Abstract
Tamoxifen, a therapeutic agent for breast cancer, has been associated with genetic polymorphisms in the metabolism of N,N-dialkylaminoethyl substituent, which plays an important role in the expression of selective estrogen receptor modulator (SERM) activity. To solve this problem, we developed a novel estrogen receptor (ER) modulator, Az-01, on the basis of the aromaticity, dipole moment, and isopropyl group of guaiazulene. Az-01 showed four-fold lower binding affinity for ER than E2 but had similar ER-binding affinity to that of 4-hydroxytamoxifen (4-HOtam). Unlike tamoxifen, Az-01 acted as a partial agonist with very weak estrogenic activity at high concentrations when used alone, and it showed potent anti-estrogenic activity in the presence of E2. The cell proliferation and inhibition activities of Az-01 were specific to ER-expressing MCF-7 cells, and no effect of Az-01 on other cell proliferation signals was observed. These findings are important for the development of new types of SERMs without the N,N-dialkylaminoethyl substituent as a privileged functional group for SERMs.
Highlights
Tamoxifen, which is used worldwide for the treatment of breast cancer, competes with female hormone 17α-estradiol (E2) for binding to estrogen receptor α (ERα) [1]
When diastereomixture 2 was reacted with guaiazulene under the reaction conditions reported by Nakatsuji et al, the carbocation intermediate generated by the pinacol rearrangement of 2 and an electron-rich five-membered ring of guaiazulene underwent an electrophilic substitution reaction followed by dehydration to give trisubstituted alkene (3) in 99% yield [18]
In a challenging study aimed at developing novel types of selective estrogen receptor modulator (SERM), we have developed a new SERM candidate, Az-01, that lacks the N,N-dialkylaminoethyl substituent on the basis of the chemical features of azulene
Summary
Tamoxifen (tam, Figure 1), which is used worldwide for the treatment of breast cancer, competes with female hormone 17α-estradiol (E2) for binding to estrogen receptor α (ERα) [1]. Tamoxifen is a selective estrogen receptor modulator (SERM) that acts as either an agonist or an antagonist depending on tissue type [2]. It exhibits anti-estrogenic effects in breast cancer and hot flashes as well as estrogenic effects in bone and cholesterol metabolism [1,2]. New-generation SERMs such as raloxifene and bazedoxifene have been developed to reduce the risk of side effects [3,4]. The N,N-dialkylaminoethyl substituent is regarded as a superior substituent in the development of SERMs
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