RESUMO
(2S,3S)-1,2:3,4-diepoxybutane (DEB) cross-links DNA guanines by forming the intermediate epoxy-adduct ((2'S,3'S)-N-7-(3',4'-epoxy-2'-hydroxybut-1'-yl)guanine [EHBG]). This process is presently considered a primary mechanism for the action of treosulfan (TREO), the prodrug that transforms to DEB via the monoepoxide intermediate (2S,3S)-1,2-epoxybutane-3,4-diol 4-methanesulfonate (EBDM). In this article, the N-7-guanine adduct of EBDM ((2'S,3'S)-N-7-(2'3'-dihydroxy-4'-methylsulfonyloxybut-1'-yl)guanine [HMSBG]) was synthesized for the first time, and its stability was investigated at physiological in vitro conditions. To synthesize HMSBG, EBDM, formed in-situ from TREO, was treated with guanosine in glacial acetic acid at 60°C followed by ribose cleavage in 1 M HCl at 80°C. HMSBG was stable during the synthesis, which showed that a ß-hydroxy group protects the sulfonate moiety against hydrolysis in acid environment. At pH 7.2 and 37°C, HMSBG exclusively underwent first-order epoxidation to EHBG with a half-life of 5.0 h. EHBG further decomposed to trihydroxybutyl-guanine, chlorodihydroxybutyl-guanine (major products), phosphodihydroxy-guanine, and a structural isomer (minor products). The isomeric derivative was identified as guanine with a fused 7-membered ring, which provided a new insight into the EHBG stability. To conclude, the exclusive conversion of HMSBG to EHBG indicates that EBDM might contribute to DNA cross-linking independently from DEB and play a more important role in the TREO action than expected before.
Assuntos
Antineoplásicos Alquilantes/química , Bussulfano/análogos & derivados , Guanina/análogos & derivados , Substâncias Intercalantes/química , Pró-Fármacos/química , Antineoplásicos Alquilantes/síntese química , Bussulfano/síntese química , Bussulfano/química , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Guanina/síntese química , Concentração de Íons de Hidrogênio , Hidrólise , Substâncias Intercalantes/síntese química , Cinética , Espectroscopia de Ressonância Magnética , Pró-Fármacos/síntese químicaRESUMO
(131)Iodine-labelled (meta-iodobenzyl)guanidine ([(131)I]-mIBG) and busulfan [butane-1,4-diylbis(methanesulfonate)] are well-established pharmaceuticals in neuroblastoma therapy. We report the design, synthesis, and testing of hybrid molecules-mBBG and pBBG-which combine key structural features of (meta-iodobenzyl)guanidine and busulfan: they contain a benzylguanidine moiety for accumulating in neuroblastoma cells via the noradrenaline transporter and, in the meta- or para-position, respectively, one of the two identical alkylating motives of busulfan for killing cells. Uptake and toxicity of hybrids mBBG and pBBG in human neuroblastoma cells compared favorably to their ancestors [(131)I]-mIBG and busulfan.
Assuntos
Bussulfano/síntese química , Guanidinas/síntese química , Alquilação , Bussulfano/química , Bussulfano/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Guanidinas/química , Guanidinas/farmacologia , Humanos , Estrutura Molecular , Neuroblastoma/tratamento farmacológico , Células Tumorais CultivadasAssuntos
Bussulfano/efeitos adversos , Carcinógenos/toxicidade , Animais , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/toxicidade , Bussulfano/síntese química , Bussulfano/química , Bussulfano/toxicidade , Testes de Carcinogenicidade , Carcinógenos/síntese química , Carcinógenos/química , Carcinógenos/farmacologia , Feminino , Regulamentação Governamental , Guias como Assunto , Humanos , Masculino , Camundongos , Modelos Biológicos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/legislação & jurisprudência , Ratos , Estados UnidosRESUMO
Two novel long chain alkanediol dimethanesulphonates, analogues of busulphan, were synthesized. Their in vitro cytotoxicity was evaluated against six solid tumor cell lines (A2780, H322, LL, WiDr, C26-10 and UMSCC-22B). 2-Tetradecylbutane-1,4-diol dimethanesulphonate was proved to be the most active compound exhibiting IC50 values between 20.82 and 26.36 microM.
Assuntos
Alcanos/síntese química , Antineoplásicos/farmacologia , Bussulfano/farmacologia , Mesilatos/síntese química , Alcanos/química , Alcanos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Bussulfano/síntese química , Bussulfano/química , Divisão Celular/efeitos dos fármacos , Concentração Inibidora 50 , Mesilatos/química , Mesilatos/farmacologia , Células Tumorais CultivadasRESUMO
In order to obtain hydrophilic analogues of 1,4-dimethylsulfonyloxybutane (busulfan) with enhanced selectivity and improved brain penetration, we have synthesized 6-O-methylsulfonyl-D-glucose, 3-O-methylsulfonyl-D-glucose, 3,6-di-O-methylsulfonyl-D-glucose, 4-O-methylsulfonyl-D-glucose, and 4,6-di-O-methylsulfonyl-D-glucose, and we have studied their interactions with the human erythrocyte GLUT1 hexose transport system. Mesylation of OH-4 and OH-6 of glucose resulted in a slightly diminished affinity for the GLUT1 glucose transporter, whereas mesylation of OH-3 led to complete loss of affinity.