Synthesis of Novel Quinolinecarboxamide Derivatives with Estrogenic Activity

Abstract

Even though estrogens have a well-established role in the growth of hormone-dependant tumors by the estrogen receptor (ER)-dependant mitogenic effect in cells containing ER, 1 a member of the nuclear receptor superfamily, 2 they exert numbers of favorable activities in women. From a therapeutical point of view, estrogen and its derivatives are well known not only as oral contraceptives, but also as a major component in hormone replacement therapy (HRT) required for bone loss prevention and for the control of cardiovascular diseases in postmenopausal women. 3The most widely used estrogens are 17β-estradiol 4 and ethynylestradiol, 5 a synthetic steroidal compound. These estrogen agonists have been used for postmenopausal women required for HRT. However, it has been known that long-term usage of estrogen causes high incidence of breast cancer, 6 which leads to development of antiestrogen such as tamoxifen, the first selective ER modulator (SERM). Recently, raloxifene as a second SERM was developed to alleviate menopausal symptoms without risk of breast cancer.8 Afterwards, the more effective SERMs are being developed and tested that act as antiestrogens on breast and endometrium while having estrogenic effects on bones, the lipid profile and the central nervous system. [9][10][11] In this point of view to develop antiestrogens, we used virtual screening system based on the structure of ER. From the initial screening, we identified compound 4 that has nonsteroidal quinoline structure. More compounds were synthesized from the leader compound 4 and tested for estrogenic activity using ERα and ERβ. Results and DiscussionSynthesis of quinolinecarboxamide derivatives. Application of such multi-component condensation approach based Doebner reation 12 for the synthesis of a clinically useful * Co-corresponding authors. Hong-Sig Sin