ABSTRACT
The crystal structures of five follicular fluid meiosis-activating sterol-related Delta(8,14)-sterol compounds are presented. These are 4,4-dimethyl-23-phenyl-24-nor-5alpha-chola-8,14-dien-3beta-ol, C(31)H(44)O, 4,4-dimethyl-22-phenyl-23,24-dinor-5alpha-chola-8,14-dien-3beta-ol, C(30)H(42)O, (20R)-4,4-dimethyl-22-oxa-5alpha,20-cholesta-8,14,24-trien-3beta-ol, C(28)H(44)O(2), 4,4-dimethyl-23-phenyl-22-oxa-24-nor-5alpha-chola-8,14-dien-3beta-ol-water (4/1), 4C(30)H(42)O(2).H(2)O, and 4,4-dimethyl-5alpha-cholesta-8,14-dien-3-one, C(29)H(46)O. Two of the derivatives are inactive and three are active as agonists. Preliminary structure-activity relationship studies showed that the positions of the double bonds in the skeleton and the structures of the side chains are important determinants for activity. The conformations of the skeletons were compared with double-bond isomers retrieved from the Cambridge Structural Database [Allen & Kennard (1993). Chem. Des. Autom. News, 8, 1, 31-37]; no significant differences were found. Thus, conformational changes induced by the double bonds are not discriminative with respect to the activity of the compounds. Comparisons of the side-chain conformations of active and inactive structures revealed that the crystal structures were not conclusive as far as correlation of conformation and activity of the side chains were concerned.
Subject(s)
Follicular Fluid/cytology , Meiosis/drug effects , Sterols/chemistry , Sterols/pharmacology , Crystallography, X-Ray , Female , Humans , Hydrogen Bonding , Models, Molecular , Molecular ConformationABSTRACT
Metabolic stability is a key issue in the development of orally active androgens for Partial Androgen Deficiency in Aging Males (PADAM) and male contraception. Rates of metabolism in human hepatocyte suspensions provide useful information on the stability of compounds that undergo a first pass metabolism. We have derived a structure-pharmacokinetic relationship for a data set of 32 in-house steroidal androgens by means of the decision-trees technique. Volume, shape, number of rotatable bonds, and surface turned out to be the most important descriptors for classification. Only 2 of the 32 compounds were misclassified. The most stable compounds were classified in three leaf nodes on different branches of the tree, suggesting that higher metabolic stability can be achieved for the same substrate by different steric modifications. Further, it is generally assumed that the first step in cytochrome P450s oxidation reactions takes place by hydrogen abstraction to form a radical intermediate. An electronic model for hydrogen abstraction in steroidal androgens was, therefore, developed by means of ab initio calculations. Activation energies of steroid radical systems calculated as energy differences between the reactants equilibrium geometry energies and their corresponding transition states energies could be used to predict relative rates of metabolism to guide the design and redesign process of metabolically more stable steroidal androgens.
Subject(s)
Androgens/metabolism , Decision Trees , Liver/metabolism , Adult , Androgens/chemistry , Androgens/pharmacokinetics , Cells, Cultured , Computer Simulation , Electrons , Energy Metabolism , Hepatocytes/cytology , Hepatocytes/metabolism , Humans , Hydrogen , Male , Middle Aged , Models, Molecular , Molecular Structure , Steroids/chemistry , Steroids/metabolism , Steroids/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Follicular Fluid-Meiosis Activating Sterol (FF-MAS) is a compound important for maturation of gametes in mammals. Therefore, it may serve as a lead compound for a novel method of contraception. We studied the Molecular Electrostatic Potential of a series of active and inactive analogues of FF-MAS. We find that double bond configurations required for activity result in a local negative electrostatic potential which is larger as well as more dense compared to those of inactive molecules. We therefore hypothesize that the interaction energy of the double bond system of the MAS compounds with its receptor substantially contributes to the overall interaction energy. This notion is supported by interaction studies of the electrostatic potential originating from the double bonds in crystal structures of cholesterol and four MAS-derived Delta(8,14) structures synthesized and crystallized by us. In addition, we were able to derive a pharmacophore model that relates the local average ESP and its distance to the 3beta-OH oxygen atom to the activity of the molecules.
Subject(s)
Cholestenes/chemistry , Oocytes , Sterols/chemistry , Animals , Cells, Cultured/drug effects , Cholestadienols/chemistry , Cholestadienols/metabolism , Cholestenes/metabolism , Cholesterol/chemistry , Crystallography, X-Ray , Female , Hydroxylation , Menotropins/pharmacology , Mice , Models, Chemical , Molecular Conformation , Molecular Structure , Oocytes/cytology , Oocytes/drug effects , Oocytes/physiology , Ovary/cytology , Ovary/drug effects , Structure-Activity RelationshipABSTRACT
The analysis of the antibiotics neomycins A, B and C was investigated. The separation of the components was studied using reversed-phase and reversed-phase ion-pair chromatography. The optimum separation was obtained utilizing a Lichrosorb RP-2 column with a mobile phase consisting of 75 mg/l sodium dodecyl sulphate, 0.5M Na2SO4 and 0.015 M sodium acetate buffer at pH 7.0. Using this mobile phase, baseline separation was obtained for all three compounds in approximately 20 min. Detection was via post-column derivatization of the analytes with ortho-phthalaldehyde in the presence of mercaptoethanol to form fluorescent iso-indole products. This system is applied to the analysis of a number of formulated products containing neomycin.
