Synthesis, structure and biological properties of Z-17alpha-(2-iodovinyl)-11beta-chloromethyl estradiol-17beta (Z-CMIV), a high affinity ligand for the characterization of estrogen receptor-positive tumors.
Linkage of a 11beta-chloromethyl group to estradiol-17beta (E2) dramatically increases the binding affinity of the steroid for the estrogen receptor (ER) with the formation of a quasi-irreversible steroid-receptor complex. We have synthesized the two isomers of 11beta-chloromethyl-17alpha-iodovinyl-estradiol (E-CMIV and Z-CMIV) by a novel route. Both derivatives demonstrated high binding affinity and selectivity for ER (RBAs: ER = 820 and 1008; SHBG = 1.2 and 0.25, respectively; E2 = 100). On the basis of X-ray crystallographic data for Z-CMIV and its precursor, we have postulated that Z-CMIV might interact strongly with aromatic amino-acids within a hydrophobic groove of the ER hormone binding domain (HBD) that incorporates pockets corresponding to the 11beta and 17alpha steroid substituents. The binding properties of Z-CMIV labeled with 125I were investigated, especially its ability to detect and quantify altered ER forms with low binding affinity for E2. Sucrose density gradient analysis revealed that Z-CMIV has a higher activation potency than E2 as it converts a higher proportion of non-activated monomers in the cytosol into activated monomers with the potential to dimerize. In in vitro (MCF-7 cells) and in vivo (rat uterus) determinations of estrogenic activity, Z-CMIV was as potent as E2 in increasing progesterone receptor (PgR) concentrations and decreasing ER levels and in stimulating uterine growth. [125I]-Z-CMIV could open the way to new applications in the diagnosis and therapy of ER-positive breast cancers, especially those containing altered (variant) ERs.
Quivy
J
J
Laboratoire J.-C. Heuson de Cancérologie Mammaire, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Leclercq
G
G
Deblaton
M
M
Henrot
P
P
Velings
N
N
Norberg
B
B
Evrard
G
G
Zeicher
M
M
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology; D018360:Crystallography, X-Ray; D003600:Cytosol / Q000737:chemistry; D015195:Drug Design; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000032:analysis* / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D011960:Receptors, Estrogen / Q000032:analysis* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014599:Uterus / Q000033:anatomy & histology / Q000737:chemistry / Q000187:drug effects
C104065:17-(2-iodovinyl)-11-chloromethylestradiol; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004958:Estradiol