Ladopoulou Eleni M, Matralis Alexios N, Nikitakis Anastasios, Kourounakis Angeliki P
Department of Medicinal Chemistry, School of Pharmacy, University of Athens, 15771 Athens, Greece.
Department of Medicinal Chemistry, School of Pharmacy, University of Athens, 15771 Athens, Greece.
Bioorg Med Chem. 2015 Nov 1;23(21):7015-23. doi: 10.1016/j.bmc.2015.09.034. Epub 2015 Sep 25.
Drugs affecting more than one target could result in a more efficient treatment of multifactorial diseases as well as fewer safety concerns, compared to a one-drug one-target approach. Within our continued efforts towards the design of multifunctional molecules against atherosclerosis, we hereby report the synthesis of 17 new morpholine derivatives which structurally vary in terms of the aromatic substitution on the morpholine ring. These derivatives simultaneously suppress cholesterol biosynthesis through SQS inhibition (IC50 values of the most active compounds are between 0.7 and 5.5 μM) while exhibiting a significant protection of hepatic microsomal membranes against lipid peroxidation (with IC50 values for the most active compounds being between 73 and 200 μM). Further evaluation of these compounds was accomplished in vivo in an animal model of acute experimental hyperlipidemia, where it was observed that compounds reduced the examined lipidemic parameters (TC, TG and LDL) by 15-80%. In order to examine the mode of binding of these molecules in the active catalytic site of SQS, we also performed docking simulation studies. Our results indicate that some of the new compounds can be considered interesting structures in the search for new multifunctional agents of potential application in atherosclerosis.
与单一药物作用单一靶点的方法相比，作用于多个靶点的药物可能会使多因素疾病的治疗更有效，且安全性问题更少。在我们持续致力于设计抗动脉粥样硬化多功能分子的过程中，在此报告17种新的吗啉衍生物的合成，这些衍生物在吗啉环上的芳基取代方面结构各异。这些衍生物通过抑制鲨烯合酶（SQS）同时抑制胆固醇生物合成（最具活性的化合物的IC50值在0.7至5.5 μM之间），同时对肝微粒体膜脂质过氧化表现出显著的保护作用（最具活性的化合物的IC50值在73至200 μM之间）。在急性实验性高脂血症动物模型中对这些化合物进行了体内进一步评估，结果观察到这些化合物使检测的血脂参数（总胆固醇、甘油三酯和低密度脂蛋白）降低了15 - 80%。为了研究这些分子在SQS活性催化位点的结合模式，我们还进行了对接模拟研究。我们的结果表明，在寻找可能用于动脉粥样硬化的新型多功能药物时，一些新化合物可被视为有趣的结构。
