Showing papers by "Robert McKenna published in 1990"

Crystallographic and molecular modeling studies on 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione and its butyl analogue, inhibitors of mammalian aromatase. Comparison with natural substrates: prediction of enantioselectivity for N-alkyl derivatives.

Abstract: Inhibitors of the cytochrome P450 enzyme aromatase, which is involved in the biosynthesis of estrogens from androgens, are of proven utility in the treatment of hormone-dependent breast cancer. The determination of the crystal structure of one such inhibitor, 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione (2) and its 3-butyl analogue (3) is described. In the absence of three-dimensional structural information for the enzyme, conformational analysis and comparison with natural substrates has been performed in order to define possible "active" conformations. The enhanced inhibitory activity of 3 may be linked to hydrophobic interactions between the side chain and that portion of the enzyme that normally interacts with the B and C rings of a steroid substrate. Information gained from this study and previous studies by other workers has been combined in order to produce a hypothesis to explain the pattern of activity of N(1)-alkyl derivatives of 2. The successful application of this hypothesis to the prediction of the relative aromatase inhibitory activities of the two enantiomers of the N-octyl derivative (4) is described.

Structure of 5'‐chloro‐3',5'‐dideoxyformycin A monohydrate. The effects of protonation on formycin structure and conformation

Abstract: C 10 H 12 ClN 5 O 2 •H 2 O cristallise dans C2 avec a=22,935, b=4,832, c=13,7712 A, β=125,19 o , Z=4; affinement jusqu'a R=0,037. Des petits changements dans la geometrie autour des atomes C(2) et N(3) du cycle purine sont relatifs par rapport aux analogues protones. Les cycles du sucre adoptent un plissement endo en C(2') et l'angle glycosidique est anti