RESUMO
A series of bis(hydroxymethyl)indolizino[6,7-b]indoles and their bis(alkylcarbamates) were synthesized for antitumor studies. These agents were designed as hybrid molecules of ß-carboline (topoisomerase inhibition moiety) and bis(hydroxymethyl)pyrrole (DNA cross-linking moiety). The preliminary antitumor studies indicated that these agents exhibited significant cytotoxicity against a variety of human tumor cells in vitro. Treatment of human breast carcinoma MX-1 xenograft-bearing nude mice with compounds 18b and 28c achieved more than 99% tumor remission. We also observed that 18a displayed potent therapeutic efficacy against human lung adenocarcinoma A549 and colon cancer HT-29 xenografts. These results revealed that compound 18a was more potent than irinotecan against HT-29 cells and was as potent as irinotecan against A549 cells in xenograft models. Furthermore, we demonstrated that these derivatives possess multiple modes of action, such as induction of DNA cross-linking, inhibition of topoisomerase I and II, and cell-cycle arrest at the S-phase.
Assuntos
Antineoplásicos/síntese química , Reagentes de Ligações Cruzadas/síntese química , DNA/metabolismo , Indóis/síntese química , Indolizinas/síntese química , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase II/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Reagentes de Ligações Cruzadas/química , Reagentes de Ligações Cruzadas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/química , Indóis/farmacologia , Indolizinas/química , Indolizinas/farmacologia , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ratos , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Transplante HeterólogoRESUMO
Ureidomustin hydrochloride (BO-1055) was designed as a water-soluble nitrogen-mustard, which exhibited potent anticancer activity and was selected as a candidate for preclinical studies. However, up to date, there is rarely an easy and economic method to quantize ureidomustin in the biological samples. The aim of this study is to develop a simple yet valid quantization method to tackle this challenge. Here we present a combined high-performance liquid chromatography with photodiode array (HPLC-PDA) method in quantizing the ureidomustin in the plasma and various organs of Sprague-Dawley rats. The method was validated in terms of precision, accuracy, and extraction recovery. Furthermore, the established method was applied to study pharmacokinetics of ureidomustin in the rat's plasma and verified via a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Calibration curves of the plasma and organ samples were falling at the range between 0.5-50µg/mL and 0.1-50µg/mL (r(2)≥0.999 and CV≤±15%), respectively. The limits of detection (LOD) were 0.1µg/mL for plasma samples and 0.05µg/mL for organ samples, while the detection limits of quantification (LOQ) were 0.5µg/mL for plasma samples and 0.1µg/mL for organ samples. The average recovery of ureidomustin was about 83%. These results demonstrated a linear pharmacokinetic pattern at dosages of 10 and 30mg/kg. The pharmacokinetic data revealed that ureidomustin was best fitted to a two-compartment model with a rapid distribution phase and a slow elimination phase. Besides, after a short intravenous administration time at the dose of 10mg/kg, ureidomustin was found to be quickly distributed to all organs in rats, accumulated mainly in the kidney, and only a limited amount was detected in the brain.
