RESUMO
1-Methyl-1-(2-chloroethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide, 1,1-di-(2-chloroethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide and 1,1-di-(2-bromoethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide, which are a novel class of nitrosoureas containing hydrazinomustard residue, have been synthesized. A dose-dependent antitumour activity was found with the three tested compounds.
Assuntos
Antineoplásicos/síntese química , Compostos de Nitrosoureia/síntese química , Semicarbazidas/síntese química , Células Tumorais Cultivadas/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Leucemia L1210/tratamento farmacológico , Leucemia P388/tratamento farmacológico , Camundongos , Camundongos Endogâmicos , Compostos de Nitrosoureia/farmacologia , Semicarbazidas/farmacologiaRESUMO
The interaction of three spin-labelled compounds, derivatives of bis-(2-chloroethyl)-hydrazine (HMSL), N-methyl,N-chloroethyl-hydrazine (MCEHSL) and bis-(2-bromoethyl)-hydrazine (BEHSL) with DNA was studied by the method of electron paramagnetic resonance (EPR). It was found that HMSL (containing two chloroethyl groups) and MCEHSL (containing one chloroethyl group) gave spin-labelled dsDNA with identical strongly immobilized EPR spectra. The conclusion was drawn that only one of the alkylating groups of HMSL reacted with DNA. In contrast, the EPR spectrum of DNA spin-labelled with BEHSL was non-immobilized due to the strong destabilizing effect of this compound on the double helix. The extent of alkylation of DNA with the three hydrazine mustard derivatives was one and the same. It was found, however, that chloroethyl-containing derivatives (HMSL and MCEHSL) had an expressed base specificity and alkylated preferably the guanilic residues, and their bromo-analogue (BEHSL) did not show any base specificity and alkylated the bases of DNA at random.
Assuntos
Óxidos N-Cíclicos , DNA/análise , Alquilação , Composição de Bases , Espectroscopia de Ressonância de Spin Eletrônica , Marcadores de SpinRESUMO
The antitumor effect of some N alpha-benzyloxycarbonyl-N,N-bis-(2-halogenethyl)hydrazide derivatives of lysine, glycine, cystine, phenylalanine and p-chlorophenylalanine, was studied. Six of eight newly synthesized compounds show considerable antitumor effect on solid Walker carcinosarcoma 256 (about 95% tumor growth inhibition). Three of these compounds under study increased the lifespan of mice with leukemia L1210. The investigation of the effect of N alpha-benzyloxycarbonyl,D,L-phenylalanine-N,N-bis(2-chloroethyl)hydrazine on various mouse tumors showed remarkable growth inhibition of the Ehrlich ascites carcinoma, sarcoma 37, colon adenocarcinoma akatol and lesser antitumor effect also on solid adenocarcinoma 755, Lewis lung carcinoma and melanoma B16. All investigated compounds exhibited depression of leukocyte count--their toxicity being, however, lower than that of sarcolysine in parallel experiments.