Quimque Mark Tristan, Notarte Kin Israel, Letada Arianne, Fernandez Rey Arturo, Pilapil Delfin Yñigo, Pueblos Kirstin Rhys, Agbay Jay Carl, Dahse Hans-Martin, Wenzel-Storjohann Arlette, Tasdemir Deniz, Khan Abbas, Wei Dong-Qing, Gose Macabeo Allan Patrick
Laboratory of Organic Reactivity, Discovery & Synthesis (LORDS), Research Center for Natural & Applied Sciences, University of Santo Tomas, España Blvd., 1015 Manila, Philippines.
The Graduate School, University of Santo Tomas, España Blvd., 1015 Manila, Philippines.
ACS Omega. 2021 Mar 16;6(12):8403-8417. doi: 10.1021/acsomega.1c00137. eCollection 2021 Mar 30.
Inhibition of the major cyclic adenosine monophosphate-metabolizing enzyme PDE4 has shown potential for the discovery of drugs for cancer, inflammation, and neurodegenerative disorders such as Alzheimer's disease. As a springboard to explore new anti-cancer and anti-Alzheimer's chemical prototypes from rare Annonaceae species, the present study evaluated anti-PDE4B along with antiproliferative and anti-cholinesterase activities of the extracts of the Philippine endemic species using assays and framed the resulting biological significance through computational binding and reactivity-based experiments. Thus, the PDE4 B2B-inhibiting dichloromethane sub-extract (UaD) of elicited antiproliferative activity against chronic myelogenous leukemia (K-562) and cytostatic effects against human cervical cancer (HeLa). The extract also profoundly inhibited acetylcholinesterase (AChE), an enzyme involved in the progression of neurodegenerative diseases. Chemical profiling analysis of the bioactive extract identified 18 putative secondary metabolites. Molecular docking and molecular dynamics simulations showed strong free energy binding mechanisms and dynamic stability at 50-ns simulations in the catalytic domains of PDE4 B2B, ubiquitin-specific peptidase 14, and Kelch-like ECH-associated protein 1 (KEAP-1 Kelch domain) for the benzylated dihydroflavone dichamanetin (), and of an AChE and KEAP-1 BTB domain for 3-(3,4-dihydroxybenzyl)-3',4',6-trihydroxy-2,4-dimethoxychalcone () and grandifloracin (), respectively. Density functional theory calculations to demonstrate Michael addition reaction of the most electrophilic metabolite and kinetically stable grandifloracin () with Cys151 of the KEAP-1 BTB domain illustrated favorable formation of a β-addition adduct. The top-ranked compounds also conferred favorable pharmacokinetic properties.
抑制主要的环磷酸腺苷代谢酶磷酸二酯酶4（PDE4）已显示出在发现用于治疗癌症、炎症和神经退行性疾病（如阿尔茨海默病）药物方面的潜力。作为从珍稀番荔枝科物种中探索新的抗癌和抗阿尔茨海默病化学原型的跳板，本研究使用实验评估了菲律宾特有物种提取物的抗PDE4B活性以及抗增殖和抗胆碱酯酶活性，并通过基于计算结合和反应性的实验构建了由此产生的生物学意义。因此，该物种的PDE4 B2B抑制性二氯甲烷亚提取物（UaD）对慢性粒细胞白血病（K-562）具有抗增殖活性，对人宫颈癌（HeLa）具有细胞生长抑制作用。该提取物还能显著抑制乙酰胆碱酯酶（AChE），这是一种与神经退行性疾病进展有关的酶。对生物活性提取物的化学图谱分析确定了18种推定的次生代谢产物。分子对接和分子动力学模拟显示，苄基化二氢黄酮二查马奈亭（）在PDE4 B2B、泛素特异性肽酶14和 Kelch样ECH相关蛋白1（KEAP-1 Kelch结构域）的催化结构域中，在50纳秒模拟时具有很强的自由能结合机制和动态稳定性，而3-(3,4-二羟基苄基)-3',4',6-三羟基-2,4-二甲氧基查耳酮（）和大花弗洛拉辛（）分别在AChE和KEAP-1 BTB结构域中具有上述特性。密度泛函理论计算表明，最具亲电性的代谢产物和动力学稳定的大花弗洛拉辛（）与KEAP-1 BTB结构域的Cys151发生迈克尔加成反应，说明了β-加成加合物的有利形成。排名靠前的化合物还具有良好的药代动力学性质。
