Guang Huang

Flavonoids and Naphthoflavonoids: Wider Roles in the Modulation of Cytochrome P450 Family 1 Enzymes.

The human cytochrome P450 family 1 enzymes consist of three members, CYP1A1, CYP1A2 and CYP1B1, which are predominantly involved in the phase I metabolism of xenobiotics. Because they have been implicated in carcinogenesis, cancer progression, and drug resistance, the inhibition of these enzymes has been widely considered an effective oncological therapeutic strategy. Some natural and synthetic flavonoids and naphthoflavonoids have been extensively documented to exert pronounced influence in the modulation of CYP1s, including functioning as inhibitors, substrates, and aryl hydrocarbon receptor (AhR) ligands. However, the molecular determinants behind these effects are still unknown. This review summarizes the structural features responsible for the CYP1 inhibitory effects of the reported flavonoids and naphthoflavonoids. Additionally, a three‐dimensional quantitative structure–activity relationship (3D‐QSAR) study was performed to better understand the effect of their structural properties on biological activities. We hope this review provides a useful foundation for the rational design of potent and selective CYP1 isozyme inhibitors, thereby accelerating the drug discovery process.

Development of 2-arylbenzo[h]quinolone analogs as selective CYP1B1 inhibitors

The CYP1B1 enzyme is regarded as a potential target for cancer prevention and therapy. Based on the structure of α-naphthoflavone (ANF), diverse 2-arylbenzo[h]quinolone derivatives were designed, synthesized and evaluated as selective CYP1B1 inhibitors. Compared with ANF, although few of the title compounds possessed comparable or slightly higher CYP1B1 inhibitory activity, these compounds displayed a significantly increased selectivity toward CYP1B1 over CYP1A2. Among them compounds 5e, 5g and 5h potently inhibited the activity of CYP1B1 with IC50 values of 3.6, 3.9 and 4.1 nM respectively, paralleled by an excellent selectivity profile. On the basis of predicted clog P values, these target compounds may exhibit improved water-solubility compared to ANF. In particular, 5h showed a great superiority in the reversal of CYP1B1-mediated docetaxel resistance in vitro. The current study may serve as a good starting point for the further development of more potent as well as specific CYP1B1 inhibitors capable of reversing CYP1B1-mediated anticancer-drug resistance.

An efficient reduction of nitro and bromine naphthalene derivatives

Reduction of 1,5-dimethoxy-4-nitronaphthalene by hydrazine hydrate was optimized in the course of current study. Influence of metals, temperature and solvents upon the process was tested. Yield of the reaction was the highest in the presence of Zn powder in DMF. Moderate heating made the process slightly more efficient than that at room temperature, whereas high temperature led to a decreased yield. The current approach made it possible to exclude high pressure and diminish experimental costs.

Synthesis and Cytotoxicity of 6-Substituted 1,4-Naphthoquinone Oxime Derivatives (II)

In the present study, a series of 1,4-naphthoquinone oxime derivatives has been synthesized. The structures were confirmed by spectroscopic methods. The newly synthesized compounds were evaluated for their in vitro cytotoxicity. Among those, the compounds 8c, 8d, 8e, 12a, and 12b demonstrated potent cytotoxic activity comparable with that of the reference drug 5-Fu.

Cytotoxicity of Synthesized 1,4-Naphthoquinone Oxime Derivatives on Selected Human Cancer Cell Lines

In an effort to develop potent and selective antitumor agents, a series of 1,4-naphthoquinone oxime derivatives were designed and synthesized. The cytotoxicity of these compounds were evaluated against five human cancer cell lines (colorectal cancer cell: HCT-15, breast cancer cell: MDA-MB-231, liver cancer cell: BEL-7402, colorectal cancer cell: HCT-116 and ovarian cancer cell: A2780) in vitro. Among them, compound 14 was found to be the most potent cytotoxic compound against three cell lines (MDA-MB-231, BEL-7402 and A2780) with IC50 values of 0.66±0.05, 5.11±0.12 and 8.26±0.22 µM, respectively. Additionally, the length of the side chains and the position of the substituent may also affect the cytotoxic activity of the naphthoquinone oxime derivatives. In general, compound 14 effectively inhibited breast cancer cell proliferation and may become a promising anticancer agent.

Recent Advances in the Development of Indazole-based Anticancer Agents

Cancer is one of the leading causes of human mortality globally; therefore, intensive efforts have been made to seek new active drugs with improved anticancer efficacy. Indazole‐containing derivatives are endowed with a broad range of biological properties, including anti‐inflammatory, antimicrobial, anti‐HIV, antihypertensive, and anticancer activities. In recent years, the development of anticancer drugs has given rise to a wide range of indazole derivatives, some of which exhibit outstanding activity against various tumor types. The aim of this review is to outline recent developments concerning the anticancer activity of indazole derivatives, as well as to summarize the design strategies and structure–activity relationships of these compounds.

An Efficient Synthesis of (R or S)-4-Methyl-1-(1,4,5,8-tetramethoxynaphthalen-2-yl)pent-3-ene-1-thiol

Based on thilation by the Lawesson’s reagent (LR), a concise and efficient synthesis of (R or S)-4-methyl-1-(1,4,5,8-tetramethoxynaphthalen-2-yl)pent-3-ene-1-thiol was developed with relatively high yield.

A simplified synthesis of 2-acetyl-1,4,5,8-tetramethoxynaphthalene and its selective demethylation product

Based on the Friedel–Crafts acylation reaction, a one-step synthesis of 2-acetyl-1,4,5,8-tetramethoxynaphthalene and its selective demethylation product was carried out under various reaction conditions. The product and yield of the reaction were highly catalyst and solvent dependent. The developed method is characterized by short process time, low cost, mild conditions, simple work-out, high yield, and low chemical waste.