2D NMR and conformational analysis of a prototype anti-tumour steroidal ester.
The synthetic 3beta-hydroxy-17alpha-aza-d-homo-5-androsten-7,17-dione-p-N-N-bis(2-chloroethyl)aminophenylacetate (SOT-19, I) was found to be a very potent anti-leukaemic agent candidate. Its high biological activity and low toxicity rationalize the study of its conformational properties. It can also serve as a prototype and therefore as a template for a series of congener compounds possessing a variety of toxicity and anti-leukaemic activity in subsequent 3D-QSAR studies. Its low energy conformers were identified through a combination of conformational search methods and 2D NOESY NMR spectroscopy. The low energy conformers were mainly compact, with the alkylating aromatic group orienting either to the alpha- or beta-surface of the steroidal plane. The preference in the orientation of the alkyl chain may be steroid dependent and related to the mechanism by which they produce their anti-leukaemic action. This hypothesis is supported by the fact that small chemical modifications of the conformation on the steroidal skeleton produce significant alterations on the anti-leukemic activity.
Kapou
Agnes
A
Laboratory of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, University of Patras, 26500 Rion-Patra, Greece.
Fousteris
Manolis A
MA
Nikolaropoulos
Sotiris S
SS
Zervou
Maria
M
Grdadolnik
Simona G
SG
Zoumpoulakis
Panagiotis
P
Kyrikou
Ioanna
I
Mavromoustakos
Thomas
T
D000970:Antineoplastic Agents / Q000032:analysis* / Q000737:chemistry; D004952:Esters; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013256:Steroids / Q000032:analysis* / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods
D000970:Antineoplastic Agents; D004952:Esters; D013256:Steroids