RESUMO
New types of selective estrogen receptor modulators (SERMs) were synthesized and evaluated for their binding affinity and biological effect on reproductive cells. A proposed lead structure (B) was derivatized to provide compounds 30 and 44, which showed good estrogen-receptor binding affinity (K(i) values: 6.3 and 10 nM, respectively), as well as minimal impact on mammary and uterine carcinoma cells. Introduction of an alkyl group in the core structure considerably enhanced receptor-binding affinity of the compounds tested. Synthesis and structure-activity relationships of these compounds are described.
Assuntos
Receptores de Estrogênio/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Fosfatase Alcalina/metabolismo , Alquilação , Animais , Ligação Competitiva/efeitos dos fármacos , Bovinos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Estradiol/metabolismo , Feminino , Humanos , Indicadores e Reagentes , Cinética , Espectroscopia de Ressonância Magnética , Receptores de Estrogênio/metabolismo , Relação Estrutura-Atividade , Útero/efeitos dos fármacos , Útero/metabolismoRESUMO
In the process of angiogenesis, endothelial adhesion molecules play a significant role in vascular morphogenesis, in coordination with angiogenic factor signaling. Here we report that a novel angiogenesis inhibitor, E7820 (an aromatic sulfonamide derivative), inhibited in vitro proliferation and tube formation of human umbilical vascular endothelial cell (HUVEC). E7820 decreased integrin alpha2, 3, 5, and beta1 in confluent culture of HUVEC, and integrin alpha2 was initially suppressed in mRNA level, followed by decrement of integrins alpha3, 5, and beta1. The inhibition of integrin alpha2 expression in HUVEC showed dose dependence but did not alter the level of CD31. Up-regulation of integrin alpha2 by phorbol 12-myristate 13-acetate abrogated the inhibitory effect of E7820 on tube formation within type I collagen gel, whereas addition of antibody against integrin alpha2 canceled the phorbol 12-myristate 13-acetate effect. These results suggest that E7820 inhibited tube formation through the suppression of integrin alpha2. Oral administration of E7820 remarkably resulted in inhibition of tumor-induced angiogenesis in mouse dorsal air sac model, and tumor growth of human colorectal tumor cell lines (WiDr and LoVo) was inhibited in xenotransplanted model in mice. This is the first time that a small molecule has been shown to modulate integrins, and this finding may provide the basis for a new approach to antiangiogenic therapy through the suppression of integrin alpha2 on endothelium.