Type II estrogen binding site agonist: synthesis and biological evaluation of the enantiomers of methyl-para-hydroxyphenyllactate (MeHPLA).
A high-affinity ligand for the type II estrogen binding site (EBS) was identified. Methyl para-hydroxyphenyllactate (MeHPLA) was observed to suppress the cellular proliferation of estrogen-sensitive MCF-7 breast cancer cells in vitro and to suppress the growth of rat uteri in vivo. The high affinity of MeHPLA for the type II EBS suggests that this interaction is responsible for the observed suppression of cell growth. In this study, the enantiomers of MeHPLA were synthesized and separated by three methods and evaluated for biological activity. When the methods were compared, it was found that the method using an optically pure amine to form the diastereomers of the enantiomers gave the superior yield. Binding studies for the enantiomers to the type II EBS showed that the S-MeHPLA had a higher affinity for the binding site. However, higher binding affinity did not translate into superior cell growth suppression. Both enantiomers suppressed cell growth equally.
Pretlow
Lester
L
Medical Technology Department, Medical College of Georgia, Augusta 30912-0500, USA. lpretlow@mail.mcg.edu
Williams
Roy
R
Elliott
Mark
M
D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000473:pathology; D002384:Catalysis; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D005260:Female; D006801:Humans; D007773:Lactates / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011960:Receptors, Estrogen / Q000819:agonists* / Q000378:metabolism*; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D007773:Lactates; D011960:Receptors, Estrogen; C055915:methyl 4-hydroxyphenyllactate