Effects of C2-Alkylation, N-Alkylation, and N,N‘-Dialkylation on the Stability and Estrogen Receptor Interaction of (4R,5S)/(4S,5R)-4,5-Bis(4-hydroxyphenyl)-2-imidazolines

Abstract

(4R,5S)/(4S,5R)-4,5-Bis(4-hydroxyphenyl)-2-imidazolines bearing 2,2'-H (3a), 2,2'-Cl (3b), 2,2',6-Cl (3c), and 2,2'-F (3d) substituents in the aromatic rings were C2-alkylated (5a-i), N-alkylated (7, 7a-c), and N,N'-dialkylated (9a-c). The synthesis started from the diastereomerically pure (1R,2S)/(1S,2R)-1,2-diamino-1,2-bis(4-methoxyphenyl)ethanes 1a-d, which were cyclized to the imidazolines 2a-d and 4a-i with triethylorthoesters or iminoethers. Ether cleavage with BBr(3) yielded the (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines 3a-d and 5a-i. The N-alkylation and N,N'-dialkylation of 2b, employed for obtaining 7a-c and 9a-c, were performed prior to the ether cleavage with alkyl iodine in dry THF. By use of HPLC, the influence of the substitution patterns in the aromatic rings and alkyl chains at the C2- or N-atoms on the hydrolysis rate of the imidazolines was studied under in vitro conditions. It appeared that only imidazolines with C2- or N-alkyl substituents show sufficient stability to interact as heterocycles with the estrogen receptor (ER). The resulting gene activation was monitored in a luciferase assay using ERalpha-positive MCF-7-2a breast cancer cells stably transfected with the plasmid ERE(wtc)luc. It is interesting to note that C2-alkylation led to a strong reduction or even a complete loss of activity whereas N-alkylation improved the estrogenic profile. The (4R,5S)/(4S,5R)-N-ethyl-4,5-bis(2-chloro-4-hydroxyphenyl)-2-imidazoline 7b has proven to be the most active compound in this structure-activity relationship study (EC(50) = 0.015 microM).

Oxetanes as Versatile Elements in Drug Discovery and Synthesis

“…The introduction of steric hindrance often deflects chemical [69] or metabolic [70] liabilities from nearby functional groups. Especially in the case of metabolically unstable methylene groups as in a benzylic position, it is common practice to block metabolic attack by the introduction of a gem-dimethyl unit.…”

Synthesis and Investigations on the Oxidative Degradation of C3/C5‐Alkyl‐1,2,4‐triarylpyrroles as Ligands for the Estrogen Receptor

“…Chlorine substituents on the aromatic rings, as well as N-alkylation, counteract these effects. [14] However, an attempt to increase the ER activation by introducing a third phenol ring (Scheme 1 c) to enable an E2-like type I binding mode [15,16] was unsuccessful. The related 2,4,5-tris(4-hydroxyphenyl)imidazoles were only weak ER agonists, which may be the consequence of nitrogen atom arrangement in the heterocycle in relation to the phenol In this study, we synthesized 1,2,4-triarylpyrroles as ligands for the estrogen receptor (ER).…”

Breast Cancer, Estrogen Receptor and Ligands

“…21) belong to the effective Type-II estrogens [129,130]. Their relative binding affinities were very low, but many of them exhibited full agonist activity in the luciferase assay with MCF-7-2a cells.…”