Then, a diastereoselective Diels-Alder reaction of a masked ortho-benzoquinone using the nine-membered ring as a steric shielding group furnished a functionalized 6/6/9 tricyclic skeleton and established the desired stereochemistry at the C3, C7, C12, and C15 positions in one step. A thiol-mediated acyl radical cyclization gave the bioinspired intermediate bearing three differentiated oxygen-containing functional groups, from which all three total syntheses could be completed in either two or three additional steps.


Assuntos
Alcaloides/síntese química , Lycopodium/química , Triterpenos Pentacíclicos/síntese química , Alcaloides/química , Benzoquinonas/síntese química , Benzoquinonas/química , Biomimética , Ciclização , Reação de Cicloadição , Triterpenos Pentacíclicos/química , Estereoisomerismo
4.
J Org Chem ; 83(17): 10564-10572, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30058334

RESUMO

Asymmetric Michael reaction of iminoglycinate 4 to α,ß-unsaturated esters had been developed with >98:<2 diastereoselectivity. A reverse of diastereoselectivity for Michael reaction could be achieved by the replacement of lithium enolate with magnesium enolate. This methodology was applied to the total syntheses of (+)-α-allokainic acid 1 and (-)-2- epi-α-allokainic acid 6 each in 11 synthetic steps starting from 4 in 17.8 and 18.0% yields, respectively.

5.
Beilstein J Org Chem ; 14: 389-396, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29520303

RESUMO

We herein report that the regioselective anodic fluorination of S-alkyl benzothioate and its derivatives in various aprotic solvents using Et3N·nHF (n = 3-5) and Et4NF·nHF (n = 3-5) as supporting electrolyte and a fluorine source successfully provided the corresponding α-fluorinated products in moderate yields. Dichloromethane containing Et4NF·4HF was found to be the most suitable combination as electrolytic solvent and supporting salt as well as fluorine source for the anodic fluorination. The electrochemical fluorination of cyclic benzothioates such as benzothiophenone was also achieved.

6.
Eur J Med Chem ; 124: 186-199, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27573544

RESUMO

Aurora kinases have emerged as important anticancer targets so that there are several inhibitors have advanced into clinical study. Herein, we identified novel indazole derivatives as potent Aurora kinases inhibitors by utilizing in silico fragment-based approach and knowledge-based drug design. After intensive hit-to-lead optimization, compounds 17 (dual Aurora A and B), 21 (Aurora B selective) and 30 (Aurora A selective) possessed indazole privileged scaffold with different substituents, which provide sub-type kinase selectivity. Computational modeling helps in understanding that the isoform selectivity could be targeted specific residue in the Aurora kinase binding pocket in particular targeting residues Arg220, Thr217 or Glu177.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Simulação por Computador , Desenho de Fármacos , Indazóis/química , Indazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Aurora Quinase A/química , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica
8.
Chem Asian J ; 10(4): 998-1003, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25523335

RESUMO

The enantioselective addition of diethylzinc or dimethylzinc to N-(diphenylphosphinoyl)imines mediated by 1 or 2 could be achieved in high yields (70-97 %) and enantioselectivities (85-98 % ee). The catalytic loading of 1 or 2 a could be reduced to 10 mol % for methylation or ethylation of imines in high yields and enantioselectivities (79-96 %) when the reaction was conducted in the presence of 1.8 equiv of methanol. N-Monosubstituted amino alcohols induced higher enantioselectivity than their N,N-disubstituted congener in our catalytic system.


Assuntos
Amino Álcoois/química , Cânfora/química , Hidrocarbonetos Aromáticos/síntese química , Estrutura Molecular
9.
Chem Asian J ; 9(9): 2444-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25044373

RESUMO

The pyrrolidine-camphorsulfonamide-based catalyst 1 a catalyzes the enantioselective conjugate addition of nitroalkanes to α,ß-unsaturated aldehydes in the presence of five equivalents of water in iPrOH to give the corresponding chiral Michael adducts in good yields and high enantioselectivities (up to 99% ee) with a catalyst loading as low as 1 mol%.

10.
J Urol ; 191(5): 1429-38, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24316097

RESUMO

PURPOSE: Hormone refractory metastatic prostate cancer is a major obstacle in clinical treatment. The key focus of this study was the discovery and development of a potential agent for this disease. MATERIALS AND METHODS: Several pharmacological and biochemical assays were used to characterize the apoptotic signaling pathways of moniliformediquinone, a natural product, in hormone refractory metastatic prostate cancer. RESULTS: Moniliformediquinone induced cell cycle arrest at the S-phase and subsequent apoptosis in the hormone refractory metastatic prostate cancer cell lines PC-3 and DU-145. Further examination showed that moniliformediquinone induced a DNA damage response associated with Chk1, Chk2, c-Jun and JNK activation. Mitochondrial apoptosis pathways were also activated, including loss of mitochondrial membrane potential, cytochrome c release, and activation of caspase-9 and 3. The antioxidant and glutathione precursor N-acetylcysteine, and the antioxidant Trolox™ completely abolished moniliformediquinone induced generation of reactive oxygen species. However, N-acetylcysteine but not Trolox blocked moniliformediquinone mediated apoptosis and related signaling cascades. Further identification showed that moniliformediquinone alone did not conjugate glutathione but significantly decreased cellular glutathione levels. The in vivo study revealed that moniliformediquinone completely inhibited tumor growth with no weight loss. CONCLUSIONS: Our data suggest that moniliformediquinone is a potential anticancer agent for hormone refractory metastatic prostate cancer by decreasing cellular glutathione, leading to a DNA damage response and cell cycle arrest at the S-phase. Mitochondrial stress also occurs due to moniliformediquinone action through loss of mitochondrial membrane potential and cytochrome c release, which in turn induce the activation of caspase cascades and apoptotic cell death.


Assuntos
Antineoplásicos/uso terapêutico , Dano ao DNA , Glutationa/fisiologia , Mitocôndrias/metabolismo , Fenantrenos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Quinonas/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Células Tumorais Cultivadas
11.
Diabetes ; 62(2): 628-38, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23069626

RESUMO

The therapeutic effect of pterosin A, a small-molecular-weight natural product, on diabetes was investigated. Pterosin A, administered orally for 4 weeks, effectively improved hyperglycemia and glucose intolerance in streptozotocin, high-fat diet-fed, and db/db diabetic mice. There were no adverse effects in normal or diabetic mice treated with pterosin A for 4 weeks. Pterosin A significantly reversed the increased serum insulin and insulin resistance (IR) in dexamethasone-IR mice and in db/db mice. Pterosin A significantly reversed the reduced muscle GLUT-4 translocation and the increased liver phosphoenolpyruvate carboxyl kinase (PEPCK) expression in diabetic mice. Pterosin A also significantly reversed the decreased phosphorylations of AMP-activated protein kinase (AMPK) and Akt in muscles of diabetic mice. The decreased AMPK phosphorylation and increased p38 phosphorylation in livers of db/db mice were effectively reversed by pterosin A. Pterosin A enhanced glucose uptake and AMPK phosphorylation in cultured human muscle cells. In cultured liver cells, pterosin A inhibited inducer-enhanced PEPCK expression, triggered the phosphorylations of AMPK, acetyl CoA carboxylase, and glycogen synthase kinase-3, decreased glycogen synthase phosphorylation, and increased the intracellular glycogen level. These findings indicate that pterosin A may be a potential therapeutic option for diabetes.


Assuntos
Produtos Biológicos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Indanos/uso terapêutico , Sesquiterpenos/uso terapêutico , Animais , Transporte Biológico/efeitos dos fármacos , Células Cultivadas , Dexametasona/efeitos adversos , Modelos Animais de Doenças , Glucose/metabolismo , Intolerância à Glucose/tratamento farmacológico , Transportador de Glucose Tipo 4/metabolismo , Humanos , Hiperglicemia/tratamento farmacológico , Insulina/sangue , Resistência à Insulina/fisiologia , Fígado/enzimologia , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos
12.
Chem Asian J ; 7(12): 2921-4, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23042702

RESUMO

An effective catalytic system that imparts high enantioselectivity has been disclosed for the synthesis of optically active alcohols, which may undergo further chemical transformations. The enantioselective alkylation of aldehydes with dialkylzincs to afford the corresponding optically active alcohols with excellent enantioselectvities has been achieved in the presence of 0.1-0.5 mol % of the camphor-derived chiral ligand (-)-2-exo-morpholinoisobornane-10-thiol (MITH) (1) at room temperature or at 0 °C.

13.
J Med Chem ; 53(11): 4545-9, 2010 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-20481438

RESUMO

A series of small molecules bearing an alpha-ketoamide warhead were synthesized and evaluated for their ability to inhibit cathepsin S, a key proteolytic enzyme upregulated in many cancers during tumor progression and metastasis. Most of the synthetic compounds were noncytotoxic, but several robustly inhibited cathepsin S (IC(50) < 10 nM) and potently suppressed cell migration, invasion, and capillary tube formation. These results highlight the potential of alpha-ketoamide therapy for preventing or delaying cancer spread.


Assuntos
Amidas/síntese química , Amidas/farmacologia , Catepsinas/antagonistas & inibidores , Desenho de Fármacos , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Amidas/química , Amidas/uso terapêutico , Catepsinas/química , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Invasividade Neoplásica , Neoplasias/enzimologia , Neoplasias/fisiopatologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Conformação Proteica
14.
ChemMedChem ; 5(2): 255-67, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20039358

RESUMO

Herein we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in-house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in-house compound library collection prior to testing. Five new series of Aurora kinase inhibitors were identified through this strategy, with IC(50) values ranging from approximately 300 nM to approximately 15 microM, by testing only 133 compounds from a database of approximately 125,000 compounds. Structure-activity relationship studies and X-ray co-crystallographic analysis of the most potent compound, a furanopyrimidine derivative with an IC(50) value of 309 nM toward Aurora kinase A, were carried out. The knowledge gained through these studies could help in the future design of potent Aurora kinase inhibitors.


Assuntos
Furanos/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/química , Aurora Quinases , Sítios de Ligação , Cristalografia por Raios X , Ensaios de Triagem em Larga Escala , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade
15.
J Org Chem ; 73(16): 6445-7, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18646857

RESUMO

This investigation describes the catalytic asymmetric addition of dimethylzinc to alpha-ketoesters in the presence of (-)-MITH ( 5) and triethyl borate as an additive to give the corresponding chiral alpha-hydroxy esters with good yields and high enantioselectivities.


Assuntos
Canfanos/química , Ésteres/química , Cetonas/química , Compostos Organometálicos/química , Aldeídos/química , Catálise , Ligantes , Morfolinas/química , Estereoisomerismo , Compostos de Sulfidrila/química
16.
J Org Chem ; 72(15): 5935-7, 2007 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-17595146

RESUMO

The asymmetric addition of alkenylzincs to aromatic and alpha-branched aliphatic aldehydes catalyzed by 1 generated the corresponding (E)-allylic alcohols with >95% ee and good to excellent chemical yields, especially >99.5% ee was observed in the case of 4-CF3-benzaldehyde. Notably, 1 is an effective ligand to catalyze the addition of disubstituted (R2 = R3 = ethyl) and bulky substituted (R2 = H, R3 = tert-butyl) alkenylzincs to benzaldehyde, affording the corresponding allylic alcohols both with 96% ee.

17.
J Org Chem ; 71(2): 833-5, 2006 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-16409006

RESUMO

[reaction: see text] A mild asymmetric arylation of aromatic aldehydes catalyzed by gamma-amino thiol 5 gave the corresponding diarylmethanols with 95 to >99.5% ee.


Assuntos
Aminas/química , Metanol/análogos & derivados , Compostos de Sulfidrila/química , Indicadores e Reagentes , Metanol/síntese química , Metanol/química , Modelos Moleculares , Conformação Molecular
19.
Chem Commun (Camb) ; (1): 54-5, 2002 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-12120307

RESUMO

Highly enantioselective silylcyanation of aliphatic and aromatic aldehydes was achieved by using a 1,2-diphenylethylenediamine linked chiral Ti(IV) complex as the catalyst.

20.
J Org Chem ; 67(4): 1308-13, 2002 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-11846679

RESUMO

Synthesis of camphor derived chiral allenes and their hydroboration-oxidation reactions are described. Reaction of (1R)-(+)-camphor with alkynyllithium followed by the reduction of the resulted propargyl alcohol derivatives using AlH3 furnished chiral allenes 2a-g in excellent yields with high diastereoselectivity. Reduction of the propargyl alcohols with aluminum hydride proceeded through selective intermolecular anti-addition of hydride ion. The stereochemistry of the chiral allenes 2 was assigned based on lanthanide shift studies and chemical correlations. Diastereoselectivity was observed in the hydroboration-oxidation of 2 which produced a mixture of (E,R) and (E,S) stereoisomers in a ratio of 6:1 to 18:1.

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