Design, synthesis and bioevaluation of novel candidate selective estrogen receptor modulators

Abstract

In an systematic attempt to develop novel Selective Estrogen Receptor Modulators (SERMs), chiral 1-((4-(2-(dialkylamino)ethoxy)phenyl)(2-hydroxynaphthalen-1-yl)methyl)piperidin-4-ols were designed based on an accepted pharmacophore model. Simpler prototypes, viz. racemic 1-((2-hydroxynaphthalen-1-yl)arylmethyl)piperidin-4-ols, were first synthesized to develop kinetic resolution to pure enantiomers. Simultaneously, a series of racemic 1-((4-(2-(dialkylamino)ethoxy)phenyl)(2-hydroxynaphthalen-1-yl)methyl)piperidin-4-ols were evaluated against estrogen-responsive human MCF-7 breast cancer cells, but the compounds were found to be moderately active. The lack of potency could be due to the molecular bulk resulting in inadequate fit at the receptor. Subsequently, the molecular motif was modified to achiral 1-(4-(2-(dialkylamino)ethoxy)benzyl)naphthalen-2-ols by removing the piperidinol moiety. Bioevaluation of this new series of compounds displayed significantly enhanced cytotoxicity against MCF-7 cells. A representative compound for this series showed estrogen receptor alpha binding activity and the action is that of an antagonist.

Mannich bases in medicinal chemistry and drug design

“…Cytotoxicity of enantiomerically-enriched Mannich bases 40 ( Fig. 7) derived from 2-naphthol, aromatic aldehydes and either 4-piperidinol (R ¼ H) or its acetylated counterpart (R ¼ COCH 3 ) against murine leukemic L1210 and human lymphoblast Molt 4/C8 and CEM cell lines has been examined by another study [55]. All of the compounds were only moderately cytotoxic, with IC 50 values in the middle micromolar range, and were also 10e70-fold less potent than that reference drug melphalan.…”

“…Substitution of the aryl group in 40 with R 1 ¼ 4dialkylaminoethoxy resulted in a series of compounds whose cytotoxicity potential against estrogen-responsive human MCF-7 breast cancer cells was found to be comparable to that of tamoxifen. However, removal of the 4-piperidinol moiety from Mannich bases 40 led to benzylnaphthols with enhanced cytotoxicity against MCF-7 cells, which is most likely due to their binding and antagonistic effects against human estrogen receptor alpha [55].…”

Syntheses, transformations and applications of aminonaphthol derivatives prepared via modified Mannich reactions

“…28 With the aim of a better biological effect, the structure of 14 was extended with different dialkylaminoethoxy substituents at position-4 of the aryl group (15aef, Scheme 6). 29 The syntheses of naphth [2,1- 3]oxazines 17 from amine, 2 equiv of formalin and 1-or 2-naphthol with water as solvent were described by Nath et al 30 The same reaction was achieved by Shingare et al with KAl(-SO 4 ) 2 $12H 2 O as a reusable, non-toxic inexpensive catalyst. It should be mentioned that, in this case, water was applied as solvent (Scheme 7).…”

Water‐Mediated Synthesis of Anthelmintic Piperidinols and Their Molecular Docking Studies

“…Piperidinols are medicinally privileged scaffolds that possess anti‐tubercular,– anti‐inflammatory, anti‐leukemia, anti‐convulsant and anti‐cancer activities . In addition, they act as sodium and calcium channel blockers, estrogen receptor modulators, liver glycogen phosphorylase inhibitors, map kinase inhibitors and dopamine D2 receptor antagonist . The traditional routes for synthesis of piperidinols involve gold mediated chemoselective reduction of amide followed by Ferrier rearrangement, silica chloride catalyzed and ultrasound assisted reduction of 4‐piperidinone, NaBH(OAc) 2 assisted reaction of aldehydes with amines, enzymatic transformation of trans‐6‐aminocyclohept‐3‐enols, phosphomolybdic acid mediated aza‐Prins‐cyclization and solid phase synthesis from 1,2,3,6‐tetrahydro‐pyridines .…”