19-nor-10-azasteroids, a new class of steroid 5 alpha-reductase inhibitors. 2. X-ray structure, molecular modeling, conformational analysis of 19-nor-10-azasteroids and comparison with 4-azasteroids and 6-azasteroids.
19-Nor-10-azasteroids are a new class of 5 alpha-reductase inhibitors whose activity depends on the presence of the bridgehead N-10 atom conjugated with the 4-en-3-one moiety in the A ring. The X-ray structure of 19-nor-10-azasteroid 1 has been determined and it is compared with the X-ray structure of testosterone. A complete conformational analysis of these compounds has been performed, determining the number and energy of the possible conformers, as well as the molecular flexibility of the 10-azasteroidal skeleton. Thus, MM2* molecular mechanics calculations and AM1 semiempirical energy refinements revealed that 19-nor-10-azasteroids 1-3 have four possible conformations with very small energy differences and that they are very flexible molecules. The conformational analysis has been extended to testosterone (4), which also showed conformational flexibility, with three different conformations, and to 6-azasteroid 5 and 4-azasteroid 6, for which only two thermally accessible conformations have been found. Compared to 19-nor-10-azasteroids 1-3, azasteroids 5 and 6 appear to be more rigid structures. By a best fit analysis of all conformers of 1-5 with the global minimum of testosterone (4-I) it has been found that the lowest energy conformers of 1, 3, and 5 are very close to the structure of 4-I, and among the conformers of 2, the best similarity has been observed for the highest energy conformer 2-IV.
Guarna
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Dipartimento di Chimica Organica Ugo Schiff, Università di Firenze, Italy. guarna@chimorg.unifi.it
Occhiato
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EG
Machetti
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F
Marrucci
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A
Danza
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G
Serio
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M
Paoli
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P
D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013739:Testosterone / Q000737:chemistry
D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D004791:Enzyme Inhibitors; D013739:Testosterone