RESUMO
The arachidonic acid metabolizing enzymes cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs) have been found to be implicated in a variety of cancers, including prostate cancer. To develop new therapeutic treatments, it therefore seemed interesting to design dual COX-2/5-LOX inhibitors. We report here the synthesis and in vitro pharmacological properties of diarylpyrazole derivatives that have in their structure key pharmacophoric elements to obtain optimal interaction with subsites of active pockets in both enzyme systems. Using a molecular modeling approach, a set of SAR data is proposed, highlighting the importance of the sulfonyl group of one of the aryl moieties in terms of proliferation inhibition and/or apoptosis induction.
Assuntos
Antineoplásicos/síntese química , Apoptose , Isoenzimas/antagonistas & inibidores , Inibidores de Lipoxigenase , Pirazóis/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Araquidonato 5-Lipoxigenase/química , Células CHO , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cricetinae , Ciclo-Oxigenase 2 , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoenzimas/química , Masculino , Proteínas de Membrana , Modelos Moleculares , Prostaglandina-Endoperóxido Sintases/química , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
The tyrosine kinase activity of the epidermal growth factor receptor (EGFR) is widely involved in signaling pathways and often deregulated in cancer. Its role in the development of prostate cancer is well established, and therapeutic strategies such as blockade of the intracellular tyrosine kinase domain with small-molecule tyrosine kinase inhibitors have been proposed. Herein we describe the synthesis and in vitro pharmacological properties of C6- and C7-substituted 4-anilinoquinazolines, analogues of Iressa and powerful proapoptotic inducers in hormone-independent prostate cancer PC3 cell lines.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Apoptose/fisiologia , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Gefitinibe , Humanos , Masculino , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/síntese química , Quinazolinas/síntese químicaRESUMO
The biological role of COX-2, the inducible form of cyclooxygenase, is to convert arachidonic acid into prostaglandins (PGs) and thromboxanes (TXs). Overexpressed in many tumors, COX-2 plays a crucial role in cancer through synthesis of PGs which stimulate PGs receptors with subsequent enhancement of cellular proliferation, promotion of angiogenesis, inhibition of apoptosis, stimulation of invasion/motility, and suppression of immune responses. Depending on the tissue specificity and the cell type, several signaling pathways (Kinases, Rho, cGMP and Wnt), and transcription factors such as AP1, NFAT or NF-kappaB, are involved in COX-2 expression. In this review, we will describe mechanisms required by COX-2 metabolites to promote cancer development, and also the signaling pathways leading to COX-2 expression. In order to counteract the negative effects of COX-2 in cancerogenesis, chemicals interfering with COX-2 activity and expression were designed. We will give in the last part of this article, an overview of these potent chemicals interfering with the COX-2 signaling pathways involved in its expression or with its activity.