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1.
Bioorg Med Chem ; 27(7): 1370-1381, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30827868

RESUMO

On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Rotenona/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Rotenona/síntese química , Rotenona/química , Rotenona/farmacologia , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 167: 485-498, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30784881

RESUMO

A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Rotenona/análogos & derivados , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Rotenona/síntese química , Rotenona/química , Rotenona/farmacologia , Relação Estrutura-Atividade
3.
J Nat Prod ; 80(10): 2751-2755, 2017 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-29039664

RESUMO

Operationally simple, stereocontrolled semisyntheses of the anticancer rotenoids elliptone and 12aß-hydroxyelliptone, isolated from Derris elliptica and Derris trifoliata, respectively, are described. Inspired by the work of Singhal, elliptone was prepared from rotenone via a dihydroxylation-oxidative cleavage, chemoselective Baeyer-Villiger oxidation, and acid-catalyzed elimination sequence. Elaboration of elliptone to 12aß-hydroxyelliptone was achieved via a diastereoselective chromium-mediated Étard-like hydroxylation. The semisynthesis of elliptone constitutes an improvement over previous methods in terms of safety, scalability, and yield, while the first synthesis of 12aß-hydroxyelliptone is also described.


Assuntos
Benzopiranos/síntese química , Derris/química , Rotenona/síntese química , Benzopiranos/química , Estrutura Molecular , Rotenona/química , Estereoisomerismo
4.
Org Biomol Chem ; 15(7): 1593-1596, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28134391

RESUMO

We describe stereocontrolled semi-syntheses of deguelin and tephrosin, anti-cancer rotenoids isolated from Tephrosia vogelii. Firstly, we present a new two-step transformation of rotenone into rot-2'-enonic acid via a zinc-mediated ring opening of rotenone hydrobromide. Secondly, following conversion of rot-2'-enonic acid into deguelin, a chromium-mediated hydroxylation provides tephrosin as a single diastereoisomer. An Étard-like reaction mechanism is proposed to account for the stereochemical outcome. Our syntheses of deguelin and tephrosin are operationally simple, scalable and high yielding, offering considerable advantages over previous methods.


Assuntos
Rotenona/análogos & derivados , Conformação Molecular , Rotenona/síntese química , Rotenona/química , Estereoisomerismo
5.
Angew Chem Int Ed Engl ; 56(1): 182-187, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-27910179

RESUMO

The total syntheses of (-)-rotenone and (-)-dalpanol have been achieved by a group-selective, stereospecific 1,2-shift of an epoxy alcohol and SN Ar cyclizations. Three oxacycles are constructed, thus illustrating a versatile synthetic route to various rotenoids.


Assuntos
Produtos Biológicos/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Rotenona/síntese química , Produtos Biológicos/química , Técnicas de Química Sintética/métodos , Ciclização , Derris/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Rotenona/análise , Estereoisomerismo
6.
Bioorg Med Chem ; 24(22): 6082-6093, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27745993

RESUMO

Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure-activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80. It also inhibited in vitro hypoxia-mediated angiogenic processes in human retinal microvascular endothelial cells (HRMEC). The docking study of 5 showed a similar binding mode as L-80: it occupied the C-terminal ATP-binding pocket of HSP90, indicating that the anticancer and antiangiogenic activities of 5 were derived from HIF-1α destabilization by inhibiting the C-terminal ATP-binding site of hHSP90.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Rotenona/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Neovascularização Patológica/patologia , Rotenona/síntese química , Rotenona/química , Rotenona/farmacologia , Relação Estrutura-Atividade
7.
J Org Chem ; 80(22): 11460-7, 2015 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-26525067

RESUMO

A highly convergent synthetic approach to rotenoid natural products is described. Successful pairing of two building blocks for Sonogashira cross-coupling and intramolecular alkyne carbonyl metathesis allows ready access to 4-acylchromene, a key substructure of these natural products, leading to syntheses of (±)-deguelin and (±)-munduserone in high overall yields.


Assuntos
Alquinos/química , Produtos Biológicos/síntese química , Rotenona/análogos & derivados , Produtos Biológicos/química , Catálise , Estrutura Molecular , Rotenona/síntese química , Rotenona/química , Estereoisomerismo
8.
Eur J Med Chem ; 104: 157-64, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26457742

RESUMO

A series of fluorophenyl and pyridine analogues of 1 and 2 were synthesized as ring-truncated deguelin surrogates and evaluated for their HIF-1α inhibition. Their structure-activity relationship was systematically investigated based on the variation of the linker B-region moiety. Among the inhibitors, compound 25 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in H1299 with less toxicity than deguelin. It also inhibited in vitro hypoxia-mediated angiogenic processes in HRMECs. The docking study indicates that 25 occupied the C-terminal ATP-binding pocket of HSP90 in a similar mode as 1, which implies that the anticancer and antiangiogenic activities of 25 are derived from HIF-1α destabilization by binding to the C-terminal ATP-binding site of hHSP90.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Rotenona/análogos & derivados , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais/efeitos dos fármacos , Humanos , Estrutura Molecular , Vasos Retinianos/citologia , Vasos Retinianos/efeitos dos fármacos , Rotenona/síntese química , Rotenona/química , Rotenona/farmacologia , Relação Estrutura-Atividade
9.
Chem Commun (Camb) ; 51(43): 9026-9, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25940751

RESUMO

Enantioselective synthesis of (-)-deguelin was accomplished via an iterative pyran-ring formation approach. The key features involve the anionic addition of a chromene unit to aryloxy alkyl aldehyde for the double cyclization precursor and iterative pyran ring formation by Pd-catalyzed O-arylation and C-arylation, respectively.


Assuntos
Rotenona/análogos & derivados , Catálise , Ciclização , Paládio/química , Piranos/química , Rotenona/síntese química , Rotenona/química , Estereoisomerismo
10.
Mol Pharmacol ; 88(2): 245-55, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25976766

RESUMO

The clinical benefit of current anticancer regimens for lung cancer therapy is still limited due to moderate efficacy, drug resistance, and recurrence. Therefore, the development of effective anticancer drugs for first-line therapy and for optimal second-line treatment is necessary. Because the 90-kDa molecular chaperone heat shock protein (Hsp90) contributes to the maturation of numerous mutated or overexpressed oncogenic proteins, targeting Hsp90 may offer an effective anticancer therapy. Here, we investigated antitumor activities and toxicity of a novel deguelin-derived C-terminal Hsp90 inhibitor, designated L80. L80 displayed significant inhibitory effects on the viability, colony formation, angiogenesis-stimulating activity, migration, and invasion of a panel of non-small cell lung cancer cell lines and their sublines with acquired resistance to paclitaxel with minimal toxicity to normal lung epithelial cells, hippocampal cells, vascular endothelial cells, and ocular cells. Biochemical analyses and molecular docking simulation revealed that L80 disrupted Hsp90 function by binding to the C-terminal ATP-binding pocket of Hsp90, leading to the disruption of the interaction between hypoxia-inducible factor (HIF)-1α and Hsp90, downregulation of HIF-1α and its target genes, including vascular endothelial growth factor (VEGF) and insulin-like growth factor 2 (IGF2), and decreased the expression of various Hsp90 client proteins. Consistent with these in vitro findings, L80 exhibited significant antitumor and antiangiogenic activities in H1299 xenograft tumors. These results suggest that L80 represents a novel C-terminal Hsp90 inhibitor with effective anticancer activities with minimal toxicities.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Benzopiranos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Choque Térmico HSP90/química , Neoplasias Pulmonares/tratamento farmacológico , Quinolinas/administração & dosagem , Rotenona/análogos & derivados , Animais , Antineoplásicos/farmacologia , Benzopiranos/síntese química , Benzopiranos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos SCID , Quinolinas/síntese química , Quinolinas/farmacologia , Rotenona/administração & dosagem , Rotenona/síntese química , Rotenona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Bioorg Med Chem ; 22(7): 2033-44, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24630696

RESUMO

UNLABELLED: Myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) is widely used in the assessment of coronary artery disease (CAD). We have developed (123)I-CMICE-013 based on rotenone, a mitochondrial complex I (MC-1) inhibitor, as a promising new MPI agent. Our synthesis results in a mixture of four species of (123)I-CMICE-013 A, B, C, D. In this study, we separated the four species and evaluated their biodistribution and imaging properties. The cold analogs (127)I-CMICE-013 A, B, C, D were isolated and characterized and their chemical structures proposed. METHODS: (123)I-CMICE-013 was synthesized by radiolabeling rotenone with Na(123)I in trifluoroacetic acid (TFA) with iodogen as the oxidizing agent at 60°C for 45min, and the four species were separated by RP-HPLC. The cold analogs (127)I-CMICE-013 A, B, C and D were isolated with a similar procedure and characterized by NMR and mass spectrometry. Biodistribution and microSPECT imaging studies were carried out on normal rats. RESULTS: We propose the mechanism of the rotenone iodination and the structures of the four species. First, I(+) forms an intermediate three-membered ring with 6' and 7' carbons. Second, the lone electron pair of the water molecule attacks the 6' or 7'-carbon, following by the formation of 6'-OH, and 7'-I bonds as in major products C and D, or 6'-I and 7'-OH bonds as in minor products A and B. The weaker 6'-I bond in the intermediate prompts the nucleophilic attachment of water at the favorable 6'-carbon to generate C and D. MicroSPECT images of (123)I-CMICE-013 A, B, C, D in rats showed clear visualization of myocardium and little interference from lung and liver. The imaging time activity curves and biodistribution data showed complex profiles for the four isomers, which is not expected from the structure activity relationship theory. CONCLUSION: (123/127)I-CMICE-013 A and B are constitutional isomers with C and D, while A and C are diastereomers of B and D, respectively. Overall, the biological characteristics of the four species are not correlated perfectly with their molecular structures.


Assuntos
Radioisótopos do Iodo/farmacocinética , Imagem de Perfusão do Miocárdio , Compostos Radiofarmacêuticos/farmacocinética , Rotenona/análogos & derivados , Tomografia Computadorizada de Emissão de Fóton Único , Animais , Radioisótopos do Iodo/química , Masculino , Estrutura Molecular , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Ratos , Ratos Sprague-Dawley , Rotenona/síntese química , Rotenona/química , Rotenona/farmacocinética , Estereoisomerismo , Distribuição Tecidual
12.
J Med Chem ; 55(24): 10863-84, 2012 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-23186287

RESUMO

Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogues do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To determine the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogues 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent antiproliferative activities with IC(50) of 140 and 490 nM in the H1299 cell line, respectively, and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 µM).


Assuntos
Inibidores da Angiogênese/síntese química , Antineoplásicos/síntese química , Benzopiranos/síntese química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Rotenona/análogos & derivados , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzopiranos/química , Benzopiranos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Embrião não Mamífero/irrigação sanguínea , Embrião não Mamífero/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Ligação Proteica , Rotenona/síntese química , Rotenona/química , Rotenona/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Peixe-Zebra
13.
Bioorg Med Chem Lett ; 22(2): 920-3, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22204911

RESUMO

Three series of novel spin-labeled rotenone derivatives were synthesized and evaluated for cytotoxicity against four tumor cell lines, A-549, DU-145, KB and KBvin. All of the derivatives showed promising in vitro cytotoxic activity against the tumor cell lines tested, with IC(50) values ranging from 0.075 to 0.738µg/mL. Remarkably, all of the compounds were more potent than paclitaxel against KBvin in vitro, and compounds 3a and 3d displayed the highest cytotoxicity against this cell line (IC(50) 0.075 and 0.092µg/mL, respectively). Based on the observed cytotoxicity, structure-activity relationships have been described.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Rotenona/síntese química , Rotenona/farmacologia , Marcadores de Spin , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Rotenona/química , Estereoisomerismo , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 21(16): 4813-8, 2011 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-21741833

RESUMO

6-Deoxyclitoriacetal (1) and a series of 11 further derivatives of it (2-12) were synthesized and evaluated for their cytotoxic and topoisomerase IIα inhibitory activities. Compounds bearing epoxide (2), morpholine (6) and benzylamine (10) moieties showed promising in vitro cytotoxic activities against four cancer cell lines, with IC(50) values ranging from 0.38 to 0.73 µM. These three compounds also strongly inhibited topoisomerase II activity at 68.3-93.5% and showed a moderately high DNA intercalating property.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Inibidores Enzimáticos/farmacologia , Rotenona/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Rotenona/análogos & derivados , Rotenona/síntese química , Estereoisomerismo , Relação Estrutura-Atividade , Temperatura
16.
Bioorg Med Chem Lett ; 20(9): 2884-7, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20359889

RESUMO

A series of novel 4-aryl-thiopyrano[3,4-b]pyran-5-one derivatives were synthesized through an efficient one-pot three-component reaction under solvent-free conditions. This work provides a new series of derivatives of thiorotenone with potential biological activity for biomedical screening.


Assuntos
Rotenona/química , Cristalografia por Raios X , Desenho de Fármacos , Conformação Molecular , Rotenona/síntese química , Rotenona/farmacologia
17.
Bioorg Med Chem Lett ; 19(15): 4303-7, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19502057

RESUMO

Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives were investigated as novel small molecule amplifiers of heat shock factor 1 transcriptional activity. Lead optimization led to the discovery of compound 4A-13, which displayed potent HSF1 activity under mild heat stress (EC(50)=2.5microM) and significant cytoprotection in both rotenone (EC(50)=0.23microM) and oxygen-glucose deprivation cell toxicity models (80% protection at 2.5microM).


Assuntos
Pirimidinonas/síntese química , Rotenona/síntese química , Triazinas/química , Uracila/análogos & derivados , Animais , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Proteínas de Ligação a DNA/química , Desenho de Fármacos , Glucose/química , Fatores de Transcrição de Choque Térmico , Humanos , Modelos Químicos , Chaperonas Moleculares/química , Doenças Neurodegenerativas/tratamento farmacológico , Oxigênio/química , Conformação Proteica , Dobramento de Proteína , Ratos , Rotenona/farmacologia , Relação Estrutura-Atividade , Fatores de Transcrição/química , Triazinas/farmacologia , Uracila/química , Uracila/farmacologia
18.
J Org Chem ; 74(14): 5097-9, 2009 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-19476326

RESUMO

Short synthetic routes to the natural products (+/-)-munduserone 1 and (+/-)-cis-12a-hydroxymunduserone 9 from protected cyanohydrin 5 and nitrochromene 4 are described. The key coupling reaction of 4 and 5 gave under inverse addition conditions 9 (28%) and 2b (21%), while under normal addition conditions, a mixture of 9 (20%), dehydromunduserone 10 (9%), and enone 2b (10%) was obtained. (+/-)-Munduserone 1 is easily obtained from both 2b and 9 by 10% methanolic HCl (86%) and Zn/AcOH (71%) treatments, respectively.


Assuntos
Nitrilos/química , Rotenona/análogos & derivados , Estrutura Molecular , Rotenona/síntese química , Rotenona/química
19.
Cancer Prev Res (Phila) ; 1(7): 577-87, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19139008

RESUMO

The natural compound deguelin has promising preventive and therapeutic activity against diverse cancers by directly binding to heat shock protein-90 and thus suppressing its function. Potential side effects of deguelin over a certain dose, however, could be a substantial obstacle to its clinical use. To develop a derivative(s) of deguelin with reduced potential side effects, we synthesized five deguelin analogues (SH-02, SH-03, SH-09, SH-14, and SH-15) and compared them with the parent compound and each other for structural and biochemical features; solubility; and antiproliferative effects on normal, premalignant, and malignant human bronchial epithelial (HBE) and non-small-cell lung cancer (NSCLC) cell lines. Four derivatives destabilized hypoxia-inducible factor-1alpha as potently as did deguelin. Reverse-phase protein array (RPPA) analysis in H460 NSCLC cells revealed that deguelin and the derivatives suppressed expression of a number of proteins including heat shock protein-90 clients and proteins involved in the phosphoinositide 3-kinase/Akt pathway. One derivative, SH-14, showed several features of potential superiority for clinical use: the highest apoptotic activity; no detectable influence on Src/signal transducer and activator of transcription signaling, which can promote cancer progression and is closely related to pathogenesis of Parkinson's disease (deguelin, SH-02 and SH-03 strongly activated this signaling); better aqueous solubility; and less cytotoxicity to immortalized HBE cells (versus deguelin) at a dose (1 micromol/L) that induced apoptotic activity in most premalignant and malignant HBE and NSCLC cell lines. These collective results suggest that the novel derivative SH-14 has strong potential for cancer chemoprevention and therapy, with equivalent efficacy and lesser toxicity (versus deguelin).


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/prevenção & controle , Neoplasias Pulmonares/prevenção & controle , Rotenona/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Quimioprevenção/métodos , Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Rotenona/síntese química , Rotenona/química , Rotenona/farmacologia , Transdução de Sinais/efeitos dos fármacos
20.
Org Lett ; 5(22): 4053-5, 2003 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-14572247

RESUMO

[reaction: see text]. A concise total synthesis of (+/-)-deguelin was achieved with a longest linear sequence of six steps in 68% yield. A key step was the platinum-catalyzed 6-endo hydroarylation of an alkynone intermediate.


Assuntos
Rotenona/análogos & derivados , Rotenona/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Catálise , Ciclização , Estrutura Molecular , Compostos de Platina/química , Rotenona/química
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