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1.
Bioorg Med Chem ; 29: 115890, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33285407

RESUMO

As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp3 carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure-activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo[5,4-d]pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antiproliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo[5,4-d]pyrimidine 7a had better anti-cancer activity than thieno[2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment.

2.
Molecules ; 25(20)2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33053730

RESUMO

A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these N-heterocyclic compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) analysis and tested for phosphoinositide 3-kinase (PI3K) enzymatic assay. The results indicated that these N-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC50 of a representative compound (19a) could reach to 3.6 nm. The structure-activity relationships (SAR) study showed that sulfonamide functionality was important for PI3Kα inhibitory activity, and 2-chloro-4-florophenyl sulfonamide (19b), or 5-chlorothiophene-2-sulfonamide (19c) showed potent inhibitory activity with a nanomolar IC50 value. The pyridyl attached to thiazolo[5,4-b]pyridine was another key structural unit for PI3Kα inhibitory potency, and replacement by phenyl lead to a significant decrease in activity. Enzymatic Inhibition results showed that compound 19a inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC50 value, but its inhibitory activity on PI3Kß was approximately 10-fold reduced. Further docking analysis revealed that the N-heterocyclic core of compound 19a was directly involved in the binding to the kinase through the key hydrogen bonds interaction.

3.
Cancer Lett ; 495: 22-32, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-32931884

RESUMO

The tubulin colchicine binding site has been recognized as an attractive drug target to combat cancer, but none of the candidate drugs have been approved for medical treatment. We recently identified a structurally distinct small molecule S-40 as an oral potent tubulin destabilizing agent. Crystal structure analysis of S-40 in a complex with tubulin at a resolution of 2.4 Å indicated that S-40 occupies all 3 zones in the colchicine pocket with interactions different from known microtubule inhibitors, presenting unique effects on assembly and curvature of tubulin dimers. S-40 overcomes paclitaxel resistance and lacks neurotoxicity, which are the main obstacles limiting clinical applications of paclitaxel. Moreover, S-40 harbors the ability to inhibit growth of cancer cell lines as well as patient-derived organoids, induce mitotic arrest and cell apoptosis. Xenograft mouse models of human prostate cancer DU145, non-small cell lung cancer NCI-H1299 and paclitaxel-resistant A549 were strongly restrained without apparent side effects by S-40 oral administration once daily. These findings provide evidence for the development of S-40 as the next generation of orally effective microtubule inhibitors for cancer therapy.

4.
J Spinal Cord Med ; : 1-6, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32182195

RESUMO

Study design: A retrospective hospital-based study.Objective: To describe the epidemiological profile of traumatic spinal cord injury (TSCI) in Guangdong Province.Setting: Two hospitals within Guangdong Province, China.Methods: Medical records of patients diagnosed with TSCI admitted to Foshan Hospital of Traditional Chinese Medicine and Zhujiang Hospital of South Medical University from 1 January 2011 to 31 December 2015 were retrospectively reviewed. Epidemiological characteristics, such as age, sex, occupation, etiology, neurological level of injury, American Spinal Injury Association Impairment Scale at admission, death and cause of death during the acute hospitalization and concomitant injuries.Results: During the study period, 482 cases were identified. Male-to-female ratio was 3.4:1, with a mean age of 41.5 ± 12.6 years old. The leading cause was falls (49.3%), followed by motor vehicle collisions (MVCs) (34.8%). The most common injury site was the cervical spinal cord, especially C4-C6, accounting for 39.8%.Conclusion: The number of TSCI patients in Guangdong Province is large and is exhibiting a rising trend. The leading causes were falls and MVCs. The low-falls (height < 1 m) group has expanded over this period. With China entering an ageing society, more appropriate preventative measures should be implemented for fall-related injuries among the elderly.

5.
Radiat Res ; 193(3): 199-208, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31910120

RESUMO

Radiation therapy is an essential component of cancer treatment. Currently, tumor control and normal tissue complication probabilities derived from a general patient population guide radiation treatment. Its outcome could be improved if radiation biomarkers could be incorporated into approaches to treatment. A substantial number of cancer patients suffer from side effects of radiation therapy. These side effects can result in treatment interruption. Such unplanned treatment interruptions not only jeopardize anticancer treatment efficacy but also result in poor post-treatment quality-of-life. To develop and translate radiation biomarkers for clinical use, NCI's Radiation Research Program, in collaboration with the Small Business Innovation Research Development Center, funded four small businesses through the request for proposals after peer review during 2015-2019. Here, we summarize publicly available information on intellectual property rights, the status of development, ongoing clinical trials, success in obtaining financing and regulatory approval. An analysis of publicly available information indicates all four companies have completed phase I of SBIR funding and advanced to further development, validation and clinical trials with phase II SBIR funding. These biomarkers are: 1. A panel of genomic biomarkers of radiation response to predict toxicity and radioimmune response (MiraDx Inc., Los Angeles, CA); 2. A multiplex assay for single nucleotide polymorphism (SNP) biomarkers of radiation sensitivity to identify a subset of prostate cancer patients for which radiotherapy is contraindicated (L2 Diagnostics, New Haven, CT); 3. A cell-free DNA assay in blood to measure tissue damage shortly after radiation exposure (DiaCarta Inc., Richmond, CA); and 4. A metabolomic/lipidomic assay to predict late effects that adversely affect quality-of-life among patients treated with radiation for prostate cancer (Shuttle Pharmaceuticals, Rockville, MD). This work also provides a bird's eye view of the process of developing radiation biomarkers for use in radiation oncology clinics, some of the challenges and future directions.


Assuntos
Comércio , Medicina de Precisão , Radioterapia , Biomarcadores/metabolismo , Humanos , Medicina de Precisão/tendências , Radioterapia/tendências
6.
J Med Chem ; 62(19): 8873-8879, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31335136

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease, and its molecular pathogenesis remains poorly understood. Recently, emerging evidence demonstrates that the PI3K signaling transduction pathway is linked to the pathology of IPF. In this work, we rationally designed a new series of 4-methylquinazoline derivatives as highly potent PI3K inhibitors that significantly suppress the phosphorylation of the main PI3K downstream effectors and displays marked antiproliferative activity in mouse MLg2908 lung fibroblasts. In a bleomycin-induced mouse pulmonary fibrosis model, 5d from the series improved mouse lung function and slowed the progression of pulmonary fibrosis. Overall, this work promises a therapeutic potential for PI3K inhibitors to treat IPF.


Assuntos
Fosfatidilinositol 3-Quinases/química , Inibidores de Fosfoinositídeo-3 Quinase/química , Quinazolinas/química , Animais , Bleomicina/toxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Conformação Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Fosforilação/efeitos dos fármacos , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
7.
J Med Chem ; 62(15): 6992-7014, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31117517

RESUMO

Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.


Assuntos
Antineoplásicos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HCT116 , Células Hep G2 , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Células K562 , Células MCF-7 , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular/métodos , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia
8.
Onco Targets Ther ; 12: 11623-11635, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32021242

RESUMO

Background: Chronic hepatitis C virus (HCV) infection is an important risk factor for hepatocellular carcinoma (HCC). EGOT is a long non-coding RNA (lncRNA) induced after HCV infection that increases viral replication by antagonizing the antiviral response. Interestingly, EGOT also acts as a crucial regulator in multiple cancers. However, its role in HCC remains unclear. Methods: Real-time PCR (RT-PCR) was used to detect the expression of EGOT in HCC samples and cell lines. CCK-8 assay and colony formation assay were performed to evaluate the effect of EGOT on proliferation. Scratch healing assay and transwell assay were used to detect the changes of migration and invasion. Flow cytometry was used to detect the effect of EGOT on apoptosis. Interaction between EGOT and miR-33a-5p was determined by bioinformatics analysis, RT-PCR, and dual-luciferase reporter assay. Western blot was used to confirm that high mobility group protein A2 (HMGA2) could be modulated by EGOT. Results: Compared with normal liver tissues, the expression level of EGOT in HCC tissues was significantly up-regulated. EGOT markedly regulated viability, migration and invasion of HCC cells. The expression level of EGOT was negatively correlated the expression level of miR-33a-5p. It is also confirmed that EGOT could specifically bind to miR-33a-5p and could reduce its expression, in turn, up-regulate the expression of HMGA2. Conclusion: Our data imply that EGOT may be a novel therapeutic target for HCC, and highlights the key role of EGOT/miR-33a-5p/HMGA2 in the progression of this deadly disease.

9.
J Med Chem ; 61(14): 6087-6109, 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-29927604

RESUMO

Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.


Assuntos
Desenho de Fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Quinazolinas/química , Quinazolinas/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Conformação Proteica , Quinazolinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
10.
Chembiochem ; 19(13): 1444-1451, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29633462

RESUMO

Cyclic adenosine diphosphate ribose (cADPR) is an endogenous Ca2+ mobilizer involved in diverse cellular processes. Mimics of cADPR play a crucial role in investigating the molecular mechanism(s) of cADPR-mediated signaling. Here, compound 3, a mimic of cADPR in which a neutral triazole moiety and an ether linkage were introduced to substitute the pyrophosphate and "northern" ribose components, respectively, was synthesized for the first time. The pharmacological activities in Jurkat cells indicated that this mimic is capable of penetrating plasma membrane and inciting Ca2+ release from the endoplasmic reticulum (ER) through the action of ryanodine receptors (RyRs) and triggering Ca2+ influx. Furthermore, a uridine moiety was introduced in place of adenine and the new cADPR mimics 4 and 5 were synthesized. The results of biological investigation showed that these mimics also targeted RyRs and retained moderate Ca2+ agonistic activities. The results indicated that the neutral cADPR mimics had the same targets for inducing Ca2+ signaling.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , ADP-Ribose Cíclica/análogos & derivados , ADP-Ribose Cíclica/metabolismo , Triazóis/metabolismo , ADP-Ribose Cíclica/síntese química , Técnicas de Silenciamento de Genes , Humanos , Células Jurkat , Mitocôndrias/metabolismo , Conformação Molecular , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Triazóis/síntese química , Triazóis/química
11.
Bioorg Med Chem ; 26(3): 637-646, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29305298

RESUMO

A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile.


Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Meia-Vida , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microssomos Hepáticos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Relação Estrutura-Atividade , Transplante Heterólogo
12.
Clin Neurol Neurosurg ; 161: 35-40, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28843115

RESUMO

OBJECTIVE: The incidence of double-level isthmic spondylolisthesis is rare. The aim of this study is to evaluate the short-term functional and radiological outcomes of surgical treatment for double-level isthmic spondylolisthesis. PATIENTS AND METHODS: Between 2004 and 2014, thirty-two patients with double-level isthmic spondylolisthesis who underwent posterior lumbar interbody fusion (PLIF) with autogenous bone chips were reviewed retrospectively. The clinical outcomes were measured by VAS (Visual analog scale) and JOA(Japanese Orthopedic Association) score. RESULTS: At an average follow-up of 2.8 years, the mean score on the VAS of back pain and sciatica decreased from 6.48 and 4.26 points preoperatively to 1.82 and 1.10 points at final follow-up, respectively. The average JOA score improved from 13.8±3.1 preoperative to 25.6±1.3 (range, 17-28) points postoperative. The average recovery rate was 77.6%. The good and excellent rate was 84.3% (27/32). The fusion rate was 87.5% (28/32). Changes in disc height, degree of listhesis, whole lumbar lordosis, and sacral inclination between the pre- and postoperative periods were significant. CONCLUSIONS: Our findings suggest that PLIF with autogenous bone chips for double-level isthmic spondylolisthesis could yield good functional short-term results. It seems to be a viable approach in the treatment of double-level isthmic spondylolisthesis.


Assuntos
Vértebras Lombares/cirurgia , Avaliação de Resultados em Cuidados de Saúde , Fusão Vertebral/métodos , Espondilolistese/cirurgia , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espondilolistese/patologia
13.
J Am Chem Soc ; 139(1): 156-170, 2017 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-27936653

RESUMO

Cyclic adenosine diphosphoribose (cADPR), an endogenous nucleotide derived from nicotinamide adenine dinucleotide (NAD+), mobilizes Ca2+ release from endoplasmic reticulum (ER) via ryanodine receptors (RyRs), yet the bridging protein(s) between cADPR and RyRs remain(s) unknown. Here we synthesized a novel photoaffinity labeling (PAL) cADPR agonist, PAL-cIDPRE, and subsequently applied it to purify its binding proteins in human Jurkat T cells. We identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as one of the cADPR binding protein(s), characterized the binding affinity between cADPR and GAPDH in vitro by surface plasmon resonance (SPR) assay, and mapped cADPR's binding sites in GAPDH. We further demonstrated that cADPR induces the transient interaction between GAPDH and RyRs in vivo and that GAPDH knockdown abolished cADPR-induced Ca2+ release. However, GAPDH did not catalyze cADPR into any other known or novel compound(s). In summary, our data clearly indicate that GAPDH is the long-sought-after cADPR binding protein and is required for cADPR-mediated Ca2+ mobilization from ER via RyRs.


Assuntos
Adenosina Difosfato Ribose/metabolismo , Proteínas de Transporte/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Marcadores de Fotoafinidade/metabolismo , Adenosina Difosfato Ribose/química , Proteínas de Transporte/química , Células Cultivadas , Clonagem Molecular , Gliceraldeído-3-Fosfato Desidrogenases/química , Gliceraldeído-3-Fosfato Desidrogenases/genética , Humanos , Células Jurkat , Ligantes , Modelos Moleculares , Conformação Molecular , Marcadores de Fotoafinidade/química
15.
Stem Cells ; 33(9): 2664-73, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26012865

RESUMO

CD38 is a multifunctional membrane enzyme and the main mammalian ADP-ribosyl cyclase, which catalyzes the synthesis and hydrolysis of cADPR, a potent endogenous Ca(2+) mobilizing messenger. Here, we explored the role of CD38 in the neural differentiation of mouse embryonic stem cells (ESCs). We found that the expression of CD38 was decreased during the differentiation of mouse ESCs initiated by adherent monoculture. Perturbing the CD38/cADPR signaling by either CD38 knockdown or treatment of cADPR antagonists inhibited the neural commitment of mouse ESCs, whereas overexpression of CD38 promoted it. Moreover, CD38 knockdown dampened reactive oxygen species (ROS) production during neural differentiation of ESCs by inhibiting NADPH oxidase activity, while CD38 overexpression enhanced it. Similarly, application of hydrogen peroxide mitigated the inhibitory effects of CD38 knockdown on neural differentiation of ESCs. Taken together, our data indicate that the CD38 signaling pathway is required for neural differentiation of mouse ESCs by modulating ROS production.


Assuntos
ADP-Ribosil Ciclase 1/biossíntese , Diferenciação Celular/fisiologia , Glicoproteínas de Membrana/biossíntese , Células-Tronco Embrionárias Murinas/metabolismo , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , ADP-Ribosil Ciclase 1/genética , Animais , Células Cultivadas , Técnicas de Silenciamento de Genes , Glicoproteínas de Membrana/genética , Camundongos
16.
Molecules ; 19(10): 15754-67, 2014 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-25268725

RESUMO

Nicotinamide adenine dinucleotide (NAD), one of the most important coenzymes in the cells, is a substrate of the signaling enzyme CD38, by which NAD is converted to a second messenger, cyclic ADP-ribose, which releases calcium from intracellular calcium stores. Starting with 2'-deoxy-2'-fluoroarabinosyl-ß-nicotinamide adenine dinucleotide (ara-F NAD), a series of NAD analogues were synthesized and their activities to inhibit CD38 NAD glycohydrolase (NADase) were evaluated. The adenosine-modified analogues showed potent inhibitory activities, among which 2'-deoxy-2'-fluoroarabinosyl-ß-nicotinamide guanine dinucleotide (ara-F NGD) was the most effective one. The structure-activity relationship of NAD analogues was also discussed.


Assuntos
ADP-Ribosil Ciclase 1/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Nucleotídeos de Guanina/química , NAD/análogos & derivados , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Técnicas de Química Sintética , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Nucleotídeos de Guanina/síntese química , Nucleotídeos de Guanina/farmacologia , Estrutura Molecular , NAD/síntese química , NAD/química , NAD/farmacologia , Ligação Proteica , Especificidade por Substrato
18.
Molecules ; 15(12): 8689-701, 2010 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-21119564

RESUMO

A novel trifluoromethylated analogue of cADPR, 8-CF3-cIDPDE (5) was designed and synthesized via construction of N1,N9-disubstituted hypoxanthine, trifluoromethylation and intramolecular condensation. A series of acyclic analogues of cADPR were also designed and synthesized. These compounds could be useful molecules for studying the structure-activity relationship of cADPR analogues and exploring the cADPR/RyR Ca2+ signalling system.


Assuntos
ADP-Ribose Cíclica/análogos & derivados , ADP-Ribose Cíclica/síntese química , Hidrocarbonetos Fluorados/síntese química , Sinalização do Cálcio , ADP-Ribose Cíclica/química , Hidrocarbonetos Fluorados/química , Hipoxantina/química , Canal de Liberação de Cálcio do Receptor de Rianodina
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