ABSTRACT
A series of androstene-3,5-diene derivatives were prepared. Despite lacking the C-3 hydroxyl previously believed necessary for ER activity, some of the analogs retained surprising affinity for ER-beta. For example, diene 4 retained excellent selectivity and potency as an ER-beta agonist and was more selective for ER-beta over the androgen receptor (AR).
Subject(s)
Androstadienes/chemical synthesis , Androstadienes/pharmacology , Estrogen Receptor beta/agonists , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/pharmacology , Androstadienes/chemistry , Animals , Binding Sites/drug effects , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Molecular Structure , Rats , Receptors, Androgen/drug effects , Selective Estrogen Receptor Modulators/chemistryABSTRACT
A series of bridged androstenediol derivatives was prepared. The bridged compounds exhibited reduced ER-beta selectivity relative to uncyclized analogs.
Subject(s)
Androstenediols/chemical synthesis , Estrogen Receptor beta/antagonists & inhibitors , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/pharmacology , Androstenediols/pharmacology , Cyclization , Estrogen Receptor beta/chemistry , Estrogen Receptor beta/metabolism , Humans , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Subject(s)
Androstenediol/analogs & derivatives , Androstenediol/pharmacology , Estrogen Receptor beta/drug effects , Selective Estrogen Receptor Modulators/pharmacology , Androstenediol/chemical synthesis , Crystallography, X-Ray , Humans , Ligands , Models, Molecular , Molecular Conformation , Selective Estrogen Receptor Modulators/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
BACKGROUND: Homocysteine is a nonessential aminoacid whose increase is related to the appearance of neural tube defects in humans. In chick embryos, high levels of homocysteine produce neural tube defects and alteration of neural crest cell migration. METHODS: In our study, 8 microl of L-homocysteine thiolatone (20 micromol) was added to chick embryos of Stages 3-8/10 (Hamburger and Hamilton, 1951), (1238 hr of incubation). Three days later, 50 embryos, externally normal or carrying isolated spinal neural tube defects, were sectioned and stained by hematoxilin-eosin or anti-fibrillin-1 antibody. RESULTS: The eye showed alterations of the optic cup as microphthalmia, or lens dislocation. In both cases, the incidence of alterations diminished with the age of the homocysteine-increased embryos. Optic cup modifications are probably associated with central nervous system alterations, because most of the affected embryos exhibited isolated spinal neural tube defects and had altered neural crest cells. We have shown for the first time that high exogenous homocysteine during early development could produce a caudally-displaced lens axis before the zonule is formed. Fibrillin-1 is the main component of elastic microfibrils, and in the adult human it is seen as a protein particularly susceptible to homocysteine attack. CONCLUSIONS: Antibody staining against fibrillin-1 showed no evident morphological differences in distribution between experimental and control embryos in the lens, suggesting that fibrillin-1 was not the cause, and malformations may be attributed to other mechanisms.
Subject(s)
Eye Abnormalities/chemically induced , Homocysteine/toxicity , Abnormalities, Drug-Induced , Animals , Antibodies, Monoclonal/metabolism , Chick Embryo , Eye/drug effects , Eye/embryology , Fibrillin-1 , Fibrillins , Immunohistochemistry , Lens Capsule, Crystalline/abnormalities , Lens Capsule, Crystalline/drug effects , Lens Capsule, Crystalline/embryology , Microfilament Proteins/metabolism , Microphthalmos/chemically induced , Microphthalmos/embryology , Morphogenesis/drug effects , Neural Tube Defects/chemically inducedABSTRACT
Transforming growth factor-beta3 (TGF-beta3) plays a critical role during palate development, since mutations of the TGF-beta3 gene give rise to cleft palate in both humans and mice. Striking alterations have been reported in the behaviour and differentiation of medial edge epithelial (MEE) cells in TGF-beta3 knockout mouse palates. In the present paper, we provide evidence of alterations in MEE intercellular adhesion in TGF-beta3 -/- mouse palates using immunohistochemistry with monoclonal antibodies to a panel of cell adhesion and cytoskeletal molecules including E-cadherin, alpha and beta catenin, beta actin, vinculin and beta2 integrin. In vitro labeling of opposing MEE with two different lipophilic markers and subsequent analysis by confocal microscopy revealed that wild type MEE cells intercalate as soon as the midline epithelial seam forms. This finding indicates that the palate may elongate in a dorso-ventral direction by means of convergent extension, as occurs in other embryonic developmental processes. In contrast, this intercalation does not occur in the TGF-beta3 -/- MEE but it can be rescued by the exogenous addition of TGF-beta3. Thus, the substantial alteration of MEE intercellular adhesion observed in TGF-beta3 -/- palates may account for the defect in palatal shelf adhesion and the formation of cleft palate.
