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Studies on framework modification and bioactivity evaluation on transition metal-catalyzed benzoheterocyclic compounds

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Benzoheterocyclic compounds are a large group of compounds in nature and small organic molecules, possessing a wide range of pharmacological activities and practical applications. To obtain derivatives from the benzoheterocyclic skeleton has always been the challenge and pursuit for chemists. Transition metal has been reported to be one of the most important catalyst groups in catalyzing different types of reactions. This thesis aims at designing and developing of transition metal-catalyzed functionalization reactions of benzopyran skeleton and quinoline skeleton, to synthesize different groups of benzopyran derivatives and quinoline derivatives efficiently and rapidly. In addition, to evaluate the application prospects of each kind of substrates, the biological activity and potential mechanism of different series of substrates are studied and discussed. Start with the quinoline skeleton, the method of applying transition metal copper to catalyze the selective trifluromethylthiolation of 8-animoquinolines with -SCF3 reagent has been developed. Under mild conditions, the protocol exhibits high regioselectivity on C-5 position of 8-aminoquinoline and broad substrates scope in good to moderate yield. Furthermore, the synthesized -SCF3 derivative SCF-1 is proved to combine with the A according to the molecular docking study in Discovery Studio. The experiments in vitro demonstrate that SCF-1 could attenuated the cell cytotoxicity both in H2O2-induced and Aβ-induced SH-SY5Y cells which give guidance for the further investigation in AD. As for benzo-2H-pyran skeleton, a highly efficient kinetic resolution of chromenes for the first time via a Cu-catalyzed asymmetric hydroboration has been reported. This novel approach features simple one-pot synthesis of chiral flavan-3-ols containing two vicinal stereogenic centers via a highly efficient kinetic resolution pathway (s factor up to 1060, >99% ee for most substrates and products, exclusively trans products). In addition, the anti-inflammation effects of these diversified flavan-3-ols have been further studied by the in vitro experiments and RNA-sequencing (RNA-seq) analysis. The modified flavan-3-ol natural product derivatives showed inhibitory effects on the expression and secretion of pro-inflammation cytokines including IL-1β, IL-6 and TNF-α, as well as inhibiting the inflammation responses through downregulating the gene transcriptions closely related to IL-17 signaling pathway, PI3K-Akt signaling pathway and TNF signaling pathway, which suggest these newly synthesized compounds are potent lead compounds for treating inflammation diseases. Next with flavonoid skeleton, a novel (+)-catechin derivative with cinnamenyl substituted (WM-21) is synthesized and proved to inhibit the production of melanin by regulating tyrosinase (TYR) activity in α-MSH-induced murine melanoma cells (B16F10) and human epidermal melanocytes (HEMs). We also found that WM-21 suppresses the UVA radiation-induced secretion of α-MSH in HaCaT cells while the melanogenesis attenuating process is confirmed by HaCaT cells and HEMs co-culture system. Moreover, WM-21 could suppress UVA-induced oxidative stress via reducing ROS production in HaCaT cells. We further found WM-21 promotes the nuclear translocation and transcriptional activity of Nrf2, which upregulate downstream HO-1 and NQO-1 expression. In conclusion, WM-21 attenuates melanogenesis by suppressing oxidative stress via activating Nrf2/HO-1 signaling, which might be used as a cosmetics ingredient or the candidate for therapy of hyperpigmentation skin disorders.

Other Abstract

苯并杂环化合物是一大类具有广泛的药理活动和实际应用的化合物和小有机分子。从苯并杂环类骨架中获取衍生物一直是化学家面临的挑战和追求。据报道,过渡金属是催化不同类型反应的最重要催化剂之一。本文旨在设计开发苯并杂环骨架和喹啉骨架的过渡金属催化功能反应,高效、快速地合成不同类别的苯并氧杂环类衍生物和喹啉衍生物。此外,为了评估各种化合物的应用前景,研究和讨论了不同系列化合物的生物活性和潜在机制。 从喹啉骨架开始,开发出用-SCF3试剂应用过渡金属铜来催化8-氨基喹啉甲酸酯的选择性三氟甲硫基化的方法。在温和条件下,该方法在8-氨基喹啉C-5位置表现出高选择性,底物范围广,产率良好至中等。此外,根据分子对接研究发现,合成-SCF3衍生SCF-1被证明与A beta结合。体外实验表明,SCF-1可以减轻H2O2或者A beta诱导的SH-SY5Y细胞的细胞毒性,为抗AD的进一步研究提供指导。 至于苯并-2氢-吡喃骨架,据报道,首次通过Cu催化不对称催化进行了高效的动力学拆分。这种新方法采用简单的一锅法合成手性黄烷醇类化合物,通过高效的动力学拆分得到高对映选择性的产物。此外,体外实验和RNA测序(RNA-seq)分析进一步研究了这些多样化的黄烷-醇的抗炎作用。合成得到的衍生物对炎症的细胞因子(包括IL-1 beta, IL-6和TNF-α)的表达和分泌表现出抑制作用,并通过降低IL-17信号通路、PI3K-Akt信号通路和TNF信号通路密切相关的转录因子来抑制炎症反应,这表明这些新合成的化合物是治疗炎症疾病的潜在强效化合物。 接下来是黄酮类骨架,通过儿茶素合成得到了一种新型的多酚化合物WM-21,该化合物可以通过调节酪氨酸酶(TYR)活性在α-MSH诱导的黑色素瘤细胞(B16F10)和人类表皮黑色素细胞(HEMs)中抑制黑色素的生产。我们还发现,WM-21抑制了HaCat细胞中α-MSH的UVA辐射诱导分泌,而黑色素细胞和HMS共培养系统证实了这个过程。此外,WM-21可以通过减少HaCaT细胞中的ROS产量来抑制UVA引起的氧化应激。我们进一步发现,WM-21促进了Nrf2的核转移和转录活动,从而调节了下游HO-1和NQO-1的表达。最后,WM-21通过激活Nrf2/HO-1信号来抑制氧化应激来减少黑色素生成,该化合物可能被用作化妆品成分或治疗皮肤疾病的候选物。

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DepartmentDepartment of Chemistry
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Wang ZH. Studies on framework modification and bioactivity evaluation on transition metal-catalyzed benzoheterocyclic compounds[D]. 香港. 香港浸会大学,2021.
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