A Study On The Snythesis And Parmacological Activity Of Rehein-piperazinyl-estrogen

Estrogen replacement therapy for osteoporosis resulting from the lake of estrogen after the menopause has widely used in most of western countries since 1980' s. But long-term estrogen administration may increase the toxic and side action on other non-bone tissues such as uterus and breast. Such side effects limit the clinical use of estrogen. Some reports indicated the presence of estrogen receptor in bone tissue suggested that estrogen may directly act on bone cells by a mechanism mediated by receptor and improve the skeletal mineralization and remodeling . In this paper a clue of a bone-seeking estrogen drug was proposed. Based on this idea, estrogen selectively transfer to bone tissue so that the concentration of estrogen in non-bone tissue is reduced and the efficiency of therapy is raised. Based on the bone-seeking and its bone resorption inhibiting properties of Rein, the bone-seeking estrogenic compounds in which Rein was regarded as a bone-seeking carrier were designed and synthesized for hoping to be used for therapy and provention of menopausal osteoporosis. At same time, Eighteen intermediates were synthesized, too.Ten target compounds(LLZ-l-LLZ-10) and other ten intermediates involved in the paper have not been reported. The constitutional formulas are the following:Their structures were confirmed by 'H-NMR. MS and IR.The effects of compounds LLZ-1 . LLZ-2. LLZ-3 . LLZ-7. LLZ-8 on the growth of long bone in vitro and on the uteruses in mice were studied. The effects of compounds LLZ-l-LLZ-10 on the proliferation of MCF-7 cells were observe, too. The results showed that the estrogen still remained its estrogenic activity on bone after was linked to Rein through a bridge, but the activity of the compound was strongest when the triethylene-glycol was used for brigde. It suggested that an over-short bridge may affect the estrogenic activity of the compound. The activities of stimulating on uterus of these compounds in vivo were lower than that of estrogen oneself. This may be resulted from a lower concentration of compound in uterus. The effects of the target compounds on the proliferation of MCF-7 were almost similar as control. It suggested that the Rein in target compounds molecular might inhibit the stimulating of estrogen on MCF-7 cells.