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1.
J Org Chem ; 83(18): 10933-10940, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30092130

RESUMO

C-H functionalization of electron-deficient heteroarenes using commercial unactivated alkyl halides through reductive quenching photoredox catalysis was developed. Mainstream approaches rely on the use of an excess of strong acids that result in regioselectivities dictated by the innate effect of the protonated heteroarene, leaving the functionalization of other carbons unexplored. We report a mild method under basic conditions that allows access to previously underexplored regioselectivities by relying on a combination of conjugate and halogen  ortho-directing effects. Overall, this methodology gives quick access to a variety of alkylated heteroarenes that will be of interest to medicinal chemistry programs.

2.
Nature ; 472(7344): 491-4, 2011 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-21499262

RESUMO

T-helper cells that produce interleukin-17 (T(H)17 cells) are a recently identified CD4(+) T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both RORα and RORγt and which inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORα and RORγt, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine T(H)17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORα and RORγt to inhibit specifically T(H)17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.


Assuntos
Autoimunidade/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Sulfonamidas/farmacologia , Células Th17/citologia , Células Th17/imunologia , Tiazóis/farmacologia , Animais , Autoimunidade/imunologia , Agonismo Inverso de Drogas , Células HEK293 , Humanos , Interleucina-17/biossíntese , Interleucina-17/imunologia , Interleucinas/biossíntese , Interleucinas/imunologia , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
3.
Angew Chem Int Ed Engl ; 56(48): 15309-15313, 2017 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-28960645

RESUMO

A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn2 (CO)10 , to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs. Photophysical and DFT studies indicate a light-initiated chain reaction mechanism propagated by . Mn(CO)5 . The rate-limiting step is the iodine abstraction from an alkyl iodide by . Mn(CO)5 .

4.
Mol Pharmacol ; 87(2): 296-304, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25473120

RESUMO

The orphan nuclear receptor liver receptor homolog 1 (LRH-1; NR5A2) is a potent regulator of cholesterol metabolism and bile acid homeostasis. Recently, LRH-1 has been shown to play an important role in intestinal inflammation and in the progression of estrogen receptor positive and negative breast cancers and pancreatic cancer. Structural studies have revealed that LRH-1 can bind phospholipids and the dietary phospholipid dilauroylphosphatidylcholine activates LRH-1 activity in rodents. Here we characterize the activity of a novel synthetic nonphospholipid small molecule repressor of LRH-1, SR1848 (6-[4-(3-chlorophenyl)piperazin-1-yl]-3-cyclohexyl-1H-pyrimidine-2,4-dione). In cotransfection studies, SR1848 reduced LRH-1-dependent expression of a reporter gene and in cells that endogenously express LRH-1 dose dependently reduced the expression of cyclin-D1 and -E1, resulting in inhibition of cell proliferation. The cellular effects of SR1848 treatment are recapitulated after transfection of cells with small-interfering RNA targeting LRH-1. Immunocytochemistry analysis shows that SR1848 induces rapid translocation of nuclear LRH-1 to the cytoplasm. Combined, these results suggest that SR1848 is a functional repressor of LRH-1 that impacts expression of genes involved in proliferation in LRH-1-expressing cancers. Thus, SR1848 represents a novel chemical scaffold for the development of therapies targeting malignancies driven by LRH-1.


Assuntos
Proliferação de Células/fisiologia , Pirimidinas/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Células HEK293 , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pirimidinas/química , Pirimidinas/farmacologia
5.
Nat Commun ; 15(1): 7574, 2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39217154

RESUMO

The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation. Here, we present two inactive CCR6 structures in ternary complexes with different allosteric antagonists, CCR6/SQA1/OXM1 and CCR6/SQA1/OXM2. The oxomorpholine analogues, OXM1 and OXM2 are highly selective CCR6 antagonists which bind to an extracellular pocket and disrupt the receptor activation network. An energetically favoured U-shaped conformation in solution that resembles the bound form is observed for the active analogues. SQA1 is a squaramide derivative with close-in analogues reported as antagonists of chemokine receptors including CCR6. SQA1 binds to an intracellular pocket which overlaps with the G protein site, stabilizing a closed pocket that is a hallmark of inactive GPCRs. Minimal communication between the two allosteric pockets is observed, in contrast to the prevalent allosteric cooperativity model of GPCRs. This work highlights the versatility of GPCR antagonism by small molecules, complementing previous knowledge of CCR6 activation, and sheds light on drug discovery targeting CCR6.


Assuntos
Receptores CCR6 , Receptores CCR6/metabolismo , Receptores CCR6/química , Humanos , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico , Ligação Proteica , Sítios de Ligação , Modelos Moleculares , Cristalografia por Raios X
6.
J Am Chem Soc ; 135(14): 5340-3, 2013 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-23530855

RESUMO

A highly diastereoselective synthesis of N-acetyl dihydrotetrafibricin methyl ester (34) is described. The synthesis features three enantioselective double allylboration reactions and an intramolecular hydrosilylation/Fleming-Tamao oxidation sequence to establish seven of the hydroxy-bearing stereocenters of 34. Especially noteworthy is the fragment-assembly double allyboration reaction of 2 and 7 using reagent 3, which provides the advanced intermediate 6 with >20:1 diastereoselectivity.


Assuntos
Macrolídeos/síntese química , Macrolídeos/química , Estrutura Molecular , Estereoisomerismo , Streptomyces/química
7.
Angew Chem Int Ed Engl ; 52(49): 12888-12891, 2013 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-24281884

RESUMO

On all fours: The title reaction with (Ipc)2 BH provides tetrasubstituted enolborinates which undergo aldol reactions with aldehydes to form products with all-carbon quaternary centers with exceptional diastereo- and enantioselectivity. A change to the substitution pattern of the starting amide leads to either diastereomer of the α-methyl-α-ethyl-ß-hydroxy carboxamide (1 or 2).


Assuntos
Amidas/química , Boranos/química , Compostos de Boro/síntese química , Morfolinas/química , Aldeídos/química , Catálise , Estereoisomerismo
8.
ACS Med Chem Lett ; 14(2): 191-198, 2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36793423

RESUMO

Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.

9.
Tetrahedron ; 67(35): 6497-6512, 2011 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-21857752

RESUMO

Interest in the synthesis of the C(23)-C(40) fragment 2 of tetrafibricin prompted us to develop a new method for the synthesis of 1,5-syn-(E)-diols. Toward this end, the kinetically controlled hydroboration of allenes 6, 33, ent-39, 42 and 45 with the Soderquist borane 25R were studied. Tetrabutylammonium allenyltrifluoroborate 45 gave superior results and was utilized in a double allylboration sequence with two different aldehydes to provide the targeted 1,5-syn-(E)-diols in generally high yields (72-98%), and with high enantioselectivity (>95% e.e.), diastereoselectivity (d.r. >20:1), and (E)/(Z) selectivity (>20:1). This new method was applied to the synthesis of the C(23)-C(40) fragment 2 of tetrafibricin.

10.
J Org Chem ; 74(24): 9413-21, 2009 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-19924881

RESUMO

Aminopentadienals resulting from the condensation of tryptamine or homoveratrylamine with glutaconaldehydes were treated with trifluoroacetic anhydride, allowing the formation of tetrahydro-beta-carbolines and tetrahydroisoquinolines bearing an enal function. In this N-acyl Pictet-Spengler reaction the electrophilicity of the aminopentadienals was dramatically increased by O,N-bistrifluoroacetylation. Recovery of the nitrogen nucleophilicity was achieved using a reductive process, and the heterocyclic amines were converted into aminonitriles by a Strecker reaction in the presence of butanal. Cyclization, by intramolecular Michael addition of the in situ generated enamines onto the enal moiety, was achieved in the presence of zinc triflate and involved cyanide ion trapping. In this manner, compounds related to protoemetine and dihydrocorynantheal were obtained, and a reduction step led to a short synthesis of (+/-)-protoemetinol.


Assuntos
Aldeídos/química , Alcadienos/química , Alcaloides/síntese química , Carbolinas/síntese química , Fluoracetatos , Tetra-Hidroisoquinolinas/síntese química , Anidridos Acéticos , Acetilação , Alcaloides/química , Aminação , Carbolinas/química , Cianetos/química , Ciclização , Hidrocarbonetos Aromáticos/química , Indóis/química , Íons , Espectroscopia de Ressonância Magnética , Mesilatos/química , Nitrilas/química , Tetra-Hidroisoquinolinas/química , Ácido Trifluoracético/química , Triptaminas/química
11.
Org Lett ; 21(12): 4540-4543, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31184183

RESUMO

The Chan-Lam reaction remains a highly utilized transformation for C-N bond formation. However, anilines remain problematic substrates due to their lower nucleophilicity. To address this problem, we developed an electrochemically mediated Chan-Lam coupling of aryl boronic acids and amines utilizing a dual copper anode/cathode system. The mild conditions identified have enabled the preparation of a wide range of functionalized biarylanilines in good yields and chemoselectivities.

12.
Med Chem ; 15(6): 676-684, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799793

RESUMO

BACKGROUND: Despite a massive industry endeavor to develop RORγ-modulators for autoimmune disorders, there has been no indication of efforts to target the close family member RORα for similar indications. This may be due to the misconception that RORα is redundant to RORγ, or the inherent difficulty in cultivating tractable starting points for RORα. RORα-selective modulators would be useful tools to interrogate the biology of this understudied orphan nuclear receptor. OBJECTIVE: The goal of this research effort was to identify and optimize synthetic ligands for RORα starting from the known LXR agonist T0901317. METHODS: Fourty-five analogs of the sulfonamide lead (1) were synthesized and evaluated for their ability to suppress the transcriptional activity of RORα, RORγ, and LXRα in cell-based assays. Analogs were characterized by 1H-NMR, 13C-NMR, and LC-MS analysis. The pharmacokinetic profile of the most selective RORα inverse agonist was evaluated in rats with intraperitoneal (i.p.) and per oral (p.o.)dosing. RESULTS: Structure-activity relationship studies led to potent dual RORα/RORγ inverse agonists as well as RORα-selective inverse agonists (20, 28). LXR activity could be reduced by removing the sulfonamide nitrogen substituent. Attempts to improve the potency of these selective leads by varying substitution patterns throughout the molecule proved challenging. CONCLUSION: The synthetic RORα-selective inverse agonists identified (20, 28) can be utilized as chemical tools to probe the function of RORα in vitro and in vivo.


Assuntos
Agonismo Inverso de Drogas , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Sulfonamidas/farmacologia , Animais , Humanos , Hidrocarbonetos Fluorados/química , Ligantes , Receptores X do Fígado/agonistas , Camundongos , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Ratos , Relação Estrutura-Atividade , Sulfonamidas/agonistas , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Células Th17
14.
Science ; 360(6384): 75-80, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29456201

RESUMO

Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron-induced variants of this reaction class have proven particularly useful in the formation of C(sp2)-C(sp3) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents. This method's tolerance of fluoroalkyl substituents proved particularly advantageous for the streamlined preparation of pharmaceutically oriented fluorinated scaffolds that previously required multiple steps, toxic reagents, and nonmodular retrosynthetic blueprints. Five specific sulfone reagents facilitate the rapid assembly of a vast set of compounds, many of which contain challenging fluorination patterns.

15.
J Med Chem ; 61(23): 10415-10439, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30130103

RESUMO

The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.


Assuntos
Desenho de Fármacos , Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Piridinas/administração & dosagem , Piridinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Piridinas/farmacocinética , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
16.
Org Lett ; 9(2): 287-9, 2007 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-17217286

RESUMO

Conditions were found for the successful Effenberger alpha,alpha'-annulation of 3,3-dimethyl-2,4,6-triprenyl cyclohexanone silyl enol ethers with malonyl chloride to give the corresponding bicyclo[3.3.1]nonane-trione in 35% yield, this result allowing a short synthesis of (+/-)-clusianone. An isomeric rearranged bicyclo[3.3.1]nonane-trione was also isolated in 25% yield, and changing the Lewis acid resulted in formation of a lavandulyl-substituted phloroglucinol derivative in 38% yield. The mechanism of formation of these two last products mimics the biogenetic pathway to PPAPs. [reaction: see text].


Assuntos
Materiais Biomiméticos/síntese química , Compostos Bicíclicos com Pontes/síntese química , Cicloexanonas/síntese química , Hidrocarbonetos Clorados/química , Benzofenonas , Benzoquinonas , Materiais Biomiméticos/química , Compostos Bicíclicos com Pontes/química , Cicloexanonas/química , Estrutura Molecular , Estereoisomerismo
17.
Org Lett ; 18(21): 5748-5751, 2016 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-27786487

RESUMO

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramolecular SN2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery.

18.
Org Lett ; 17(23): 5756-9, 2015 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-26572219

RESUMO

A nontoxic and inexpensive photocatalytic initiation of anti-Markovnikov hydrothiolation of olefins using visible light is reported. This method is characterized by low catalyst loading, thereby enabling a mild and selective method for radical initiation in thiol-ene reactions between a wide scope of olefins and thiols.

19.
Org Lett ; 17(17): 4292-5, 2015 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-26290951

RESUMO

A versatile synthesis of 7-azaindoles from substituted 2-fluoropyridines is described. C3-metalation and 1,4-addition to nitroolefins provide substituted 2-fluoro-3-(2-nitroethyl)pyridines. A facile oxidative Nef reaction/reductive amination/intramolecular SNAr sequence furnishes 7-azaindolines. Finally, optional regioselective electrophilic C5-substitution (e.g., bromination or nitration) and subsequent in situ oxidation delivers highly functionalized 7-azaindoles in high overall efficiency.

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