Kapou Agnes, Fousteris Manolis A, Nikolaropoulos Sotiris S, Zervou Maria, Grdadolnik Simona G, Zoumpoulakis Panagiotis, Kyrikou Ioanna, Mavromoustakos Thomas
Laboratory of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, University of Patras, 26500 Rion-Patra, Greece.
J Pharm Biomed Anal. 2005 Jul 1;38(3):428-34. doi: 10.1016/j.jpba.2005.01.012. Epub 2005 Feb 17.
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.
合成的3β-羟基-17α-氮杂-d-高-5-雄甾烯-7,17-二酮对-对-双(2-氯乙基)氨基苯乙酸酯(SOT-19, I)被发现是一种非常有效的抗白血病药物候选物。其高生物活性和低毒性使其构象性质的研究具有合理性。它还可以作为原型，因此作为一系列同类化合物的模板，在后续的3D-QSAR研究中具有各种毒性和抗白血病活性。通过构象搜索方法和二维NOESY NMR光谱相结合的方式确定了其低能构象。低能构象主要是紧凑的，烷基化芳基朝向甾体平面的α-或β-表面。烷基链取向的偏好可能取决于甾体，并与其产生抗白血病作用的机制有关。甾体骨架上构象的微小化学修饰会导致抗白血病活性发生显著变化，这一事实支持了这一假设。
