ABSTRACT
The title hydrated tetrol, C(19)H(32)O(4)·3H(2)O, was synthesized by stereoselective reduction of the compound 3ß,5α,6ß-trihy-droxy-androstan-17-one. All rings are fused trans. The organic mol-ecules are connected head-to-tail along the c axis via O-Hâ¯O hydrogen bonds. Layers of water mol-ecules in the ab plane inter-connect these chains. A quantum chemical ab initio Roothan Hartree-Fock calculation of the isolated mol-ecule gives values for the mol-ecular geometry close to experimentally determined ones, apart from the C-O bond lengths, whose calculated values are significantly smaller than the measured ones, probably a consequence of the involvement of the C-OH groups in the hydrogen-bonding network.
ABSTRACT
The title compound, C(19)H(30)O(4), is an androstan-17-one derivative synthesized from the dehydro-epiandrosterone through a sequential addition of an oxidant, followed by a trans-diaxial opening of the epoxide generated, with Bi(OTf)(3) (OTf is trifluoro-methane-sulfonate). The six-membered rings have a slightly flattened chair conformation, while the five-membered ring adopts a 14-α envelope conformation. All rings are trans fused. In the crystal, the mol-ecules are connected by O-Hâ¯O hydrogen bonds involving the hydroxyl and carbonyl groups, forming a three-dimensional network. A quantum mechanical ab initio Roothan Hartree-Fock calculation of the free mol-ecule gives bond lengths, valency angles and ring torsion angles of the free molecule at equilibrium geometry (energy minimum) close to the experimental values.
ABSTRACT
The title compounds, C(17)H(13)FN(2)O(3) and C(18)H(16)N(2)O(4), are new potent aromatase inhibitors combining the common features of second- and third-generation nonsteroid anti-aromatase compounds. The molecules have a propeller shape, with dihedral angles between adjacent planes in the range 49-86°. A quantum mechanical ab initio Roothaan-Hartree-Fock calculation for the isolated molecules shows values for these angles close to the ideal value of 90°. Docking studies of the molecules in the aromatase substrate show that their strong inhibitor potency can be attributed to molecular flexibility, hydrophobic interactions, heme Fe coordination and hydrogen bonding.
Subject(s)
Aromatase Inhibitors/chemistry , Aromatase Inhibitors/pharmacology , Benzodioxoles/chemistry , Imidazoles/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Molecular Structure , Quantum TheoryABSTRACT
The title compound, C(19)H(26)O(2), a B-norandrogen with a 6beta-methyl group, is a recently identified and experimentally tested potent new aromatase inhibitor. It shares structural and physicochemical similarities both with the natural substrate of the enzyme, androstenedione, and with exemestane, another potent aromatase inhibitor having a 6-methylidene group. X-ray diffraction results indicate that the B-nor molecule and exemestane have nearly the same oxygen-oxygen and methyl-methyl separations, though they have distinct configurations of the hydrophobic groups at the 6-position. These structural comparisons allow correlations to be inferred between the active site geometry of the molecules and the aromatase inhibition power of the studied compound.
Subject(s)
Androstadienes/chemistry , Androstenedione/chemistry , Aromatase Inhibitors/chemistry , Norsteroids/chemistry , Androstenedione/pharmacology , Aromatase Inhibitors/pharmacology , Binding Sites , Catalysis , Crystallography, X-Ray , Molecular Structure , Protein Binding , X-Ray DiffractionABSTRACT
The title compound, alternatively called 24-nor-5 beta-chol-22-ene-3 beta,7 alpha,12 alpha-triyl triformate, C(26)H(38)O(6), has a cis junction between two of the six-membered rings. All three of the six-membered rings have chair conformations that are slightly flattened and the five-membered ring has a 13 beta,14 alpha-half-chair conformation. The 3 beta, 7 alpha and 12 alpha ring substituents are axial and the 17 beta group is equatorial. The 3 beta-formyloxy group is involved in one weak intermolecular C-H...O bond, which links the molecules into dimers in a head-to-head fashion.
Subject(s)
Daphnia/drug effects , Dimethyl Sulfoxide/toxicity , Solvents/toxicity , Water Pollutants, Chemical/toxicity , Animals , Dose-Response Relationship, Drug , Hydrophobic and Hydrophilic Interactions , Lethal Dose 50 , Luminescent Measurements , Photobacterium/drug effects , Photobacterium/physiologyABSTRACT
The title compound, C23H32O4, has a 3beta configuration, with the epoxy O atom at 16alpha,17alpha. Rings A and C have slightly distorted chair conformations. Because of the presence of the C5=C6 double bond, ring B assumes an 8beta,9alpha-half-chair conformation slightly distorted towards an 8beta-sofa. Ring D has a conformation close to a 14alpha-envelope. The acetoxy and acetyl substituents are twisted with respect to the average molecular plane of the steroid. The conformation of the molecule is compared with that given by a quantum chemistry calculation using the RHF-AM1 (RHF = Roothaan Hartree-Fock) Hamiltonian model. Cohesion of the crystal can be attributed to van der Waals interactions and weak intermolecular C-H.O interactions, which link the molecules head-to-tail along [101].
Subject(s)
Pregnanes/chemistry , Pregnenolone/chemistry , Crystallography, X-Ray , Molecular Structure , Pregnenolone/analogs & derivativesABSTRACT
The synthesis of two novel radiolabelled estrogen derivatives, [125I](E)-3-methoxy-17alpha-iodovinylestra-1,3,5(10),6-tetraen-17beta-ol (E[125I]IVDE) and [125I](Z)-3-methoxy-17alpha-iodovinylestra-1,3,5(10),6-tetraen-17beta-ol (Z[125I]IVDE), was carried out aiming to study the influence of the introduction of a C6-C7 double bond on the biological properties of the estradiol molecule. 3-Methoxyestra-1,3,5(10),6-tetraen-17-one was synthesised starting from a suitably protected estrone and subsequently converted into the 17alpha-ethynyl derivative. The radioiodinated derivatives were stereoselectively formed by radioiododestannylation of the corresponding tributylstannyl precursors. The biodistribution of the novel [125I]iodovinylestradiol derivatives was evaluated in immature female mice. Biological data indicated that the Z-isomer, owing to its higher in vivo uptake by the target tissue, has the preferable configuration for further development of similar compounds for estrogen receptor detection.
Subject(s)
Estradiol Congeners/chemical synthesis , Estradiol Congeners/pharmacokinetics , Estradiol/analogs & derivatives , Estradiol/chemical synthesis , Estradiol/pharmacokinetics , Animals , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/metabolism , Female , Humans , Iodine Radioisotopes , Mice , Radionuclide Imaging , Receptors, Estrogen/metabolism , Stereoisomerism , Tissue Distribution , Uterus/metabolismABSTRACT
The compounds named in the title were prepared by routes which included the reduction of suitable 16 alpha,17-epoxypregnan-20-ones with aluminium amalgam to give 16 alpha-hydroxypregnan-20-ones, and reduction of the 20-oxo function either with sodium borohydride to obtain the 3,16 alpha,20 beta-triols or with lithium-liquid ammonia to obtain the 3,16 alpha,20 alpha-triols.
