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 CultivadasRESUMO
An improved synthesis of gamma-hydroxybutenolides 1a-d was achieved via crossed aldol condensation between aldehydes 2a-d and the protected gamma-hydroxy-beta-methylbutenolides 3 or 4 using the bulky Lewis acid, aluminum tris(2,6-diphenylphenoxide) (ATPH). Using this same methodology, the gamma-hydroxybutenolides 17a-d having various heteroaromatic rings were synthesized and their anti-tumor activities were evaluated.
Assuntos
Antineoplásicos/síntese química , Oxibato de Sódio/síntese química , Oxibato de Sódio/farmacologia , Aldeídos/química , Antineoplásicos/farmacologia , Antígeno CD11b/biossíntese , Cromatografia Líquida de Alta Pressão , Citometria de Fluxo , Células HL-60 , Humanos , Indicadores e Reagentes , Receptores de Lipopolissacarídeos/biossíntese , Espectroscopia de Ressonância Magnética , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Timidina/metabolismoRESUMO
The antitumoral activity of 13-demethyl or 13-substituted all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9CRA) was tested using the myeloid leukemia cell line HL-60. Cell proliferation, differentiation and apoptosis were evaluated by flow cytometry and DNA fragmentation assay. The ability to bind to human RXRalpha and to activate either human retinoic acid response element (RARE)-mediated gene expression or rat CRABPII retinoid X response element (RXRalpha)-mediated gene expression were determined using luciferase reporter plasmids. In terms of the magnitude of the regulatory activity for the proliferation and differentiation of HL-60 cells, the compounds ranked as follows: ATRA>13-ethyl ATRA>13-demethyl ATRA>13-phenylethyl ATRA>13-propyl ATRA>13-butyl ATRA (ATRA analogues) and 9CRA>13-ethyl 9CRA>13-demethyl 9CRA>13-propyl 9CRA>13-phenetyl 9CRA>13-butyl 9CRA (9CRA analogues). Regarding the magnitude of the apoptosis-inducing activity, the order was: 9CRA>13-ethyl 9CRA>13-demethyl 9CRA, with ATRA and its analogues and the other 9CRA analogues virtually inactive. Similar trends were observed in binding affinity for RXRalpha and transactivation activity toward RARE- or RXRE-mediated gene expression. The results clearly indicate that the presence of a methyl group at C-13 is essential for the antitumoral activity of ATRA and 9CRA, and that bulky substituents exceeding two carbon atoms or the absence of substitution at position 13 significantly reduce the binding affinity for RAR and RXR, leading to a decreased RAR/RARE and/or RXR/RXRE-mediated gene expression.
Assuntos
Antineoplásicos/farmacologia , Tretinoína/farmacologia , Alitretinoína , Antígeno CD11b/análise , Ciclo Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HL-60 , Humanos , Receptores do Ácido Retinoico/química , Receptores do Ácido Retinoico/efeitos dos fármacos , Receptores do Ácido Retinoico/fisiologia , Receptores X de Retinoides/química , Receptores X de Retinoides/efeitos dos fármacos , Receptores X de Retinoides/fisiologia , Tretinoína/análogos & derivadosRESUMO
It is generally accepted that the availability of vitamin K in vivo depends on its homologues, the biological activities of which would differ among organs. To test this hypothesis, we examined the uptake, metabolism, and utilization of menaquinone-4 (MK-4) and phylloquinone (PK) using 18O-labeled compounds in two cultured human cell lines (HepG2 and MG-63). Lipid extracts were prepared from the cells and media after 1, 3, and 6h of incubation. The detection of the vitamin K analogues (18O-, 16O-quinone, and epoxide forms) was carried out with LC-APCI-MS/MS as previously reported. The 18O of vitamin K was replaced with atmospheric 16O2 during the formation of vitamin K epoxide with a carboxylative catalytic reaction. As a result, a significant difference was observed between MK-4 and PK in the amounts taken up into the cells. The 18O-labeled MK-4 was rapidly and remarkably well absorbed into the cells and metabolized to the epoxide form via a hydroquinone form as compared to the 18O-labeled PK. The difference in uptake of MK-4 and PK was not affected by treatment with warfarin although the metabolism of both compounds was markedly inhibited. This methodology should be utilized to clarify some of the actions of vitamin K in target cells and facilitate the development of new vitamin K drugs.
Assuntos
Vitamina K 1/metabolismo , Vitamina K 2/análogos & derivados , Vitamina K/análogos & derivados , Calibragem , Linhagem Celular , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Humanos , Indicadores e Reagentes , Espectrometria de Massas , Padrões de Referência , Vitamina K/química , Vitamina K/metabolismo , Vitamina K 1/química , Vitamina K 2/química , Vitamina K 2/metabolismoRESUMO
Retinoidal gamma-hydroxybutenolides 2a-d having various lengths of conjugated double bond were prepared in three steps from the corresponding aldehyde 4. Their biological activities were then measured. Of these compounds, only compound 2c possessing a structure similar to that of retinoic acid showed differentiation-inducing activity and very strong apoptosis-inducing activity in HL-60 cells.
Assuntos
4-Butirolactona/análogos & derivados , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Hidrogênio/química , Neoplasias/patologia , Tretinoína/química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Estrutura Molecular , Neoplasias/genética , Transcrição Gênica/efeitos dos fármacosRESUMO
13-Demethyl or 13-substituted all-E- and 9Z-retinoic acids were synthesized using a palladium-catalyzed coupling reaction of enol triflates and tributylstannylolefins. Their biological activities were then measured. The 13-ethyl analogs exhibited approximately one-half of the antiproliferative and differentiation-inducing activity of ATRA in HL-60 cells. In contrast, in the 9Z-derivatives, all analogs, except for the 13-butyl derivatives, showed apoptosis-inducing activity.