Taïbi Nadia, Al-Balas Qosay Ali, Bekari Nadjia, Talhi Oualid, Al Jabal Ghazi Ahmad, Benali Yasmine, Ameraoui Rachid, Hadjadj Mohamed, Taïbi Amina, Boutaiba Zahra Mouna, Abou-Mustapha Mohamed, Khammar Farida, Dergal Fayçal, Hassaine Ridha, Boukenna Leila, Bachari Khaldoun, Soares Silva Artur Manuel
Centre de Recherche Scientifique et Technique en Analyses Physico-chimiques CRAPC, BP 384, Bou-Ismail, 42004, Tipaza, Algeria; Université des Sciences et de La Technologie Houari Boumediene (USTHB), Faculté des Sciences Biologiques (FSB), Laboratoire de Recherche sur Les Zones Arides, (LRZA), BP 32 El Alia 16111, Bab Ezzouar, 16111, Algeria.
Departments of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.
Chem Biol Interact. 2021 Aug 25;345:109511. doi: 10.1016/j.cbi.2021.109511. Epub 2021 May 11.
Methylglyoxal is a dicarbonyl compound recruited as a potential cytotoxic marker, initially presents in cells and considered as a metabolite of the glycolytic pathway. Our aim is to demonstrate the inhibitory effect of 3, 3'-[3-(5-chloro-2-hydroxyphenyl)-3-oxopropane-1, 1-diyl] Bis (4-hydroxycoumarin) on the glyoxalase system, and indirectly its anticancer activity. The docking of OT-55 was conducted by using Flexible docking protocol, ChiFlex and libdock tools inside the active site of Glo-I indicated that both hydrogen bonding and hydrophobic interactions contributed significantly in establishing potent binding with the active site which is selected as a strong inhibitor with high scoring values and maximum Gibbs free energy. Coumarin-liposome formulation was characterized and evaluated in vivo against chemically induced hepatocarcinoma in Wistar rats. After Diethylnitrosamine (DEN) induction, microscopic assessment was realized; precancerous lesions were developed showing an increase of both tumor-associated lymphocyte and multiple tumor acini supported by the blood investigation. Our finding also suggested a preferential uptake of liposomes respectively in liver, kidney, lung, brain and spleen in the DEN-treated animals. OT-55 has also been shown to inhibit the activity of Glo-I in vitro as well as in DEN-treated rats. An abnormal high level of MGO of up to 50% was recorded followed by a reduction in glucose consumption and lactate dehydrogenase production validated in the positive control. MGO generates apoptosis as depicted by focal hepatic lesions. Also, no deleterious effects in the control group were observed after testing our coumarin but rather a vascular reorganization leading to nodular regenerative hyperplasia. Involved in the detoxification process, liver GSH is restored in intoxicated rats, while no changes are seen between controls. At the endothelial cell, OT-55 appears to modulate the release of NO only in the DEN-treated group. OT-55 would behave both as an anticancer agent but also as an angiogenic factor regarding results obtained.
甲基乙二醛是一种二羰基化合物，被用作潜在的细胞毒性标志物，最初存在于细胞中，被认为是糖酵解途径的一种代谢产物。我们的目的是证明3,3'-[3-(5-氯-2-羟基苯基)-3-氧代丙烷-1,1-二基]双(4-羟基香豆素)对乙二醛酶系统的抑制作用，并间接证明其抗癌活性。使用Flexible docking协议、ChiFlex和libdock工具在乙二醛酶I的活性位点内对OT-55进行对接，结果表明氢键和疏水相互作用在与活性位点建立有效结合中都发挥了重要作用，该活性位点被选为具有高分值和最大吉布斯自由能的强抑制剂。对香豆素-脂质体制剂进行了表征，并在体内对Wistar大鼠化学诱导的肝癌进行了评估。在二乙基亚硝胺(DEN)诱导后，进行了显微镜评估；出现了癌前病变，显示肿瘤相关淋巴细胞和多个肿瘤腺泡增加，血液检查也证实了这一点。我们的研究结果还表明，在DEN处理的动物中，脂质体分别优先被肝脏、肾脏、肺、脑和脾脏摄取。OT-55在体外以及在DEN处理的大鼠中也显示出抑制乙二醛酶I的活性。记录到异常高水平的甲基乙二醛高达50%，随后葡萄糖消耗和乳酸脱氢酶产生减少，在阳性对照中得到验证。甲基乙二醛如局灶性肝损伤所示会引发细胞凋亡。此外，在测试我们的香豆素后，对照组未观察到有害影响，而是出现了导致结节性再生性增生的血管重组。参与解毒过程的肝脏谷胱甘肽在中毒大鼠中得以恢复，而对照组之间未见变化。在内皮细胞中，OT-55似乎仅在DEN处理组中调节一氧化氮的释放。就所获得的结果而言，OT-55既表现为抗癌剂，也表现为血管生成因子。
