RESUMO
The endogenous steroid 2-methoxyestradiol (2-ME) is a metabolite of 17ß-estradiol and its biosynthesis is well established. Moreover, 2-ME is also biosynthesized from estrone. For several years, 2-ME was perceived as an inactive metabolite devoid of any interesting biological activities. Since the late 1980s, a number of biological and pharmacological studies have revealed that 2-ME possesses interesting anti-cancer effects without any undesirable estrogen activity. In particular, the anti-vascular effects and anti-angiogenic activities that 2-ME exhibit, are of great interest and importance, in view of the development of new anti-cancer drugs based on 2-ME. Several clinical trial development programs have been initiated using the steroid 2-ME. In addition, based on the many pharmacological activities reported for 2-ME, but also due to the general interest in total and semi-synthesis of endogenous steroids, several research groups working with organic synthesis have prepared this steroid. Herein, the anti-cancer effects, the results from the clinical trial development programs and the synthetic studies towards 2-ME, are reviewed.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Estradiol/análogos & derivados , 2-Metoxiestradiol , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto/métodos , Estradiol/síntese química , Estradiol/farmacologia , Estradiol/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Receptores de Estrogênio/antagonistas & inibidores , Resultado do TratamentoRESUMO
The synthesis, cytotoxicity, inhibition of tubulin polymerization data and anti-angiogenetic effects of seven 1,5-disubstituted 1,2,3-triazole analogs and two 1,4-disubstituted 1,2,3-triazole analogs of combretastatin A-1 (1) are reported herein. The biological studies revealed that the 1,5-disubstituted 1,2,3-triazoles 3-methoxy-6-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzene-1,2-diol (6), 3-methoxy-6-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzene-1,2-diamine (8) and 5-(2,3-difluoro-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole (9) were the three most active compounds regarding inhibition of both tubulin polymerization and angiogenesis. Molecular modeling studies revealed that combretastatins 1 and 2 and analogs 5-11 could be successfully docked into the colchicine binding site of α,ß-tubulin.
Assuntos
Inibidores da Angiogênese/síntese química , Modelos Moleculares , Estilbenos/química , Triazóis/química , Moduladores de Tubulina/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Sítios de Ligação , Linhagem Celular , Humanos , Simulação de Dinâmica Molecular , Polimerização/efeitos dos fármacos , Estrutura Terciária de Proteína , Triazóis/síntese química , Triazóis/farmacologia , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
Procaspase-activating compound 1, PAC-1, has been introduced as a direct activator of procaspase-3 and has been suggested as a therapeutic agent against cancer. Its activation of procaspase-3 is dependent on the chelation of zinc. We have tested PAC-1 and an analogue of PAC-1 as zinc chelators in vitro as well as their ability to activate caspase-3 and induce cell death in chicken cerebellar granule neuron cultures. These neurons are non-dividing, primary cells with normal caspase-3. The results reported herein show that PAC-1 chelates zinc, activates procaspase-3, and leads to caspase-3-dependent cell death in neurons, as the specific caspase-3-inhibitor Ac-DEVD-cmk inhibited both the caspase-3 activity and cell death. Thus, chicken cerebellar granule neurons is a suitable model to study mechanisms of interference with apoptosis of PAC-1 and similar compounds. Furthermore, the present study also raises concern about potential neurotoxicity of PAC-1 if used in cancer therapy.