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1.
Bioorg Med Chem Lett ; 35: 127778, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33422603

RESUMO

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.


Assuntos
Éteres/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Tretinoína/farmacologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Éteres/síntese química , Éteres/química , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Células Th17 , Tretinoína/síntese química , Tretinoína/química
2.
Org Biomol Chem ; 18(25): 4788-4801, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32530010

RESUMO

Human aldo-keto reductases (AKRs) are enzymes involved in the reduction, among other substrates, of all-trans-retinal to all-trans-retinol (vitamin A), thus contributing to the control of the levels of retinoids in organisms. Structure-activity relationship studies of a series of C11-to-C14 methyl-shifted (relative to natural C13-methyl) all-trans-retinal analogues as putative substrates of AKRs have been reported. The synthesis of these retinoids was based on the formation of a C10-C11 single bond of the pentaene skeleton starting from a trienyl iodide and the corresponding dienylstannanes and dienylsilanes, using the Stille-Kosugi-Migita and Hiyama-Denmark cross-coupling reactions, respectively. Since these reagents differ by the location and presence of methyl groups at the dienylorganometallic fragment, the study also provided insights into the ability of the different positional isomers to undergo cross-coupling and the sensitivity of these processes to steric hindrance. The resulting C11-to-C14 methyl-shifted all-trans-retinal analogues were found to be active substrates when tested with AKR1B1 and AKR1B10 enzymes, although relevant differences in substrate specificities were noted. For AKR1B1, all analogues exhibited higher catalytic efficiency (kcat/Km) than parent all-trans-retinal. In addition, only all-trans-11-methylretinal, the most hydrophobic derivative, showed a higher value of kcat/Km = 106 000 ± 23 200 mM-1 min-1 for AKR1B10, which is in fact the highest value from all known retinoid substrates of this enzyme. The novel structures, identified as efficient AKR substrates, may serve in the design of selective inhibitors with potential pharmacological interest.


Assuntos
Aldo-Ceto Redutases/antagonistas & inibidores , Tretinoína/farmacologia , Aldo-Ceto Redutases/metabolismo , Humanos , Estrutura Molecular , Tretinoína/síntese química , Tretinoína/química
3.
Carbohydr Polym ; 231: 115733, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31888823

RESUMO

All-trans retinoic acid (ATRA) was grafted to hyaluronan (HA) via esterification. The reaction was mediated by mixed anhydrides. A perfect control of the degree of substitution (0.5-7.5%) was obtained by varying the molar ratio of retinoic acid in the feed. The degree of substitution plays a significant role in the long-term stability. The photodegradation of HA-ATRA upon UVA irradiation resulted in ß-ionone, ß-cyclocitral and 5,6-epoxy-(E)-retinoic acid. The photostability of the conjugate had increased with the combination with morin. The chemical structure of HA-ATRA and its degradation products was elucidated using NMR spectroscopy, SEC-MALLS, and gas chromatography-mass spectrometry (GC-MS). ATRA did not loss its biological activity after conjugation, as demonstrated by gene expression. The derivative was able to penetrate across the stratum corneum. Besides, HA-ATRA downregulated the expression of anti-inflammatory interleukins 6 and 8. HA-ATRA would be expected to be used for transdermal drug delivery or cosmetics.


Assuntos
Antioxidantes/farmacologia , Ácido Hialurônico/química , Pele/efeitos dos fármacos , Tretinoína/química , Administração Cutânea , Anidridos/química , Animais , Antioxidantes/química , Esterificação , Flavonoides/química , Ácido Hialurônico/síntese química , Ácido Hialurônico/farmacologia , Camundongos , Células NIH 3T3 , Norisoprenoides/química , Norisoprenoides/farmacologia , Fotólise/efeitos dos fármacos , Pele/efeitos da radiação , Tretinoína/síntese química , Tretinoína/farmacologia , Raios Ultravioleta
4.
J Liposome Res ; 30(3): 263-273, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31185768

RESUMO

Acne vulgaris is one of the most common chronic diseases worldwide with the high prevalence ratio of about 80-85% in patients who are in puberty period. For the treatment options, many conventional dosage forms are available; however, existing limitations of systemic administration of drugs (oral antibiotics), such as adverse events and resistance, led for seek of new formulation options. In this study, liposomes containing tetracycline HCl and tretinoin were prepared by the film formation method. In vitro characterization studies revealed that liposomes (111.10 ± 8.02 nm; P.D.I.=0.198 ± 0.03; Z.P.=25.83 ± 0.40 mV) with an encapsulation efficiency more than 80% for both APIs were formulated. In order to maintain a suitable viscosity for topical application, optimized liposomal formulations were dispersed in carbopol-based gel. In vitro release of APIs was sustained for 24 hours with released amounts of 56.44% and 58.44% for tetracycline HCl and tretinoin, respectively. Stability evaluation of both liposomes and liposomes in hydrogels was investigated for 6 months at 4 °C and 25 °C; and no statistically significant change was observed in terms of particle size, zeta potential, encapsulation efficiency, appearance, pH, and viscosity. Cytotoxicity tests confirmed the nontoxic structure of liposomal gel formulations on mice fibroblast cells. In addition, antibacterial efficacy has been proven with Staphylococcus aureus and Streptococcus epidermidis strains as well as the effect on biofilm formation and eradication. As a result, we hereby presented a new combination drug product, which consists of dual active ingredients having comedolytic and bacteriostatic effects in a single, safe, and stable liposome formulation.


Assuntos
Acne Vulgar/tratamento farmacológico , Antibacterianos/farmacologia , Hidrogéis/farmacologia , Staphylococcus/efeitos dos fármacos , Tetraciclina/farmacologia , Tretinoína/farmacologia , Acne Vulgar/patologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Células Cultivadas , Combinação de Medicamentos , Composição de Medicamentos , Hidrogéis/síntese química , Hidrogéis/química , Lipossomos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Tamanho da Partícula , Tetraciclina/síntese química , Tetraciclina/química , Tretinoína/síntese química , Tretinoína/química
5.
Bioorg Med Chem Lett ; 26(16): 3846-9, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27450787

RESUMO

Previously we identified the first retinoid X receptor-alpha (RXRα) modulators that regulate the RXRα biological function via binding to the coregulator-binding site. Here we report the characterization of the interactions between the hit molecule and RXRα through computational modeling, mutagenesis, SAR and biological evaluation. In addition, we reported studies of additional new compounds and identified a molecule that mediated the NF-κB pathway by inhibiting the TNFα-induced IκBα degradation and p65 nuclear translocation.


Assuntos
Receptor X Retinoide alfa/metabolismo , Tretinoína/síntese química , Benzopiranos/síntese química , Benzopiranos/química , Benzopiranos/metabolismo , Sítios de Ligação , Células HEK293 , Humanos , Ligantes , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , NF-kappa B/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Receptor X Retinoide alfa/antagonistas & inibidores , Receptor X Retinoide alfa/genética , Transdução de Sinais , Relação Estrutura-Atividade , Tretinoína/química , Tretinoína/metabolismo
6.
J Med Chem ; 58(4): 1900-14, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25634130

RESUMO

The synthesis and in vitro and in vivo antibreast and antiprostate cancers activities of novel C-4 heteroaryl 13-cis-retinamides that modulate Mnk-eIF4E and AR signaling are discussed. Modifications of the C-4 heteroaryl substituents reveal that the 1H-imidazole is essential for high anticancer activity. The most potent compounds against a variety of human breast and prostate cancer (BC/PC) cell lines were compounds 16 (VNHM-1-66), 20 (VNHM-1-81), and 22 (VNHM-1-73). In these cell lines, the compounds induce Mnk1/2 degradation to substantially suppress eIF4E phosphorylation. In PC cells, the compounds induce degradation of both full-length androgen receptor (fAR) and splice variant AR (AR-V7) to inhibit AR transcriptional activity. More importantly, VNHM-1-81 has strong in vivo antibreast and antiprostate cancer activities, while VNHM-1-73 exhibited strong in vivo antibreast cancer activity, with no apparent host toxicity. Clearly, these lead compounds are strong candidates for development for the treatments of human breast and prostate cancers.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Tretinoína/análogos & derivados , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fator de Iniciação 4E em Eucariotos/antagonistas & inibidores , Fator de Iniciação 4E em Eucariotos/metabolismo , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Nus , Camundongos SCID , Estrutura Molecular , Neoplasias da Próstata/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Adrenérgicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Tretinoína/síntese química , Tretinoína/química , Tretinoína/farmacologia , Células Tumorais Cultivadas
7.
Bioorg Med Chem Lett ; 24(15): 3622-5, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24930828

RESUMO

Retinoids are a class of chemical compounds which include both natural dietary vitamin A (retinol) metabolites and active synthetic analogs. Both experimental and clinical studies have revealed that retinoids regulate a wide variety of essential biological processes. In this study, we synthesized (11)C-labeled all-trans-retinoic acid (ATRA), the most potent biologically active metabolite of retinol and used in the treatment of acute promyelocytic leukemia. The synthesis of (11)C-labeled ATRA was accomplished by a combination of rapid Pd(0)-mediated C-[(11)C]methylation of the corresponding pinacol borate precursor prepared by 8 steps and hydrolysis. [(11)C]ATRA will prove useful as a PET imaging agent, particularly for elucidating the improved therapeutic activity of ATRA (natural retinoid) for acute promyelocytic leukemia by comparing with the corresponding PET probe [(11)C]Tamibarotene (artificial retinoid).


Assuntos
Antineoplásicos/síntese química , Compostos de Boro/química , Leucemia Promielocítica Aguda/tratamento farmacológico , Paládio/química , Tretinoína/síntese química , Alcenos/química , Antineoplásicos/uso terapêutico , Isótopos de Carbono , Catálise , Meios de Contraste , Humanos , Metilação , Tomografia por Emissão de Pósitrons , Tretinoína/uso terapêutico
8.
Bioorg Med Chem Lett ; 22(13): 4453-7, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22658364

RESUMO

Protein knockdown can be achieved by the use of a small molecule that possesses affinity for both the target protein and ubiquitin ligase. We have designed such a degradation-inducing molecule targeting cIAP1 and CRABP-II, which are involved in proliferation of several cancer cell lines and in neuroblastoma growth, respectively. As a CRABP-II-recognizing moiety, all-trans retinoic acid (ATRA, 3), a physiological ligand of CRABP, was chosen. As a cIAP1-recognizing moiety, MV1 (5), which is a cIAP1/cIAP2/XIAP pan-ligand, was chosen. Although cIAP1 itself possesses ubiquitin ligase activity, we expected that its decomposition would be efficiently mediated by related molecules, including cIAP2 and XIAP, which also possess ubiquitin ligase activity. The designed degradation inducer 6, in which ATRA (3) and MV1 (5) moieties are connected via a linker, was synthesized and confirmed to induce efficient degradation of both cIAP1 and CRABP-II. It showed potently inhibited the proliferation of IMR32 cells.


Assuntos
Proteínas Inibidoras de Apoptose/metabolismo , Oligopeptídeos/química , Receptores do Ácido Retinoico/metabolismo , Tretinoína/análogos & derivados , Tretinoína/química , Caspases/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Proteínas Inibidoras de Apoptose/genética , Ligantes , Oligopeptídeos/síntese química , Receptores do Ácido Retinoico/genética , Tretinoína/síntese química
9.
Bioorg Med Chem Lett ; 21(14): 4248-51, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21684744

RESUMO

As a model compound for the transcription factor hijacking mechanism of action of DNA damaging agent that simultaneously bind to the nuclear receptor, we designed and synthesized a chimeric molecule, RA-mustard, which can bind with both retinoic acid receptor α (RARα) and DNA. The interaction between RA-mustard with RARα was confirmed by binding assay using RARα-overexpressing cell extract. RA-mustard-modified DNA diminished the RARα-dependent luciferase expression in the RARα-abundant cells.


Assuntos
Alquilantes/química , Clorambucila/química , DNA/química , Receptores do Ácido Retinoico/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Tretinoína/química , Animais , Células COS , Clorambucila/síntese química , Clorambucila/farmacologia , Chlorocebus aethiops , Simulação por Computador , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico , Tretinoína/síntese química , Tretinoína/farmacologia
10.
Bioorg Med Chem ; 19(9): 2939-49, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21489804

RESUMO

Retinoid X receptor (RXR) agonists are interesting candidates for the treatment of metabolic syndrome. 9-Cis-retinoic acid (9cRA: 1) is a natural RXR agonist, that also works as a retinoic acid receptor (RAR) agonist. This fact prompted us to study the structure-activity relationship (SAR) of RXR agonists derived from 1. Though 3 and 4, in which the cyclohexene part of 1 is replaced with bulkier hydrophobic moieties, show RXR-selective agonistic activity, some analogs containing other ring structures show RAR agonistic activity. Thus, we were interested in establishing what kind of ring skeleton is required for RXR-selective agonistic activity. In this study, we systematically prepared 5 and 6, in which the cyclohexene ring of 1 is replaced with various cyclic terpenoid moieties, and evaluated their RXR and RAR agonistic activities. Our previously reported CsF-promoted Stille coupling reaction was employed as a key step for the comprehensive synthesis of 5 and 6. The results of transcriptional assay showed that compounds 5b-f, which possess a menthane skeleton, exhibit RXR-selective agonistic activity. These results should be helpful for the design of superior RXR-selective agonists based on the structure of 1.


Assuntos
Receptores X de Retinoides/agonistas , Terpenos/química , Tretinoína/química , Alitretinoína , Sítios de Ligação , Simulação por Computador , Interações Hidrofóbicas e Hidrofílicas , Receptores X de Retinoides/metabolismo , Relação Estrutura-Atividade , Tretinoína/síntese química , Tretinoína/farmacologia
11.
Leuk Lymphoma ; 51(6): 1108-14, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20536349

RESUMO

The binding of all-trans retinoic acid (ATRA) to retinoid receptor-alpha (RAR-alpha) relieves transcriptional repression induced by the promyelocytic leukemia-retinoic acid receptor (PML-RAR) oncoprotein. The ATRA molecule contains a cyclohexenyl ring, a polyene chain containing conjugated double alkene bonds, and a terminal carboxyl group. To determine the contributions of these structural components of ATRA to its clinical efficacy, we synthesized three novel retinoids. These consisted of either a modified conjugated alkene backbone with an intact acid moiety (13a) or a modified conjugated alkene backbone and conversion of the acid group to either an ester (13b) or an aromatic amide (13c). Reporter assays demonstrated that compound 13a successfully relieved transcriptional repression by RAR-alpha, while 13b and 13c could not, demonstrating the critical role of the acid moiety in this binding. However, only ATRA was able to significantly inhibit the proliferation of APL cells while 13a, 13b, or 13c was not. Furthermore, only 13a led to partial non-significant differentiation of NB4 cells, demonstrating the importance of C9-C10 double bonds in differentiation induced CD11 expression. Our results demonstrate that both the acid moiety and conjugated double bonds present in the ATRA molecule are important for its biological activity in APL and have important implications for the design of future novel retinoids.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proteínas de Fusão Oncogênica/metabolismo , Tretinoína/farmacologia , Apoptose/efeitos dos fármacos , Antígenos CD11/análise , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lactente , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Luciferases/genética , Luciferases/metabolismo , Estrutura Molecular , Proteínas de Fusão Oncogênica/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Elementos de Resposta/genética , Transfecção , Tretinoína/síntese química , Tretinoína/metabolismo
12.
Chem Pharm Bull (Tokyo) ; 58(3): 418-22, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20190455

RESUMO

Palladium-catalyzed cross-coupling reactions of a 2-substituted 3-iodobenzo[b]furans and stannanyl ester afforded the stereoselective production of 9Z-retinoic acid ester analogs in good yields. These esters were then converted to the corresponding acids via basic hydrolysis in excellent yields, and their biological activities were evaluated. The analog changed the connected position of polyene side chain from 2-position to 3-position of benzo[b]furan decreased the biological activities dramatically, and the introduction of various substituents at 2-position afforded almost no effect on the activities.


Assuntos
Benzofuranos/química , Receptores do Ácido Retinoico/química , Receptores X de Retinoides/química , Tretinoína/síntese química , Tretinoína/farmacologia , Alitretinoína , Animais , Linhagem Celular Tumoral , Humanos , Ligantes , Estrutura Molecular , Ratos , Receptores do Ácido Retinoico/genética , Receptores X de Retinoides/genética , Estereoisomerismo , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética , Ativação Transcricional/efeitos dos fármacos , Tretinoína/química
13.
J Pharm Pharmacol ; 61(10): 1353-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19814868

RESUMO

OBJECTIVES: All-trans retinoic acid (ATRA), an active metabolite of vitamin A, is widely used in the treatment of acute promyelocytic leukaemia and myelodysplastic syndrome. However, its high lipophilicity is thought to be responsible for the slow dissolution and low bioavailability following oral administration. In order to obtain compounds with better solubility characteristics to improve the transportation and bioavailability of ATRA, derivatives of ATRA containing glutamic acid or its sodium salt were synthesised. METHODS: The ATRA derivatives synthesised - all-trans retinoyl glutamate (RAE) and all-trans retinoyl sodium glutamate (RAENa(2)) - were characterised in terms of melting point, optical rotation, mass spectrometry, NMR and partition coefficient. A liposomal preparation formed from RAE was characterised by particle size and zeta potential. The anti-tumour activity of RAE and RAENa(2) was compared with that of ATRA in mice bearing S(180) tumours and their effects on the cell cycle were determined in human pro-myelocytic leukaemia HL-60 cells. KEY FINDINGS: RAE and RAENa(2) were more active than ATRA against tumour growth. Flow cytometry indicated that RAE and RAENa(2) induced HL-60 cell cycle arrest, similar to ATRA. DNA fragmentation studies suggested that apoptosis may be one of the mechanisms responsible for the anti-tumour activities. CONCLUSIONS: The two derivatives of ATRA, RAE and RAENa(2), exhibited improved aqueous solubility and were more effective in mice bearing S(180) tumours.


Assuntos
Antineoplásicos/farmacologia , Glutamatos/farmacologia , Pró-Fármacos/farmacologia , Tretinoína/análogos & derivados , Tretinoína/farmacologia , Carga Tumoral/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Glutamatos/síntese química , Glutamatos/química , Células HL-60 , Humanos , Lipossomos/administração & dosagem , Camundongos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Pró-Fármacos/química , Tretinoína/síntese química , Tretinoína/química
14.
Bioorg Med Chem ; 16(18): 8471-81, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18760926

RESUMO

Various 5-substituted retinoic acids were prepared by a palladium-catalyzed cross coupling reactions of vinyl nonaflates and E- or Z-3-tributylstannyl-2-beten-1-ol as a key reaction. These coupling products were then converted to the corresponding all-E- and 9Z-retinoic acid analogs via Horner-Emmons reaction and subsequent basic hydrolysis, and their biological activities were evaluated. The all-E-derivatives, 5-butyl and isobutyl analogs exhibited stronger effects for anti-proliferative and differentiation-inducing activities in HL-60 cells. In contrast, in 9Z-derivatives, none of the analogs showed any activity.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Tretinoína/farmacologia , Células HL-60 , Humanos , Estereoisomerismo , Relação Estrutura-Atividade , Tretinoína/análogos & derivados , Tretinoína/síntese química , Células Tumorais Cultivadas
15.
Antivir Ther ; 13(2): 199-209, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18505171

RESUMO

BACKGROUND: Retinoids have a pronounced antiviral effect against several viruses. In this study we aimed to investigate the effect of retinoids on human herpesvirus 8 (HHV-8). METHODS: A panel of retinoic acid compounds were tested for their antiviral activity against HHV-8 in human umbilical vascular endothelial cells (HUVECs) and in a human epithelial cell line. The presence, transcription and antigen expression of HHV-8 in infected cells - in the presence or absence of retinoic acid compounds - were evaluated by PCR, reverse transcriptase PCR and immunofluorescence assays; HHV-8 viral load was determined by real-time quantitative PCR. Angiogenesis induced by HHV-8 was also assessed using Cultrex basement membrane extract. RESULTS: The compounds tested specifically inhibited viral promoters, during the early and late phases of infection in both cell systems tested, and resulted in up to 100-fold reduction of viral titre and release of progeny virus. The inhibition of viral replication induced by retinoids in endothelial cells, the primary target of HHV-8-driven transformation in Kaposi's Sarcoma, prevented endothelial cells from developing spindle morphology and in vitro tube formation, characteristic changes associated with HHV-8 infection and transformation. CONCLUSIONS: We show that retinoids inhibit HHV-8 replication and identify new retinoid compounds with a strong antiviral effect. Selective retinoids, particularly those with retinoic acid receptor agonist activity, may be good candidates for the development of antiviral drugs.


Assuntos
Herpesvirus Humano 8/efeitos dos fármacos , Tretinoína/análogos & derivados , Tretinoína/farmacologia , Replicação Viral/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Células Cultivadas , Células Endoteliais/virologia , Células Epiteliais/virologia , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/isolamento & purificação , Herpesvirus Humano 8/fisiologia , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tretinoína/síntese química , Tretinoína/química , Carga Viral
16.
Bioorg Med Chem ; 16(6): 3352-60, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18166465

RESUMO

We have developed new, simple, and efficient procedures for the synthesis of two promising histone deacetylase inhibitors (HDIs), CI-994, (N-(2-aminophenyl)-4-acetylaminobenzamide), and MS-275 (N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxycarbonyl)aminomethyl]benzamide) from commercially available acetamidobenzoic acid and 3-(hydroxymethyl)pyridine, respectively. The procedures provide CI-994 and MS-275 in 80% and 72% overall yields, respectively. We found that the combination of four HDIs (CI-994, MS-275, SAHA, and TSA) with retinoids all-trans-retinoic acid (ATRA) or 13-cis-retinoic acid (13-CRA) or our atypical retinoic acid metabolism blocking agents (RAMBAs) 1 (VN/14-1) or 2 (VN/66-1) produced synergistic anti-neoplastic activity on human LNCaP prostate cancer cells. The combination of 2 and SAHA induced G1 and G2/M cell cycle arrest and a decrease in the S phase in LNCaP cells. 2+SAHA treatment effectively down-regulated cyclin D1 and cdk4, and up-regulated pro-differentiation markers cytokeratins 8/18 and pro-apoptotic Bad and Bax. Following subcutaneous administration, 2, SAHA or 2+SAHA were well tolerated and caused significant suppression/regression of tumor growth compared with control. These results demonstrate that compound 2 and its combination with SAHA are potentially useful agents that warrant further preclinical development for treatment of prostate cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases , Neoplasias da Próstata/tratamento farmacológico , Tretinoína/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/síntese química , Benzamidas/síntese química , Benzamidas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Masculino , Neoplasias Experimentais/tratamento farmacológico , Fenilenodiaminas/síntese química , Fenilenodiaminas/farmacologia , Neoplasias da Próstata/patologia , Piridinas/síntese química , Piridinas/farmacologia , Transplante Heterólogo , Tretinoína/agonistas , Tretinoína/análogos & derivados , Tretinoína/síntese química
17.
Bioconjug Chem ; 18(4): 1185-93, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17518439

RESUMO

A series of four porphyrin-retinamides containing either all-trans- or 13-cis-retinoid acid residues, directly linked to the para-phenyl position of meso-tetraphenylporphyrin or via a low-molecular-weight PEG spacer, have been synthesized. The biological properties of these conjugates were evaluated in a model cell line, human HEp2, and in neuroblastoma SK-N-DZ cells, which exhibit moderate expression of retinoic acid receptors and retinoic acid-induced differentiation. The directly linked porphyrin-retinamides were taken up by a greater extent (20-50% more) in SK-N-DZ than in HEp2 cells. However, the PEG-containing conjugates accumulated maximally within both cell lines and approximately by the same amount, probably due to their increased amphiphilicity. Among all conjugates, the porphyrin-PEG-13-cis-retinamide accumulated the most in both cell lines (about 5 times more than the non-pegylated conjugates). None of the porphyrin-retinamide conjugates were toxic toward HEp2 cells at concentrations up to 100 microM, and only the hydrophobic non-pegylated conjugates were moderately toxic to SK-N-DZ cells [IC50 (dark) = 56-92 microM, and IC50 (at 1 J/cm2) = 6-8 microM]. All conjugates preferentially localized within cellular vesicles that correlated well to the lysosomes and, in addition, the PEG-containing porphyrin-retinamides were also found in the ER.


Assuntos
Porfirinas/síntese química , Tretinoína/análogos & derivados , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Corantes Fluorescentes , Humanos , Luz , Polietilenoglicóis/química , Porfirinas/química , Porfirinas/farmacologia , Tretinoína/síntese química , Tretinoína/química , Tretinoína/farmacologia
18.
Bioorg Med Chem ; 14(23): 7875-9, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16908162

RESUMO

Synthesis of the beta-carotene oxidation product, 2,3-dihydro-5,8-endoperoxy-beta-apo-carotene-13-one (1) was achieved in six steps starting from beta-ionone. Photo-oxygenation of all trans-retinoic acid (8) and 13-cis-retinoic acid (9) produced a mixture of 5S*,8S*-epidioxy-5,8-dihydroretinoic acid (10) and 13-cis-5S*,8S*-epidioxy-5,8-dihydroretinoic acid (11). Methylation of the crude photo-oxygenation mixture afforded the corresponding methyl esters 12 and 13, respectively, both of which underwent ready aerial oxidation yielding hitherto unknown oxidation products of retinoic acid identified as methyl 5S*,8S*-epidioxy-9,10beta-epoxy-5,8,9,10-tetrahydroretinoate (14) and methyl 13-cis-5S*,8S*-epidioxy-9,10beta-epoxy-5,8,9,10-tetrahydroretinoate (15). Evaluation of 1, all trans-retinoic acid (8), 13-cis-retinoic acid (9), and the photo-oxygenation products 10-15 in a panel of five cancer cell lines showed 1 to be inactive and that 11 is significantly cytotoxic compared with the other retinoic acid analogs suggesting the requirement of the carboxylic acid moiety and the cis-geometry of the 13(14) double bond for cytotoxic activity.


Assuntos
Antineoplásicos/síntese química , Tretinoína/síntese química , beta Caroteno/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Norisoprenoides/química , Oxirredução , Fotoquímica , Relação Estrutura-Atividade , Tretinoína/química , beta Caroteno/química
19.
Bioorg Med Chem ; 14(15): 5099-109, 2006 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16713268

RESUMO

9-cis-Retinoic acid (RA) analogues devised to lock the 9-cis double bond by ring formation were synthesized using two stereoselective carbon-carbon bond formation reactions as key steps. The palladium-mediated Suzuki reaction was adopted to construct a 7E-double bond (RA numbering) and the Horner-Emmons olefination was employed for stereoselective 11E-double bond (RA numbering) formation. The synthesized 9-cis-RA analogues that are locked by five-membered ring systems (cyclopentene, dihydrofuran, and dihydrothiophene) were shown to have comparable thrombomodulin induction activities to that of 9-cis RA. Conformational analysis of these compounds showed their similarity to 9-cis RA in the spatial orientation of the side chain and the terminal carboxy group.


Assuntos
Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Trombomodulina/biossíntese , Tretinoína/síntese química , Tretinoína/farmacologia , Alitretinoína , Catálise , Células Cultivadas , Humanos , Conformação Molecular , Paládio/química , Estereoisomerismo , Relação Estrutura-Atividade , Tretinoína/química
20.
J Nat Prod ; 68(10): 1536-40, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16252921

RESUMO

Insect cells convert vitamin A into a number of retinoids that are evolutionarily conserved with those of mammalian cells. However, insect cells also produce additional natural retinoids. Namely, two retinoic acid peptides, N-trans-retinoylserine (1) and N-trans-retinoylalanine (2), have been isolated from a cell line of the common cabbage looper, Trichoplusia ni. These are the first examples of naturally occurring retinoic acid linked to amino acids through an amide bond; the amino acid moieties are depicted in the more common l-configuration, although the absolute configuration was not determined due to the minuscule sample amount.


Assuntos
Alanina/análogos & derivados , Mariposas/química , Serina/análogos & derivados , Tretinoína/análogos & derivados , Alanina/síntese química , Alanina/química , Alanina/isolamento & purificação , Animais , Cromatografia , Estrutura Molecular , Serina/síntese química , Serina/química , Serina/isolamento & purificação , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo , Tretinoína/síntese química , Tretinoína/química , Tretinoína/isolamento & purificação
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