RESUMO
Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either α or ß position of the hydrazine moiety in procarbazine (Pcb) has been carried on in 5-steps process. The overall yield was 32.7%. The new entity Z-GP-Pcb was confirmed targeting to fibroblast activation protein-α (FAPα). Z-GP-Pcb may be hydrolyzed by either isolated rhFAPα or tumor homogenate. It was shown far less cytotoxicity against NCI-H460 cell line than Pcb. Z-GP-Pcb was displayed the potency to reduce spermatoxcity in H22-bearing mice. The mechanism may be ascribed to the blockade of dehydrogenation by α-glycerolphosphate dehydrogenase. This candidate was further proved equal antitumor activity to Pcb. However, the introduction of Z-GP scaffold decreased myelosuppression. All the evidences support that Z-GP-Pcb is a better antitumor agent than Pcb.
Assuntos
Antineoplásicos/uso terapêutico , Células Sanguíneas/efeitos dos fármacos , Dipeptídeos/uso terapêutico , Procarbazina/uso terapêutico , Pró-Fármacos/uso terapêutico , Espermatozoides/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Contagem de Células Sanguíneas , Plaquetas/efeitos dos fármacos , Linhagem Celular Tumoral , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Dipeptídeos/toxicidade , Desenho de Fármacos , Endopeptidases , Eritrócitos/efeitos dos fármacos , Gelatinases/metabolismo , Humanos , Hidrólise , Leucócitos/efeitos dos fármacos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Tamanho do Órgão , Procarbazina/síntese química , Procarbazina/farmacologia , Procarbazina/toxicidade , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Pró-Fármacos/toxicidade , Serina Endopeptidases/metabolismo , Contagem de Espermatozoides , Testículo/efeitos dos fármacosRESUMO
The interaction of tyrosinase with the anticancer drug procarbazine has been investigated. In the presence of the enzyme alone no oxidation of this dialkylhydrazine above the background level was observed. However, when phenolic substrates (4-tert-butylcatechol or N-acetyl-l-tyrosine) were included in the reaction mixture, procarbazine was rapidly degraded. Oxygen consumption measurements showed that in a mixture both the phenolic substrate and the drug were oxidized. The major product of procarbazine degradation was isolated and identified as azoprocarbazine, the first active metabolite of this drug detected in previous in vivo and in vitro studies. This indirect oxidation of the hydrazine group in this anticancer agent indicates possible application of a hydrazine linker in construction of tyrosinase-activated anti-melanoma prodrugs.
Assuntos
Antineoplásicos/metabolismo , Melanoma/tratamento farmacológico , Monofenol Mono-Oxigenase/metabolismo , Procarbazina/análogos & derivados , Agaricales/enzimologia , Antineoplásicos/síntese química , Antineoplásicos/química , Hidrazinas/química , Hidrazinas/metabolismo , Estrutura Molecular , Oxirredução , Consumo de Oxigênio/fisiologia , Procarbazina/síntese química , Procarbazina/química , Procarbazina/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Relação Estrutura-AtividadeAssuntos
Procarbazina/efeitos adversos , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Testes de Carcinogenicidade , Carcinógenos/síntese química , Carcinógenos/química , Carcinógenos/farmacologia , Carcinógenos/toxicidade , Feminino , Regulamentação Governamental , Guias como Assunto , Haplorrinos , Humanos , Masculino , Camundongos , Modelos Biológicos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/legislação & jurisprudência , Procarbazina/síntese química , Procarbazina/química , Procarbazina/toxicidade , Ratos , Estados UnidosRESUMO
Serum from procarbazine (PCZ)-treated rats is dysmorphogenic to rat embryos cultured in vitro, but PCZ is not effective when added directly to culture medium, even with an exogenous metabolizing system. Methylazoxyprocarbazine (MPCZ) is a metabolite which we have identified by HPLC in the dysmorphogenic serum of PCZ-treated rats. PCZ, MPCZ, and benzylazoxyprocarbazine (BPCZ, an isomer of MPCZ) were tested in rat whole embryo culture to determine their effects on embryo development. The parent compound, PCZ, produced no effect on embryo growth or development at concentrations up to 200 micrograms/ml. MPCZ proved to be the most potent of the agents tested. There was significant embryo lethality at concentrations of > or = 10 micrograms/ml while 25 micrograms/ml had significantly reduced embryonic developmental score (DEVS), and 35 micrograms/ml reduced DEVS, head length, and somite number. There was 89% embryo lethality at the 50 micrograms/ml exposure level. At concentrations > 5 micrograms/ml, there were significant increases in anomalies, primarily, failure of neural tube closure, erratic neural seam, and microcephaly. In contrast, BPCZ produced embryo lethality and reductions in DEVS only at 100 micrograms/ml. These data suggest that MPCZ, which has been identified in PCZ-treated rat serum, may be the proximate dysmorphogenic metabolite of PCZ.
Assuntos
Embrião de Mamíferos/efeitos dos fármacos , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Procarbazina/análogos & derivados , Procarbazina/toxicidade , Animais , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Técnicas de Cultura de Órgãos , Procarbazina/síntese química , Ratos , Ratos Sprague-DawleyRESUMO
Eight analogues of the antineoplastic compound procarbazine were prepared by varying one portion of the molecule, keeping either the methylhydrazinomethyl or the N-(1-methylethyl)benzamido portion of procarbazine intact. Preliminary screening results indicated that none of the analogues tested in leukemias L1210 and P388 were as active as the original compound.
Assuntos
Antineoplásicos/síntese química , Procarbazina/análogos & derivados , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Técnicas In Vitro , Leucemia L1210/tratamento farmacológico , Leucemia Experimental/tratamento farmacológico , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Procarbazina/síntese química , Procarbazina/farmacologiaRESUMO
With the objective of developing new antitumor agents, two groups of hydrazine compounds, having structural features in common with the antitumor agents procarbazine and 1-acetyl-2-picolinoylhydrazine, were synthesized. The L-1210 leukemia system was used to evaluate compounds of both groups. The aliphatic procarbazines also were screened for antitumor activity as bis(benzyloxycarbonyl) derivatives and as derivatives having a phthalazine nucleus. No L-1210 antitumor activity was exhibited by these compounds.