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1.
J Chem Inf Model ; 61(3): 1402-1411, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33655751

RESUMO

SARS-CoV-2 is a positive-sense RNA virus that requires an RNA-dependent RNA polymerase (RdRp) for replication of its viral genome. Nucleoside analogs such as Remdesivir and ß-d-N4-hydroxycytidine are antiviral candidates and may function as chain terminators or induce viral mutations, thus impairing RdRp function. Recently disclosed Cryo-EM structures of apo, RNA-bound, and inhibitor-bound SARS-CoV-2 RdRp provided insight into the inhibitor-bound structure by capturing the enzyme with its reaction product: Remdesivir covalently bound to the RNA primer strand. To gain a structural understanding of the binding of this and several other nucleoside analogs in the precatalytic state, molecular models were developed that predict the noncovalent interactions to a complex of SARS-CoV-2 RdRp, RNA, and catalytic metal cations. MM-GBSA evaluation of these interactions is consistent with resistance-conferring mutations and existing structure-activity relationship (SAR) data. Therefore, this approach may yield insights into antiviral mechanisms and guide the development of experimental drugs for COVID-19 treatment.


Assuntos
Tratamento Farmacológico da COVID-19 , Nucleosídeos/análogos & derivados , Nucleosídeos/farmacologia , RNA Viral/metabolismo , RNA Polimerase Dependente de RNA/metabolismo , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Antivirais/farmacologia , COVID-19/metabolismo , Desenho de Fármacos , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , SARS-CoV-2/metabolismo
2.
Bioorg Med Chem Lett ; 29(11): 1336-1339, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954428

RESUMO

Potent and selective substrate-based covalent inhibitors of MALT1 protease were developed from the tetrapeptide tool compound Z-VRPR-fmk. To improve cell permeability, we replaced one arginine residue. We further optimized a series of tripeptides and identified compounds that were potent in both a GloSensor reporter assay measuring cellular MALT1 protease activity, and an OCI-Ly3 cell proliferation assay. Example compounds showed good overall selectivity towards cysteine proteases, and one compound was selected for further profiling in ABL-DLBCL cells and xenograft efficacy models.


Assuntos
Inibidores de Caspase/farmacologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Peptídeos/farmacologia , Inibidores de Caspase/síntese química , Inibidores de Caspase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Peptídeos/síntese química , Peptídeos/química , Relação Estrutura-Atividade
3.
J Med Chem ; 62(4): 1971-1988, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30653918

RESUMO

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis ( http://ftmap.bu.edu/ ). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Lactamas Macrocíclicas/farmacologia , Lactonas/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/química , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/metabolismo , Lactonas/síntese química , Lactonas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
4.
Oncotarget ; 9(90): 36102-36109, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30546830

RESUMO

Synthetic monocarbonyl analogs of curcumin (MACs) are cytotoxic against several cancers including head and neck cancer, pancreatic cancer, colon cancer, and breast cancer. Mechanisms of action include depolarization of the mitochondrial membrane potential and inhibition of NF-κB, leading to apoptosis. We previously demonstrated that UBS109 (MAC), has preventive effects on bone loss induced by breast cancer cell lines. We determined whether UBS109 could inhibit and prevent lung metastasis, since lung metastasis of breast cancer is a major problem in addition to bone metastasis. A breast cancer lung metastasis (colonization) model was created by injection of breast cancer cells MDA-MB-231 into the tail vein of athymic nude mice, nu/nu. Animals were treated with vehicle or UBS109 at 5 or 15 mg/kg body weight by intraperitoneal injection once daily 5 days a week for 5 weeks. UBS109 at 15 mg/kg significantly inhibited lung metastasis/colonization as demonstrated by reduced lung weight consisting of tumor nodules. The body weight of animals treated with UBS109 15 mg/kg remained the same as in the other groups. UBS109 killed completely (100%) MDA-MB-231 breast cancer cells at 1.25 µM in a cytotoxicity assay in vitro. UBS109 15 mg/kg i.p. showed a maximal blood concentration (Cmax) of 432 ± 387 ng/mL at 15 min post injection. This is approximately 1.5 ng/ml in the blood of mice and equals 1.5 µM of UBS109. These in vitro and in vivo results are consistent with each other.

5.
J Org Chem ; 83(24): 15449-15462, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30458107

RESUMO

A modular and diastereodivergent synthesis of tetrahydro-1 H-pyrrolo[1,2 d]diazepine-(2,5)-diones is presented. The tetrahydropyrrolodiazepinedione scaffold is obtained via a base-mediated three-step isomerization/tandem cyclization of amino acid-coupled homoallylic amino esters. Diastereoselectivity of the process is mediated by the interplay of a kinetic cyclization event and a propensity for thermodynamic epimerization at two labile chiral centers, giving rise to two distinct major diastereomers dependent on starting material stereochemistry and reaction conditions selected. Herein, we present a synthetic and computational study for this tandem process on a variety of amino ester substrates.


Assuntos
Lactamas/química , Pirróis/química , Pirróis/síntese química , Técnicas de Química Sintética , Ciclização , Cinética , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Termodinâmica
6.
J Clin Invest ; 128(10): 4397-4412, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30024860

RESUMO

The paracaspase MALT1 plays an essential role in activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) downstream of B cell and TLR pathway genes mutated in these tumors. Although MALT1 is considered a compelling therapeutic target, the development of tractable and specific MALT1 protease inhibitors has thus far been elusive. Here, we developed a target engagement assay that provides a quantitative readout for specific MALT1-inhibitory effects in living cells. This enabled a structure-guided medicinal chemistry effort culminating in the discovery of pharmacologically tractable, irreversible substrate-mimetic compounds that bind the MALT1 active site. We confirmed that MALT1 targeting with compound 3 is effective at suppressing ABC DLBCL cells in vitro and in vivo. We show that a reduction in serum IL-10 levels exquisitely correlates with the drug pharmacokinetics and degree of MALT1 inhibition in vitro and in vivo and could constitute a useful pharmacodynamic biomarker to evaluate these compounds in clinical trials. Compound 3 revealed insights into the biology of MALT1 in ABC DLBCL, such as the role of MALT1 in driving JAK/STAT signaling and suppressing the type I IFN response and MHC class II expression, suggesting that MALT1 inhibition could prime lymphomas for immune recognition by cytotoxic immune cells.


Assuntos
Inibidores de Caspase , Sistemas de Liberação de Medicamentos , Linfoma Difuso de Grandes Células B , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas de Neoplasias , Transdução de Sinais , Animais , Inibidores de Caspase/química , Inibidores de Caspase/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/enzimologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/química , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
7.
Molecules ; 20(5): 7474-94, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25915462

RESUMO

Increased activity of transcription factor NF-κB has been implicated in many B-cell lymphomas. We investigated effects of synthetic compound calafianin monomer (CM101) on biochemical and biological properties of NF-κB. In human 293 cells, CM101 selectively inhibited DNA binding by overexpressed NF-κB subunits REL (human c-Rel) and p65 as compared to NF-κB p50, and inhibition of REL and p65 DNA binding by CM101 required a conserved cysteine residue. CM101 also inhibited DNA binding by REL in human B-lymphoma cell lines, and the sensitivity of several B-lymphoma cell lines to CM101-induced proliferation arrest and apoptosis correlated with levels of cellular and nuclear REL. CM101 treatment induced both phosphorylation and decreased expression of anti-apoptotic protein Bcl-XL, a REL target gene product, in sensitive B-lymphoma cell lines. Ectopic expression of Bcl-XL protected SUDHL-2 B-lymphoma cells against CM101-induced apoptosis, and overexpression of a transforming mutant of REL decreased the sensitivity of BJAB B-lymphoma cells to CM101-induced apoptosis. Lipopolysaccharide-induced activation of NF-κB signaling upstream components occurred in RAW264.7 macrophages at CM101 concentrations that blocked NF-κB DNA binding. Direct inhibitors of REL may be useful for treating B-cell lymphomas in which REL is active, and may inhibit B-lymphoma cell growth at doses that do not affect some immune-related responses in normal cells.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linfoma de Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-rel/antagonistas & inibidores , Tirosina/análogos & derivados , Células 3T3 , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Humanos , Células L , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Subunidade p50 de NF-kappa B/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Fator de Transcrição RelA/antagonistas & inibidores , Tirosina/farmacologia , Proteína bcl-X/biossíntese
8.
Nat Chem Biol ; 10(9): 723-31, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25038790

RESUMO

The potential utility of synthetic macrocycles (MCs) as drugs, particularly against low-druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of MCs for good target protein-binding activity or bioavailability. To address this knowledge gap, we analyze the binding modes of a representative set of MC-protein complexes. The results, combined with consideration of the physicochemical properties of approved macrocyclic drugs, allow us to propose specific guidelines for the design of synthetic MC libraries with structural and physicochemical features likely to favor strong binding to protein targets as well as good bioavailability. We additionally provide evidence that large, natural product-derived MCs can bind targets that are not druggable by conventional, drug-like compounds, supporting the notion that natural product-inspired synthetic MCs can expand the number of proteins that are druggable by synthetic small molecules.


Assuntos
Compostos Macrocíclicos/metabolismo , Ligação Proteica/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Disponibilidade Biológica , Cristalografia por Raios X , Desenho de Fármacos , Espectrometria de Massas , Modelos Moleculares , Peso Molecular , Preparações Farmacêuticas/metabolismo , Proteínas/metabolismo , Bibliotecas de Moléculas Pequenas
9.
Tetrahedron ; 69(27-28)2013 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-24273349

RESUMO

Catalytic enantioselective methods for the generation of cyclopropanes has been of longstanding pharmaceutical interest. Chiral dirhodium(II) catalysts prove to be an effective means for the generation of diverse cyclopropane libraries. Rh2(R-DOSP)4 is generaally the most effective catalyst for asymmetric intermolecular cyclopropanation of methyl aryldiazoacetates with styrene. Rh2(S-PTAD)4 provides high levels of enantioinduction with ortho-substituted aryldiazoacetates. The less-established Rh2(R-BNP)4 plays a complementary role to Rh2(R-DOSP)4 and Rh2(S-PTAD)4 in catalyzing highly enantioselective cyclopropanation of 3- methoxy-substituted aryldiazoacetates. Substitution on the styrene has only moderate influence on the asymmetric induction of the cyclopropanation.

10.
J Am Chem Soc ; 127(45): 15696-7, 2005 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-16277499

RESUMO

A new method for the Brønsted acid-catalyzed addition of amide nucleophiles to imines to produce protected aminal products is described. Simple Brønsted acids (phenyl phosphinic acid and trifluoromethanesulfonimide) were shown to be excellent catalysts, providing high yields of the aminal product. A catalytic asymmetric imine amidation using sulfonamides as nucleophiles was successful when a hindered biaryl phosphoric acid catalyst derived from 2,2'-diphenyl-[3,3'-biphenanthrene]-4,4'-diol (VAPOL) was used. Excellent yields and enantioselectivities were found in these additions (up to 99% ee).

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