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1.
Front Immunol ; 8: 1206, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28993781

RESUMO

Current tumor therapies, including immunotherapies, focus on passive eradication or at least reduction of the tumor mass. However, cancer patients quite often suffer from tumor relapse or metastasis after such treatments. To overcome these problems, we have developed a natural killer T (NKT) cell-targeted immunotherapy focusing on active engagement of the patient's immune system, but not directly targeting the tumor cells themselves. NKT cells express an invariant antigen receptor α chain encoded by Trav11 (Vα14)-Traj18 (Jα18) gene segments in mice and TRAV10 (Vα24)-TRAJ18 (Jα18) in humans and recognize glycolipid ligand in conjunction with a monomorphic CD1d molecule. The NKT cells play a pivotal role in the orchestration of antitumor immune responses by mediating adjuvant effects that activate various antitumor effector cells of both innate and adaptive immune systems and also aid in establishing a long-term memory response. Here, we established NKT cell-targeted therapy using a newly discovered NKT cell glycolipid ligand, RK, which has a stronger capacity to stimulate both human and mouse NKT cells compared to previous NKT cell ligand. Moreover, RK mediates strong adjuvant effects in activating various effector cell types and establishes long-term memory responses, resulting in the continuous attack on the tumor that confers long-lasting and potent antitumor effects. Since the NKT cell ligand presented by the monomorphic CD1d can be used for all humans irrespective of HLA types, and also because NKT cell-targeted therapy does not directly target tumor cells, this therapy can potentially be applied to all cancer patients and any tumor types.

2.
Nat Prod Commun ; 11(7): 997-1000, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30452181

RESUMO

Piceatannol (3,3',4,5'-tetrahydroxy-trans-stilbene, 2), an oxygenated analog of resveratrol (1), was synthesized. It is one of the naturally occurring polyphenolic stilbenoids contained in red wine, and possesses many kinds of beneficial effects such as anticancer activity. The trans-stilbene skeleton of 2 was constructed by Pd-catalyzed Suzuki-Miyaura cross coupling reaction of triflate 8 with (E)-alkenylboronoate 13. The key intermediate 13 was prepared diastereoselectively by acid-catalyzed hydroboration of pinacolborane 12 to alkyne 11.


Assuntos
Resveratrol/análogos & derivados , Estilbenos/síntese química , Estrutura Molecular
3.
Bioorg Med Chem ; 22(2): 827-33, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24360828

RESUMO

RCAI-147 is one of the hydroxylated analogues of KRN7000 which is known as a ligand for the activation of CD1d mediated invariant natural killer T cells (iNKT cells) and releases both T helper 1 (Th1) cytokines such as IFN-γ and T helper 2 (Th2) cytokines such as IL-4. KRN7000 has been anticipated as an antitumor drug or an adjuvant for viral infection such as influenza, because of its strong secretion of IFN-γ. In an interesting twist, it has been obvious in our previous paper that RCAI-147 induces much more Th2 cytokines (IL-4) than Th1 cytokines (IFN-γ) from iNKT cells compared to KRN7000, and shows fairly good result in the experimental autoimmune encephalomyelitis (EAE) test. Therefore, synthesis of RCAI-172 (C6-OH epimer of RCAI-147) was attempted to examine the biological activity. As a result, RCAI-172 was synthesized and its biological activity biased to Th2 response largely compared to that of KRN7000. However, this level decreased to approximately 61% compared to that of RCAI-147. And the clinical score of RCAI-172 for EAE suppression was disappointing. There exist seven chiral centers in the aglycon part of RCAI-172, and even though the change of configuration is just one position (C6-OH), the effect on both Th1/Th2 response and EAE test is fairly large.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Galactosilceramidas/farmacologia , Interferon gama/biossíntese , Interleucina-4/biossíntese , Animais , Feminino , Galactosilceramidas/síntese química , Galactosilceramidas/química , Interferon gama/sangue , Interleucina-4/sangue , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/metabolismo
4.
Bioorg Med Chem ; 21(11): 3066-79, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23602521

RESUMO

We synthesized ten new analogs of 6'-modified KRN7000 (A): RCAI-58, 61, 64, 83, 85-87, 113, 119, and 125. They could be synthesized by α-selective galactosylation of ceramide 9 with the 6-modified D-galactopyranosyl fluorides (8a-8f) or L-arabinopyranosyl fluoride (17), or by etherification of the known alcohol 19. Bioassay of the ten analogs demonstrated that RCAI-61 (1, 6'-O-methylated analog of A) was the most potent immunostimulant among them, and could induce the production of a large amount of IFN-γ even at a low concentration in mice in vivo.


Assuntos
Adjuvantes Imunológicos/síntese química , Antineoplásicos/síntese química , Galactosilceramidas/síntese química , Interferon gama/agonistas , Células Matadoras Naturais/efeitos dos fármacos , Adjuvantes Imunológicos/farmacologia , Animais , Antineoplásicos/farmacologia , Bioensaio , Galactosilceramidas/farmacologia , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-12/agonistas , Interleucina-12/biossíntese , Interleucina-12/imunologia , Interleucina-4/antagonistas & inibidores , Interleucina-4/biossíntese , Interleucina-4/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Camundongos
5.
Carbohydr Res ; 370: 46-66, 2013 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-23454137

RESUMO

KRN7000 is one of the α-galactosylceramides, which has a 2-hexacosanoylamino-3,4-dihydroxyoctadecyl group. This compound, known as a ligand for the activation of CD1d mediated invariant natural killer T cells (iNKT cells) which release both T helper 1 (Th1) cytokines such as IFNγ and Th2 cytokines such as IL-4, has been anticipated as an antitumor drug, because of its strong secretion of IFNγ. This time, we focused on the hydroxylated analogues of KRN7000 which could be thought of as increasing hydrophilicity and showing bias to Th2 cytokine (IL-4) secretion. Therefore, they may become the drugs for autoimmune diseases for the following reasons: (i) compound OCH, one of the α-galactosylceramide analogues with a shorter sphingosine chain than KRN7000, increases hydrophilicity relative to KRN7000; and (ii) OCH is known to induce much more Th2 cytokines (IL-4) than Th1 cytokines from iNKT cells compared to KRN7000. Naturally, OCH has become one of the candidate drugs for autoimmune diseases. The more hydroxylated derivatives of KRN7000 are anticipated to induce Th2 bias. Therefore, eight analogues with 1-4 excess hydroxyl groups on the lipid chain of KRN7000 were synthesized to examine if they behave in the same way as OCH. As a result, three out of eight compounds biased largely to IL-4 secretion, and their effectiveness for experimental autoimmune encephalomyelitis (EAE) was examined. It was recognized that two compounds (†)RCAI-147/-160 showed good suppression of EAE symptoms.


Assuntos
Galactosilceramidas/síntese química , Galactosilceramidas/farmacologia , Animais , Técnicas de Química Sintética , Feminino , Galactosilceramidas/química , Hidroxilação , Interleucina-4/biossíntese , Camundongos , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
6.
Biosci Biotechnol Biochem ; 76(6): 1055-67, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22790924

RESUMO

KRN7000, an anticancer drug candidate developed by Kirin Brewery Co. in 1995, is an α-galactosyl ceramide. It is a ligand making a complex with CD1d protein, and it stimulates invariant natural killer T (NKT) cells, which are one of the lineages of immunocytes. NKT cells activated by recognition of the CD1d/KRN7000 complex with its invariant T-cell receptor (TCR) can induce both protective and regulatory immune responses. To determine the recognition and activation mechanisms of NKT cells and to develop drug candidates more effective than KRN7000, a large number of analogs of KRN7000 have been synthesized. Some of them show potent bioactivities and have the potential of being utilized as therapeutic agents. In this review, structure-activity relationship studies of novel glycolipids which stimulate NKT cells efficiently are summarized.


Assuntos
Antineoplásicos/síntese química , Galactosilceramidas/síntese química , Glicoesfingolipídeos/síntese química , Células T Matadoras Naturais/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Citocinas/biossíntese , Citocinas/imunologia , Galactosilceramidas/farmacologia , Galactosilceramidas/uso terapêutico , Glicoesfingolipídeos/farmacologia , Glicoesfingolipídeos/uso terapêutico , Humanos , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Células T Matadoras Naturais/imunologia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Relação Estrutura-Atividade , Equilíbrio Th1-Th2/efeitos dos fármacos
7.
Carbohydr Res ; 345(12): 1663-84, 2010 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-20591421

RESUMO

Alpha-Galactosylceramide (alphaGalCer, KRN7000) has been identified as a modulator of immunological processes through its capacity to bind iNKT cells mediated by CD1d molecules. Some analogues in while the amide group in alphaGalCer is replaced with ester or ether groups were synthesized from d-arabinitol or l-ribose to evaluate their ability to activate iNKT cells. Ester analogues 30a, 31a, and 61 showed activity for IFNgamma and IL-4 production of iNKT cells, while ether (31b) and 4-methoxy ester (76) analogues of alpha-galactosylceramide were not active for iNKT cells.


Assuntos
Ésteres/farmacologia , Éteres/farmacologia , Galactosilceramidas/farmacologia , Células T Matadoras Naturais/efeitos dos fármacos , Animais , Ésteres/síntese química , Ésteres/química , Éteres/síntese química , Éteres/química , Galactosilceramidas/síntese química , Galactosilceramidas/química , Interferon gama/biossíntese , Interferon gama/sangue , Interleucina-4/biossíntese , Interleucina-4/sangue , Camundongos , Conformação Molecular , Células T Matadoras Naturais/imunologia , Estereoisomerismo
8.
Int Immunol ; 22(4): 319-28, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20181652

RESUMO

NKT cells are characterized by their production of both T(h)1 and T(h)2 cytokines immediately after stimulation with alpha-galactosylceramide (alpha-GalCer), which is composed of alpha-galactopyranose linked to ceramide (itself composed of sphingosine and fatty-acyl chains); the chain length of the ceramide varies and this affects the ability of alpha-GalCer to stimulate cytokine production. However, the contribution of its galactopyranose sugar moiety remains unclear. We synthesized alpha-carba-GalCer, which has an alpha-linked carba-galactosyl moiety; here, the 5a'-oxygen atom of the D-galactopyranose ring of alpha-GalCer is replaced by a methylene group. The alpha-carba-GalCer was more stable and showed higher affinity to the NKT receptor. It thus enhanced and prolonged production of IL-12 and IFN-gamma compared with alpha-GalCer, resulting in augmented NKT cell-mediated adjuvant effects in vivo. The alpha-carba-GalCer, which has an ether linkage, was more resistant to degradation by liver microsomes than was alpha-GalCer, which has an acetal bond. Modulation of the sugar moiety in glycolipids might therefore provide optimal therapeutic reagents for protective immune responses against tumor or pathogens.


Assuntos
Adjuvantes Imunológicos/farmacologia , Cicloexanóis/farmacologia , Citocinas/biossíntese , Galactosilceramidas/farmacologia , Células T Matadoras Naturais/efeitos dos fármacos , Células Th1/imunologia , Adjuvantes Imunológicos/síntese química , Adjuvantes Imunológicos/química , Animais , Linhagem Celular , Cicloexanóis/síntese química , Cicloexanóis/química , Citocinas/análise , Galactosilceramidas/síntese química , Galactosilceramidas/química , Glicolipídeos/metabolismo , Humanos , Injeções Intravenosas , Ligantes , Camundongos , Células T Matadoras Naturais/imunologia
9.
Blood ; 115(2): 230-7, 2010 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-19897575

RESUMO

Establishment of a system with efficient generation of natural killer T (NKT) cells from embryonic stem (ES) cells would enable us to identify the cells with NKT-cell potential and obtain NKT cells with desired function. Here, using cloned ES (NKT-ES) cells generated by the transfer of nuclei from mature NKT cells, we have established a culture system that preferentially developed functional NKT cells and also identified early NKT progenitors, which first appeared on day 11 as a c-kit(+) population in the cocultures on OP9 cells with expression of Notch ligand, delta-like1 (OP9/Dll-1) and became c-kit(lo/-) on day 14. Interestingly, in the presence of Notch signals, NKT-ES cells differentiated only to thymic CD44(lo) CD24(hi) NKT cells producing mainly interleukin-4 (IL-4), whereas NKT cells resembling CD44(hi) CD24(lo) liver NKT cells producing mainly interferon gamma (IFN-gamma) and exhibiting strong adjuvant activity in vivo were developed in the switch culture starting at day 14 in the absence of Notch. The cloned ES culture system offers a new opportunity for the elucidation of the molecular events on NKT-cell development and for the establishment of NKT-cell therapy.


Assuntos
Diferenciação Celular/imunologia , Núcleo Celular/imunologia , Células-Tronco Embrionárias/imunologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Animais , Antígeno CD24/imunologia , Antígeno CD24/metabolismo , Proteínas de Ligação ao Cálcio , Núcleo Celular/metabolismo , Células Cultivadas , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Receptores de Hialuronatos/imunologia , Receptores de Hialuronatos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/metabolismo , Técnicas de Transferência Nuclear , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores Notch/imunologia , Receptores Notch/metabolismo , Fatores de Tempo
10.
Int Immunol ; 22(1): 1-6, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19858073

RESUMO

Invariant NKT (iNKT) cells bridge innate and acquired immunity and play an important role in both protective and regulatory responses. The nature of the response is dictated by the initial cytokine environment: interaction with IL-10-producing cells induces negative regulatory T(h)2/regulatory T cell-type iNKT cells, while that with IL-12-producing cells results in pro-inflammatory T(h)1-type responses. Particularly, in the anti-tumor response, iNKT cells mediate adjuvant activity by their production of IFN-gamma, which in turn activates both innate and acquired immune systems. Thus, upon activation of iNKT cells, both MHC(-) and MHC(+) tumor cells can be efficiently eliminated. On the basis of these mechanisms, iNKT cell-targeted adjuvant cell therapies have been developed and have shown great promise in initial clinical trials on cancer patients.


Assuntos
Interferon gama/imunologia , Células T Matadoras Naturais/imunologia , Neoplasias/imunologia , Imunidade Adaptativa , Animais , Vacinas Anticâncer , Ensaios Clínicos como Assunto , Citotoxicidade Imunológica , Glicolipídeos/metabolismo , Humanos , Imunidade Inata , Neoplasias/terapia
11.
Biosci Biotechnol Biochem ; 73(10): 2299-302, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19809187

RESUMO

Basidifferquinones, isolated from Streptomyces sp., are potent inducers of fruiting-body formation in the basidiomycete, Polyporus arcularius. The first synthesis of (+/-)-basidifferquinone C was accomplished by starting from 3,5-dihydroxy-2-naphthoic acid.


Assuntos
Antraquinonas/síntese química , Antraquinonas/farmacologia , Carpóforos/efeitos dos fármacos , Carpóforos/crescimento & desenvolvimento , Polyporus/efeitos dos fármacos , Polyporus/crescimento & desenvolvimento , Quinonas/síntese química , Quinonas/farmacologia , Ácidos Carboxílicos/química , Naftalenos/química
12.
Bioorg Med Chem ; 16(19): 8896-906, 2008 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-18790646

RESUMO

RCAI-17, 22, 24-26, 29, 31, 34-36, 38-40, and 88, the analogs of KRN7000 with a sulfonamide linkage instead of an amide bond, were synthesized to examine their bioactivity for mouse natural killer (NK) T cells. RCAI-17, 22, 24-26, 29, 31, 34-36, and 88 are the aromatic sulfonamide analogs, while RCAI-39 and 40 are the aliphatic ones. RCAI-38 is a C-galactoside analog of RCAI-26, which is the p-toluenesulfonamide analog of KRN7000. According to their bioassay, these sulfonamide analogs were shown to be the stimulants of mouse NKT cells to induce the production of Th2-biased cytokines in vitro, while RCAI-38 did not induce any cytokine production.


Assuntos
Adjuvantes Imunológicos/farmacologia , Antineoplásicos/farmacologia , Citocinas/biossíntese , Galactosilceramidas/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Sulfonamidas/farmacologia , Adjuvantes Imunológicos/síntese química , Animais , Antineoplásicos/síntese química , Bioensaio , Feminino , Galactosilceramidas/síntese química , Interferon gama/biossíntese , Interleucina-13/biossíntese , Interleucina-4/biossíntese , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo
13.
Int Immunol ; 18(9): 1397-404, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16914507

RESUMO

CD1d-restricted NKT cells are activated by TCR-mediated stimulation via CD1d plus lipid antigens such as alpha-galactosylceramide (alpha-GalCer). These cells suppressed autoimmunity and graft rejection, but sometimes enhanced resistance to infection and tumor immunity. This double-action phenomenon of NKT cells is partly explained by cytokines produced by NKT cells. Therefore, roles of cytokines from activated NKT cells have been extensively examined; however, their roles on T cell homeostatic proliferation in lymphopenic condition have not been investigated. Here, we showed that alpha-GalCer enhanced homeostatic proliferation of CD8+ but not CD4+ T cells and this effect of alpha-GalCer was required for NKT cells. IL-4 was essential and sufficient for this NKT cell action on CD8+ T cell homeostatic proliferation. Importantly, the expression of IL-4Ralpha and STAT6 in CD8+ T cells was essential for the NKT activity, indicating a direct action of IL-4 on CD8+ T cells. Consistent with this, the level of IL-4Ralpha expression on memory phenotype CD8(+) T cells was higher than that on naive phenotype one and CD4+ T cells. Thus, these results showed the 'involvement' of IL-4 that is produced from activated NKT cells for CD8+ T cell homeostatic proliferation in vivo.


Assuntos
Antígenos CD1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Interleucina-4/metabolismo , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Animais , Antígenos CD1/imunologia , Antígenos CD1d , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Galactosilceramidas/farmacologia , Homeostase , Interleucina-4/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT6/imunologia , Fator de Transcrição STAT6/metabolismo
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