Synthesis of C4-substituted 1,2,3,4-tetrahydroisoquinolin-6-ols as potential estrogen receptor modulators.

Mabank, Tanya; Chan Vinh Lam; Brunsveld, Luc; Green, Ivan R.; van Otterlo, Willem A. L.

Substituted tetrahydroisoquinolines (THIQs) have recently served as scaffolds for therapeutics with function as selective estrogen receptor modulators (SERMs) or downregulators/degraders (SERDs). A small library of 4,4-disubstituted 6-hydroxy-tetrahydroisoquinolines was synthesized by the following step-wise procedure: bisalkylation of 2-(3-methoxyphenyl)acetonitrile, followed by reduction of the nitrile group and application of a Pictet-Spengler cyclization. Acid-mediated hydrolysis of the aminals provided the tetrahydroammonium chlorides which were converted into their trifluoromethylsulfonamido derivatives. Final conversion of the 6-aryl methyl ethers into their respective phenols provided the desired series of 4,4-bisalkylated 2- [(trifluoromethyl)sulfonyl]-1,2,3,4-tetrahydroisoquinolin-6-ols. These compounds were evaluated in a SUMOtagged ERa cofactor recruitment assay, but unfortunately were found to be devoid of activity.

SELECTIVE estrogen receptor modulators; METHYL ether; ESTROGEN receptors; TETRAHYDROISOQUINOLINES; ACETONITRILE

ARKIVOC: Online Journal of Organic Chemistry, 2024, Vol 2024, p1

1551-7004

Academic Journal

10.24820/ark.5550190.p012.308