Assuntos
Antineoplásicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Paclitaxel/análogos & derivados , Paclitaxel/química , Taxoides , Alcaloides/síntese química , Alcaloides/química , Alcaloides/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Hidrocarbonetos Aromáticos com Pontes/síntese química , Cristalografia por Raios X , Feminino , Humanos , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos , Conformação Molecular , Estrutura Molecular , Neoplasias Ovarianas , Paclitaxel/síntese química , Paclitaxel/toxicidade , Células Tumorais CultivadasRESUMO
Adozelesin (U-73975) is a potent synthetic cyclopropylpyrroloindole (CPI) analog of the cytotoxic DNA-binding antibiotic, CC-1065. In contrast to the natural product, adozelesin and related CPI analogs do not cause delayed death in non-tumored mice. Adozelesin, selected from a series of analogs for its superior in vivo antitumor activity and ease of formulation, is highly active when administered i.v. against i.p. - or s.c.- implanted murine tumors, including L1210 leukemia, B16 melanoma, M5076 sarcoma, and colon 38 carcinoma, and produces long-term survivors in mice bearing i.v.-inoculated L1210 and Lewis lung carcinoma. Modest activity is shown against the highly drug-resistant pancreas 02 carcinoma. Adozelesin is also highly effective against human tumor xenografts s.c.-implanted in athymic (nude) mice, including colon CX-1 adenocarcinoma, lung LX-1 tumor, clear cell Caki-1 carcinoma, and ovarian 2780 carcinoma. Its broad spectrum of in vivo activity compares favorably with three widely used antitumor drugs, i.e. cisplatin, cyclophosphamide, and doxorubicin. Adozelesin appears to be more effective than these drugs in the treatment of very resistant tumors such as s.c.-implanted mouse B16 melanoma, pancreatic 02 carcinoma, and human colon CX-1 and human lung LX-1 tumor xenografts. Based on its high potency and high efficacy against a broad spectrum of experimental tumors, adozelesin was chosen for clinical investigation and development.
Assuntos
Antineoplásicos/uso terapêutico , Ácidos Cicloexanocarboxílicos/uso terapêutico , DNA de Neoplasias/metabolismo , Indóis , Animais , Benzofuranos , Neoplasias do Colo/tratamento farmacológico , Cicloexenos , Duocarmicinas , Feminino , Humanos , Leucemia L1210/tratamento farmacológico , Leucemia Experimental/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Nus , Estrutura Molecular , Transplante de Neoplasias , Neoplasias Pancreáticas/tratamento farmacológico , Sarcoma Experimental/tratamento farmacológicoRESUMO
The synthesis, physicochemical properties, and biological activities of a series of novel spiro cyclopropyl compounds, modeled on the potent antitumor antibiotic CC-1065 (1), are described. Many of these synthetic analogues are significantly more effective than 1 against murine tumors. In particular, compound 27 exhibits high activity and potency. Structure-activity analysis supports a molecular mechanism for biological action involving hydrophobic interaction of the drug with DNA and acid-catalyzed alkylation of DNA.
