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1.
Chemistry ; 30(7): e202302996, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37721804

RESUMO

α-Sulfinyl esters can be readily prepared through thiol substitution of α-bromo esters followed by oxidation to the sulfoxide. Enzymatic resolution with lipoprotein lipase provides both the unreacted esters and corresponding α-sulfinyl carboxylic acids in high yields and enantiomeric ratios. Subsequent decarboxylative halogenation, dihalogenation, trihalogenation and cross-coupling gives rise to functionalized sulfoxides. The method has been applied to the asymmetric synthesis of a potent inhibitor of 15-prostaglandin dehydrogenase.


Assuntos
Ácidos Carboxílicos , Ésteres , Estereoisomerismo , Sulfóxidos , Halogenação
2.
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
3.
PLoS One ; 17(5): e0268787, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35587945

RESUMO

Emerging evidence implicates the eicosanoid molecule prostaglandin E2 (PGE2) in conferring a regenerative phenotype to multiple organ systems following tissue injury. As aging is in part characterized by loss of tissue stem cells' regenerative capacity, we tested the hypothesis that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) contributes to the diminished organ fitness of aged mice. Here we demonstrate that genetic loss of 15-PGDH (Hpgd) confers a protective effect on aging of murine hematopoietic and gastrointestinal (GI) tissues. Aged mice lacking 15-PGDH display increased hematopoietic output as assessed by peripheral blood cell counts, bone marrow and splenic stem cell compartments, and accelerated post-transplantation recovery compared to their WT counterparts. Loss of Hpgd expression also resulted in enhanced GI fitness and reduced local inflammation in response to colitis. Together these results suggest that 15-PGDH negatively regulates aged tissue regeneration, and that 15-PGDH inhibition may be a viable therapeutic strategy to ameliorate age-associated loss of organ fitness.


Assuntos
Hidroxiprostaglandina Desidrogenases , Envelhecimento/genética , Animais , Dinoprostona/metabolismo , Hidroxiprostaglandina Desidrogenases/genética , Camundongos
4.
Oncogene ; 21(9): 1443-9, 2002 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-11857087

RESUMO

Silencing of hMLH1 expression by aberrant hMLH1 promoter methylation accounts for the majority of sporadic colon cancers with microsatellite instability. We have previously shown hMLH1 silencing is biallelic and actively maintained. To study the mechanism of aberrant hMLH1 methylation, we assayed whether an hMLH1 methylated cell could transfer methylation and silencing to an exogenous hMLH1 promoter in somatic cell hybrids between hMLH1 methylated-silenced and hMLH1 unmethylated-expressing colon cancer cells. Conversely, we assayed whether these hybrids could reactivate expression of initially methylated and silenced hMLH1 alleles. Compellingly, within the hybrids each hMLH1 allele remained unchanged, retaining the expression status of its parental cell of origin. This chromosomal autonomy may not be simply determined by DNA methylation, as it is reasserted after experimentally forced demethylation of all hMLH1 alleles in the hybrids. Confirming findings included hMLH1 methylated cells being unable to methylate single transferred exogenous hMLH1 expressing chromosomes or transfected hMLH1 reporter constructs. hMLH1 silencing does not conform to either a dominant or recessive model, and is not determined by trans-acting factors differing between hMLH1 expressing or silenced genomes. We posit that hMLH1 methylation is dependent on and maintained by cis chromosomal marks, whose nature remains to be elucidated.


Assuntos
Cromossomos Humanos Par 3/genética , Neoplasias do Colo/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Proteínas Adaptadoras de Transdução de Sinal , Alelos , Azacitidina/farmacologia , Western Blotting , Proteínas de Transporte , Cromossomos Humanos Par 3/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Genes Reporter/genética , Humanos , Células Híbridas/metabolismo , Proteína 1 Homóloga a MutL , Proteínas Nucleares , Plasmídeos/genética , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
5.
Science ; 348(6240): aaa2340, 2015 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-26068857

RESUMO

Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.


Assuntos
Hidroxiprostaglandina Desidrogenases/fisiologia , Prostaglandinas/metabolismo , Regeneração/fisiologia , Animais , Transplante de Medula Óssea , Colite/enzimologia , Colite/prevenção & controle , Dinoprostona/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hematopoese/efeitos dos fármacos , Hidroxiprostaglandina Desidrogenases/antagonistas & inibidores , Hidroxiprostaglandina Desidrogenases/genética , Regeneração Hepática/efeitos dos fármacos , Camundongos , Camundongos Knockout , Piridinas/química , Piridinas/farmacologia , Regeneração/efeitos dos fármacos , Regeneração/genética , Tiofenos/química , Tiofenos/farmacologia
6.
J Natl Cancer Inst ; 97(15): 1124-32, 2005 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-16077070

RESUMO

BACKGROUND: Increased DNA methylation is an epigenetic alteration that is common in human cancers and is often associated with transcriptional silencing. Aberrantly methylated DNA has also been proposed as a potential tumor marker. However, genes such as vimentin, which are transcriptionally silent in normal epithelium, have not until now been considered as targets for cancer-associated aberrant methylation and for use as cancer markers. METHODS: We applied methylation-specific polymerase chain reaction to the vimentin gene, which is transcriptionally silent in normal colonocytes, and compared methylation of vimentin exon 1 in cancer tissues and in fecal DNA from colon cancer patients versus control samples from healthy subjects. RESULTS: Vimentin exon-1 sequences were unmethylated in 45 of 46 normal colon tissues. In contrast, vimentin exon-1 sequences were methylated in 83% (38 of 46) and 53% (57 of 107) of tumors from two independently collected groups of colon cancer patients. When evaluated as a marker for colon cancer detection in fecal DNA from another set of colon cancer patients, aberrant vimentin methylation was detected in fecal DNA from 43 of 94 patients, for a sensitivity of 46% (95% confidence interval [CI] = 35% to 56%). The sensitivity for detecting stage I and II cancers was 43% (26 of 60 case patients) (95% CI = 31% to 57%). Only 10% (20 of 198 case patients) of control fecal DNA samples from cancer-free individuals tested positive for vimentin methylation, for a specificity of 90% (95% CI = 85% to 94%). CONCLUSIONS: Aberrant methylation of exon-1 sequences within the nontranscribed vimentin gene is a novel molecular biomarker of colon cancer and can be successfully detected in fecal DNA to identify nearly half of individuals with colon cancer.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Metilação de DNA , DNA de Neoplasias/análise , Fezes/química , Vimentina/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenoma/diagnóstico , Adenoma/genética , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Transformação Celular Neoplásica , Humanos , Sangue Oculto , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
7.
Proc Natl Acad Sci U S A ; 100(14): 8412-7, 2003 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-12829793

RESUMO

We identify a gene, SLC5A8, and show it is a candidate tumor suppressor gene whose silencing by aberrant methylation is a common and early event in human colon neoplasia. Aberrant DNA methylation has been implicated as a component of an epigenetic mechanism that silences genes in human cancers. Using restriction landmark genome scanning, we performed a global search to identify genes that would be aberrantly methylated at high frequency in human colon cancer. From among 1,231 genomic NotI sites assayed, site 3D41 was identified as methylated in 11 of 12 colon cancers profiled. Site 3D41 mapped to exon 1 of SLC5A8, a transcript that we assembled. In normal colon mucosa we found that SLC5A8 exon 1 is unmethylated and SLC5A8 transcript is expressed. In contrast, SLC5A8 exon 1 proved to be aberrantly methylated in 59% of primary colon cancers and 52% of colon cancer cell lines. SLC5A8 exon 1 methylated cells were uniformly silenced for SLC5A8 expression, but reactivated expression on treatment with a demethylating drug, 5-azacytidine. Transfection of SLC5A8 suppressed colony growth in each of three SLC5A8-deficient cell lines, but showed no suppressive effect in any of three SLC5A8-proficient cell lines. SLC5A8 exon 1 methylation is an early event, detectable in colon adenomas, and in even earlier microscopic colonic aberrant crypt foci. Structural homology and functional testing demonstrated that SLC5A8 is a member of the family of sodium solute symporters, which are now added as a class of candidate colon cancer suppressor genes.


Assuntos
Adenocarcinoma/genética , Adenoma/genética , Neoplasias do Colo/genética , Metilação de DNA , Inativação Gênica , Genes Supressores de Tumor , Mucosa Intestinal/metabolismo , Azacitidina/farmacologia , Sequência de Bases , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/fisiologia , Metilação de DNA/efeitos dos fármacos , DNA de Neoplasias/genética , Éxons/genética , Inativação Gênica/efeitos dos fármacos , Humanos , Mucosa Intestinal/patologia , Transporte de Íons , Dados de Sequência Molecular , Transportadores de Ácidos Monocarboxílicos , Proteínas Recombinantes de Fusão/fisiologia , Sódio/metabolismo , Transfecção , Células Tumorais Cultivadas/química , Células Tumorais Cultivadas/efeitos dos fármacos , Ensaio Tumoral de Célula-Tronco
8.
Proc Natl Acad Sci U S A ; 99(7): 4562-7, 2002 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-11904375

RESUMO

Chromatin remodeling enzymes are increasingly implicated in a variety of important cellular functions. Various components of chromatin remodeling complexes, including several members of the SWI/SNF family, have been shown to be disrupted in cancer. In this study we identified as a target for gene inactivation in colon cancer the gene for helicase-like transcription factor (HLTF), a SWI/SNF family protein. Loss of HLTF expression accompanied by HLTF promoter methylation was noted in nine of 34 colon cancer cell lines. In these cell lines HLTF expression was restored by treatment with the demethylating agent 5-azacytidine. In further studies of primary colon cancer tissues, HLTF methylation was detected in 27 of 63 cases (43%). No methylation of HLTF was detected in breast or lung cancers, suggesting selection for HLTF methylation in colonic malignancies. Transfection of HLTF suppressed 75% of colony growth in each of three different HLTF-deficient cell lines, but showed no suppressive effect in any of three HLTF-proficient cell lines. These findings show that HLTF is a common target for methylation and epigenetic gene silencing in colon cancer and suggest HLTF is a candidate colon cancer suppressor gene.


Assuntos
Neoplasias do Colo/genética , Proteínas de Ligação a DNA/genética , Inativação Gênica , Fatores de Transcrição/genética , Sequência de Bases , Metilação de DNA , Humanos , Dados de Sequência Molecular , Mutação , Células Tumorais Cultivadas
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