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1.
J Med Chem ; 64(18): 13212-13214, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34498872

RESUMO

Inhibitors of cholesteryl ester transfer protein (CETP) elevate HDL levels human clinical trials. However, the first CETP inhibitors proved toxic in pivotal trials or showed minimal therapeutic benefit. Anacetrapib showed some clinical benefit but is high lipophilic. This Viewpoint highlights efforts to optimize anacetrapib to a best-in-class CETP inhibitor.

2.
Metabolites ; 11(8)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34436447

RESUMO

Osteosarcoma (OS) is the most common primary bone malignancy and largely effects adolescents and young adults, with 60% of patients under the age of 25. There are multiple cell models of OS described in vitro that express the specific genetic alterations of the sarcoma. In the work reported here, multiple mass spectrometry imaging (MSI) modalities were employed to characterise two aggregated cellular models of OS models formed using the MG63 and SAOS-2 cell lines. Phenotyping of the metabolite activity within the two OS aggregoid models was achieved and a comparison of the metabolite data with OS human tissue samples revealed relevant fatty acid and phospholipid markers. Although, annotations of these species require MS/MS analysis for confident identification of the metabolites. From the putative assignments however, it was suggested that the MG63 aggregoids are an aggressive tumour model that exhibited metastatic-like potential. Alternatively, the SAOS-2 aggregoids are more mature osteoblast-like phenotype that expressed characteristics of cellular differentiation and bone development. It was determined the two OS aggregoid models shared similarities of metabolic behaviour with different regions of OS human tissues, specifically of the higher metastatic grade.

3.
J Med Chem ; 64(15): 10951-10966, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34260245

RESUMO

Influenza viruses cause approximately half a million deaths every year worldwide. Vaccines are available but partially effective, and the number of antiviral medications is limited. Thus, it is crucial to develop therapeutic strategies to counteract this major pathogen. Influenza viruses enter the host cell via their hemagglutinin (HA) proteins. The HA subtypes of influenza A virus are phylogenetically classified into groups 1 and 2. Here, we identified an inhibitor of the HA protein, a tertiary aryl sulfonamide, that prevents influenza virus entry and replication. This compound shows potent antiviral activity against diverse H1N1, H5N1, and H3N2 influenza viruses encoding HA proteins from both groups 1 and 2. Synthesis of derivatives of this aryl sulfonamide identified moieties important for antiviral activity. This compound may be considered as a lead for drug development with the intent to be used alone or in combination with other influenza A virus antivirals to enhance pan-subtype efficacy.


Assuntos
Antivirais/farmacologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A/efeitos dos fármacos , Sulfonamidas/farmacologia , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
4.
J Am Chem Soc ; 143(13): 4921-4927, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33755457

RESUMO

Alkenyl boronates add to Ir(π-allyl) intermediates with high enantioselectivity. A 1,2-metalate shift forms a second C-C bond and sets a 1,3-stereochemical relationship. The three-component coupling provides tertiary boronic esters that can undergo multiple additional functionalizations. An extension to trisubstituted olefins sets three contiguous stereocenters.


Assuntos
Compostos Alílicos/química , Ácidos Borônicos/química , Metais/química , Catálise , Estereoisomerismo
5.
J Med Chem ; 64(5): 2739-2761, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33620219

RESUMO

Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity. Assaying parasites with resistance to antimalarials led us to test whether the series had a similar mechanism of action to chloroquine (CQ). Treatment of synchronized Plasmodium falciparum parasites with active analogues revealed a pattern of intracellular inhibition of hemozoin (Hz) formation reminiscent of CQ's action. Drug selections yielded only modest resistance that was associated with amplification of the multidrug resistance gene 1 (pfmdr1). Thus, we have identified a novel chemical series that targets the historically druggable heme polymerization pathway and that can form the basis of future optimization efforts to develop a new malaria treatment.


Assuntos
Amidas/farmacologia , Antimaláricos/farmacologia , Hemoglobinas/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Tetrazóis/farmacologia , Amidas/síntese química , Amidas/farmacocinética , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Hemeproteínas/antagonistas & inibidores , Células Hep G2 , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/farmacocinética
6.
JCI Insight ; 6(6)2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33600377

RESUMO

The splenic microenvironment regulates hematopoietic stem and progenitor cell (HSPC) function, particularly during demand-adapted hematopoiesis; however, practical strategies to enhance splenic support of transplanted HSPCs have proved elusive. We have previously demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the small molecule (+)SW033291 (PGDHi), increases BM prostaglandin E2 (PGE2) levels, expands HSPC numbers, and accelerates hematologic reconstitution after BM transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, specifically 15-PGDH high-expressing macrophages, megakaryocytes (MKs), and mast cells (MCs), regulates steady-state hematopoiesis and potentiates recovery after BMT. Notably, PGDHi-induced neutrophil, platelet, and HSPC recovery were highly attenuated in splenectomized mice. PGDHi induced nonpathologic splenic extramedullary hematopoiesis at steady state, and pretransplant PGDHi enhanced the homing of transplanted cells to the spleen. 15-PGDH enzymatic activity localized specifically to macrophages, MK lineage cells, and MCs, identifying these cell types as likely coordinating the impact of PGDHi on splenic HSPCs. These findings suggest that 15-PGDH expression marks HSC niche cell types that regulate hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to therapeutically target multiple HSC niches, promote hematopoietic regeneration, and improve clinical outcomes of BMT.

7.
J Med Chem ; 63(17): 9773-9786, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787093

RESUMO

A series of N-acyl benzothiazoles shows selective and potent cytotoxicity against cancer cell lines expressing cytochrome P450 4F11. A prodrug form is metabolized by cancer cells into an active inhibitor of stearoyl-CoA desaturase (SCD). Substantial variation on the acyl portion of the inhibitors allowed the identification of (R)-27, which balanced potency, solubility, and lipophilicity to allow proof-of-concept studies in mice. The prodrugs were activated inside the tumor, where they can arrest tumor growth. Together, these observations offer promise that a tumor-activated prodrug strategy might exploit the essentiality of SCD for tumor growth, while avoiding toxicity associated with systemic SCD inhibition.


Assuntos
Benzotiazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Animais , Benzotiazóis/farmacocinética , Linhagem Celular Tumoral , Família 4 do Citocromo P450/metabolismo , Feminino , Humanos , Camundongos , Pró-Fármacos/metabolismo , Distribuição Tecidual
8.
Anal Chem ; 92(18): 12538-12547, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32786495

RESUMO

Mass spectrometry imaging (MSI) is an established analytical tool capable of defining and understanding complex tissues by determining the spatial distribution of biological molecules. Three-dimensional (3D) cell culture models mimic the pathophysiological environment of in vivo tumors and are rapidly emerging as a valuable research tool. Here, multimodal MSI techniques were employed to characterize a novel aggregated 3D lung adenocarcinoma model, developed by the group to mimic the in vivo tissue. Regions of tumor heterogeneity and the hypoxic microenvironment were observed based on the spatial distribution of a variety of endogenous molecules. Desorption electrospray ionization (DESI)-MSI defined regions of a hypoxic core and a proliferative outer layer from metabolite distribution. Targeted metabolites (e.g., lactate, glutamine, and citrate) were mapped to pathways of glycolysis and the TCA cycle demonstrating tumor metabolic behavior. The first application of imaging mass cytometry (IMC) with 3D cell culture enabled single-cell phenotyping at 1 µm spatial resolution. Protein markers of proliferation (Ki-67) and hypoxia (glucose transporter 1) defined metabolic signaling in the aggregoid model, which complemented the metabolite data. Laser ablation inductively coupled plasma (LA-ICP)-MSI analysis localized endogenous elements including magnesium and copper, further differentiating the hypoxia gradient and validating the protein expression. Obtaining a large amount of molecular information on a complementary nature enabled an in-depth understanding of the biological processes within the novel tumor model. Combining powerful imaging techniques to characterize the aggregated 3D culture highlighted a future methodology with potential applications in cancer research and drug development.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Ácido Cítrico/análise , Glutamina/análise , Ácido Láctico/análise , Neoplasias Pulmonares/diagnóstico , Adenocarcinoma de Pulmão/metabolismo , Ácido Cítrico/metabolismo , Glutamina/metabolismo , Humanos , Ácido Láctico/metabolismo , Neoplasias Pulmonares/metabolismo , Imagem Multimodal , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Células Tumorais Cultivadas
9.
ACS Infect Dis ; 6(8): 2057-2072, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32686409

RESUMO

The few frontline antileishmanial drugs are poorly effective and toxic. To search for new drugs for this neglected tropical disease, we tested the activity of compounds in the Medicines for Malaria Venture (MMV) "Pathogen Box" against Leishmania amazonensis axenic amastigotes. Screening yielded six discovery antileishmanial compounds with EC50 values from 50 to 480 nM. Concentration-response assays demonstrated that the best hit, MMV676477, had mid-nanomolar cytocidal potency against intracellular Leishmania amastigotes, Trypanosoma brucei, and Plasmodium falciparum, suggesting broad antiparasitic activity. We explored structure-activity relationships (SAR) within a small group of MMV676477 analogs and observed a wide potency range (20-5000 nM) against axenic Leishmania amastigotes. Compared to MMV676477, our most potent analog, SW41, had ∼5-fold improved antileishmanial potency. Multiple lines of evidence suggest that MMV676477 selectively disrupts Leishmania tubulin dynamics. Morphological studies indicated that MMV676477 and analogs affected L. amazonensis during cell division. Differential centrifugation showed that MMV676477 promoted partitioning of cellular tubulin toward the polymeric form in parasites. Turbidity assays with purified Leishmania and porcine tubulin demonstrated that MMV676477 promoted leishmanial tubulin polymerization in a concentration-dependent manner. Analogs' antiparasitic activity correlated with their ability to facilitate purified Leishmania tubulin polymerization. Chemical cross-linking demonstrated binding of the MMV676477 scaffold to purified Leishmania tubulin, and competition studies established a correlation between binding and antileishmanial activity. Our studies demonstrate that MMV676477 is a potent antiparasitic compound that preferentially promotes Leishmania microtubule polymerization. Due to its selectivity for and broad-spectrum activity against multiple parasites, this scaffold shows promise for antiparasitic drug development.


Assuntos
Leishmania , Malária , Animais , Antiparasitários/farmacologia , Polimerização , Suínos , Tubulina (Proteína)
10.
J Am Chem Soc ; 142(28): 11972-11977, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32573218

RESUMO

Photocatalytic α-functionalization of amines provides a mild and atom-economical means to synthesize α-branched amines. Prior examples featured symmetrical or electronically biased substrates. Here we report a controllable α-functionalization of amines in which regioselectivity can be tuned with minor changes to the reaction conditions.


Assuntos
Aminas/síntese química , Aminas/química , Catálise , Estrutura Molecular , Processos Fotoquímicos , Estereoisomerismo
11.
Biol Blood Marrow Transplant ; 26(8): 1552-1556, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32422251

RESUMO

Aplastic anemia (AA) is a human immune-mediated bone marrow failure syndrome that is treated by stem cell transplantation for patients who have a matched related donor and by immunosuppressive therapy (IST) for those who do not. Responses to IST are variable, with patients still at risk for prolonged neutropenia, transfusion dependence, immune suppression, and severe opportunistic infections. Therefore, additional therapies are needed to accelerate hematologic recovery in patients receiving front-line IST. We have shown that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) with the small molecule SW033291 (PGDHi) increases bone marrow (BM) prostaglandin E2 levels, expands hematopoietic stem cell (HSC) numbers, and accelerates hematologic reconstitution following murine BM transplantation. We now report that in a murine model of immune-mediated BM failure, PGDHi therapy mitigated cytopenias, increased BM HSC and progenitor cell numbers, and significantly extended survival compared with vehicle-treated mice. PGDHi protection was not immune-mediated, as serum IFN-γ levels and BM CD8+ T lymphocyte frequencies were not impacted. Moreover, dual administration of PGDHi plus low-dose IST enhanced total white blood cell, neutrophil, and platelet recovery, achieving responses similar to those seen with maximal-dose IST with lower toxicity. Taken together, these data demonstrate that PGDHi can complement IST to accelerate hematologic recovery and reduce morbidity in severe AA.


Assuntos
Anemia Aplástica , Transplante de Células-Tronco Hematopoéticas , Anemia Aplástica/tratamento farmacológico , Animais , Transplante de Medula Óssea , Humanos , Hidroxiprostaglandina Desidrogenases , Camundongos
12.
PLoS Pathog ; 16(4): e1008407, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32240278

RESUMO

Influenza A viruses are human pathogens with limited therapeutic options. Therefore, it is crucial to devise strategies for the identification of new classes of antiviral medications. The influenza A virus genome is constituted of 8 RNA segments. Two of these viral RNAs are transcribed into mRNAs that are alternatively spliced. The M1 mRNA encodes the M1 protein but is also alternatively spliced to yield the M2 mRNA during infection. M1 to M2 mRNA splicing occurs at nuclear speckles, and M1 and M2 mRNAs are exported to the cytoplasm for translation. M1 and M2 proteins are critical for viral trafficking, assembly, and budding. Here we show that gene knockout of the cellular protein NS1-BP, a constituent of the M mRNA speckle-export pathway and a binding partner of the virulence factor NS1 protein, inhibits M mRNA nuclear export without altering bulk cellular mRNA export, providing an avenue to preferentially target influenza virus. We performed a high-content, image-based chemical screen using single-molecule RNA-FISH to label viral M mRNAs followed by multistep quantitative approaches to assess cellular mRNA and cell toxicity. We identified inhibitors of viral mRNA biogenesis and nuclear export that exhibited no significant activity towards bulk cellular mRNA at non-cytotoxic concentrations. Among the hits is a small molecule that preferentially inhibits nuclear export of a subset of viral and cellular mRNAs without altering bulk cellular mRNA export. These findings underscore specific nuclear export requirements for viral mRNAs and phenocopy down-regulation of the mRNA export factor UAP56. This RNA export inhibitor impaired replication of diverse influenza A virus strains at non-toxic concentrations. Thus, this screening strategy yielded compounds that alone or in combination may serve as leads to new ways of treating influenza virus infection and are novel tools for studying viral RNA trafficking in the nucleus.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antivirais/farmacologia , Núcleo Celular/virologia , Vírus da Influenza A/metabolismo , Influenza Humana/virologia , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Vírus da Influenza A/genética , RNA Mensageiro/genética , RNA Viral/genética , Replicação Viral/efeitos dos fármacos
13.
ACS Chem Biol ; 15(1): 158-170, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31874028

RESUMO

Selective toxicity among cancer cells of the same lineage is a hallmark of targeted therapies. As such, identifying compounds that impair proliferation of a subset of non-small-cell lung cancer (NSCLC) cell lines represents one strategy to discover new drugs for lung cancer. Previously, phenotypic screens of 202 103 compounds led to the identification of 208 selective NSCLC toxins ( McMillan , E. A. , Cell , 2018 , 173 , 864 ). The mechanism of action for the majority of these compounds remains unknown. Here, we discovered the target for a series of quinazoline diones (QDC) that demonstrate selective toxicity among 96 NSCLC lines. Using photoreactive probes, we found that the QDC binds to both mitochondrial complex I of the electron transport chain and hydroxyacyl CoA dehydrogenase subunit alpha (HADHA), which catalyzes long-chain fatty acid oxidation. Inhibition of complex I is the on-target activity for QDC, while binding to HADHA is off-target. The sensitivity profile of the QDC across NSCLC lines correlated with the sensitivity profiles of six additional structurally distinct compounds. The antiproliferative activity of these compounds is also the consequence of binding to mitochondrial complex I, reflecting significant structural diversity among complex I inhibitors. Small molecules targeting complex I are currently in clinical development for the treatment of cancer. Our results highlight complex I as a target in NSCLC and report structurally diverse scaffolds that inhibit complex I.


Assuntos
Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/dietoterapia , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Inibidores Enzimáticos/química , Neoplasias Pulmonares/dietoterapia , Quinazolinonas/química , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/metabolismo , Técnicas de Inativação de Genes , Humanos , Subunidade alfa da Proteína Mitocondrial Trifuncional/genética , Subunidade alfa da Proteína Mitocondrial Trifuncional/metabolismo , Estrutura Molecular , Terapia de Alvo Molecular , Oxirredução , Consumo de Oxigênio , Ligação Proteica , Conformação Proteica , Proteômica , Quinazolinonas/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato
14.
Org Lett ; 21(4): 1148-1151, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30714741

RESUMO

The kigamicins are polycyclic aromatic natural products featuring a tetrahydroxanthone and up to four sugar residues. They are toxic to human cancer cells under nutrient-poor conditions. A synthesis of the natural product skeleton has been achieved from chiral pool materials. Key steps include a regioselective hydration of a diarylalkyne and two oxidative cyclizations.

15.
Org Lett ; 21(3): 648-651, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653329

RESUMO

Dysoline, a novel chromone alkaloid isolated from Dysoxylum binectariferum, was reported to have selective cytotoxicity for HT1080 fibrosarcoma cells (IC50 of 0.21 µM). Given the scarcity of natural material, a concise synthesis of (+)-dysoline was developed, allowing for further biological evaluation. An enantioselective nucleophile-catalyzed aldol lactonization formed the piperidine ring with control of relative and absolute stereochemistry. Construction of the C6-chromone core with complete regioselectivity was achieved using a Danheiser benzannulation.

16.
J Am Chem Soc ; 140(41): 13242-13252, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-30240211

RESUMO

A three-component coupling using lithiated indoles, boronate esters and allylic acetates generates chiral indolines with adjacent quaternary stereocenters. Successful stereocontrol required the use of phosphoramidite ligands not previously described for organopalladium chemistry. Mechanistic studies indicate a monodentate PdL intermediate, and a stepwise allylation-aryl/alkyl migration. A protodeborylation strategy was used to install a C-H bond in place of the C-B bond. A photoredox coupling was used to replace C-B bond with a C-C bond in a highly diastereoselective manner. In the specific case of methyl-vinyl ketone, a novel radical-mediated annulation provides polycyclic products with high enantio- and diastereoselectivity.

17.
Antiviral Res ; 158: 288-302, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30144461

RESUMO

Specific host pathways that may be targeted therapeutically to inhibit the replication of Ebola virus (EBOV) and other emerging viruses remain incompletely defined. A screen of 200,000 compounds for inhibition of an EBOV minigenome (MG) assay that measures the function of the viral polymerase complex identified as hits several compounds with an amino-tetrahydrocarbazole scaffold. This scaffold was structurally similar to GSK983, a compound previously described as having broad-spectrum antiviral activity due to its impairing de novo pyrimidine biosynthesis through inhibition of dihydroorotate dehydrogenase (DHODH). We generated compound SW835, the racemic version of GSK983 and demonstrated that SW835 and brequinar, another DHODH inhibitor, potently inhibit the MG assay and the replication of EBOV, vesicular stomatitis virus (VSV) and Zika (ZIKV) in vitro. Nucleoside and deoxynucleoside supplementation studies demonstrated that depletion of pyrimidine pools contributes to antiviral activity of these compounds. As reported for other DHODH inhibitors, SW835 and brequinar also induced expression of interferon stimulated genes (ISGs). ISG induction was demonstrated to occur without production of IFNα/ß and independently of the IFNα receptor and was not blocked by EBOV-encoded suppressors of IFN signaling pathways. Furthermore, we demonstrated that transcription factor IRF1 is required for this ISG induction, and that IRF1 induction requires the DNA damage response kinase ATM. Therefore, de novo pyrimidine biosynthesis is critical for the replication of EBOV and other RNA viruses and inhibition of this pathway activates an ATM and IRF1-dependent innate immune response that subverts EBOV immune evasion functions.


Assuntos
Ebolavirus/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Nucleosídeos/farmacologia , Pirimidinas/antagonistas & inibidores , Pirimidinas/biossíntese , Replicação Viral/efeitos dos fármacos , Células A549 , Antivirais/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Dano ao DNA , Células HEK293 , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Evasão da Resposta Imune , Imunidade Inata/genética , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/farmacologia , Interferon-alfa/metabolismo , Interferon beta/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Vírus de RNA/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Vesiculovirus/efeitos dos fármacos , Zika virus/efeitos dos fármacos
18.
J Med Chem ; 61(12): 5199-5221, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29869888

RESUMO

Stearoyl-CoA desaturase (SCD) catalyzes the first step in the conversion of saturated fatty acids to unsaturated fatty acids. Unsaturated fatty acids are required for membrane integrity and for cell proliferation. For these reasons, inhibitors of SCD represent potential treatments for cancer. However, systemically active SCD inhibitors result in skin toxicity, which presents an obstacle to their development. We recently described a series of oxalic acid diamides that are converted into active SCD inhibitors within a subset of cancers by CYP4F11-mediated metabolism. Herein, we describe the optimization of the oxalic acid diamides and related N-acyl ureas and an analysis of the structure-activity relationships related to metabolic activation and SCD inhibition.


Assuntos
Família 4 do Citocromo P450/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos , Ácido Oxálico/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Estearoil-CoA Dessaturase/metabolismo , Relação Estrutura-Atividade
19.
Haematologica ; 103(6): 1054-1064, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29472361

RESUMO

Hematopoietic stem cell transplantation following myeloablative chemotherapy is a curative treatment for many hematopoietic malignancies. However, profound granulocytopenia during the interval between transplantation and marrow recovery exposes recipients to risks of fatal infection, a significant source of transplant-associated morbidity and mortality. We have previously described the discovery of a small molecule, SW033291, that potently inhibits the prostaglandin degrading enzyme 15-PGDH, increases bone marrow prostaglandin E2, and accelerates hematopoietic recovery following murine transplant. Here we describe the efficacy of (+)-SW209415, a second-generation 15-PGDH inhibitor, in an expanded range of models relevant to human transplantation. (+)-SW209415 is 10,000-fold more soluble, providing the potential for intravenous delivery, while maintaining potency in inhibiting 15-PGDH, increasing in vivo prostaglandin E2, and accelerating hematopoietic regeneration following transplantation. In additional models, (+)-SW209415: (i) demonstrated synergy with granulocyte colony-stimulating factor, the current standard of care; (ii) maintained efficacy as transplant cell dose was escalated; (iii) maintained efficacy when transplant donors and recipients were aged; and (iv) potentiated homing in xenotransplants using human hematopoietic stem cells. (+)-SW209415 showed no adverse effects, no potentiation of in vivo growth of human myeloma and leukemia xenografts, and, on chronic high-dose administration, no toxicity as assessed by weight, blood counts and serum chemistry. These studies provide independent chemical confirmation of the activity of 15-PGDH inhibitors in potentiating hematopoietic recovery, extend the range of models in which inhibiting 15-PGDH demonstrates activity, allay concerns regarding potential for adverse effects from increasing prostaglandin E2, and thereby, advance 15-PGDH as a therapeutic target for potentiating hematopoietic stem cell transplantation.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Hidroxiprostaglandina Desidrogenases/antagonistas & inibidores , Adulto , Fatores Etários , Animais , Transplante de Medula Óssea , Feminino , Transplante de Células-Tronco Hematopoéticas , Xenoenxertos , Humanos , Masculino , Camundongos
20.
Antiviral Res ; 150: 193-201, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29294299

RESUMO

Ebola virus (EBOV) is an enveloped negative-sense, single-stranded RNA virus of the filovirus family that causes severe disease in humans. Approved therapies for EBOV disease are lacking. EBOV RNA synthesis is carried out by a virus-encoded complex with RNA-dependent RNA polymerase activity that is required for viral propagation. This complex and its activities are therefore potential antiviral targets. To identify potential lead inhibitors of EBOV RNA synthesis, a library of small molecule compounds was screened against a previously established assay of EBOV RNA synthesis, the EBOV minigenome assay (MGA), in 384 well microplate format. The screen identified 56 hits that inhibited EBOV MGA activity by more than 70% while exhibiting less than 20% cell cytotoxicity. Inhibitory chemical scaffolds included angelicin derivatives, derivatives of the antiviral compound GSK983 and benzoquinolines. Structure-activity relationship (SAR) studies of the benzoquinoline scaffold produced ∼50 analogs and led to identification of an optimized compound, SW456, with a submicromolar IC50 in the EBOV MGA and antiviral activity against infectious EBOV in cell culture. The compound was also active against a MGA for another deadly filovirus, Marburg virus. It also exhibited antiviral activity towards a negative-sense RNA virus from the rhabdovirus family, vesicular stomatitis virus, and a positive-sense RNA virus, Zika virus. Overall, these data demonstrate the potential of the EBOV MGA to identify anti-EBOV compounds and identifies the benzoquinoline series as a broad-spectrum antiviral lead.


Assuntos
Antivirais/farmacologia , Ebolavirus/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Quinolinas/farmacologia , Replicação Viral/efeitos dos fármacos , Antivirais/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Ebolavirus/genética , Humanos , Quinolinas/química , Bibliotecas de Moléculas Pequenas
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