Jiajia Mou

: Berberine (BBR) is a quaternary ammonium alkaloid isolated from the Traditional Chinese Medicine Coptis chinensis. It possesses a plethora of pharmacological activities because its unique structure properties make it readily interact with macromolecules through π-π stacking and electrostatic interaction. Its anti-tumor effects are receiving more and more attention in recent years. Cytotoxicity and anti-proliferation are the important anti-tumor modes of BBR, which have been studied by many research groups. : This study aims to review the structural modifications of BBR and its cytotoxic derivatives. Also, to study the corresponding structure-activity relationship. BBR showed potential activities toward tumor cells, however, its modest activity and poor physicochemical properties hindered its application in clinical. Structural modification is a common and effective approach to improve BBR's cytotoxic or anti-proliferative activities. : The structural modifications of BBR, the cytotoxic or anti-proliferative activities of its derivatives, and the corresponding structure-activity relationship (SAR) were summarized in the review. : The concluded SAR of BBR derivatives with their cytotoxic or anti-proliferative activities will provide great prospects for the future anti-tumor drug design with BBR as the lead compound.

α‐glucosidase inhibitors (AGIs) were commonly used in clinical for the treatment of type 2 diabetes. Xanthones were naturally occurring antioxidants, and they may also be potential AGIs. In this study, eleven 1,6‐ and 1,3‐substituted xanthone compounds were designed and synthesized, of which four were new compounds. Their α‐glucosidase inhibitory activities in vitro and in silico were evaluated. Five xanthone compounds with higher activity than acarbose were screened out, and the xanthones substituted at the 1,6‐positions were more likely to be potential α‐glucosidase non‐competitive inhibitors. The binding mode of xanthones with α‐glucosidase was further studied by molecular docking method, and the results showed that the inhibitory effect of non‐competitive inhibitors on site 1 of α‐glucosidase may be related to the hydrogen bonds formed by the compounds with amino acid residues ASN165, HIS209, TRY207, ASP243, and SER104. This study provided a theoretical basis of the rapid discovery and structural modification of non‐competitive xanthone inhibitors of α‐glucosidase.

Berberine (BBR) is a plant derived quaternary benzylisoquinoline alkaloid, which has been widely used in traditional medicines for a long term. It possesses broad pharmacological effects and is widely applied in clinical. In recent years, the anti-tumor effects of BBR have attracted more and more attention of the researchers. The canonical right-handed double-stranded helical deoxyribonucleic acid (B-DNA) and its polymorphs occur under various environmental conditions and are involved in a plethora of genetic instability-related diseases especially tumor. BBR showed differential binding effects towards various polymorphic DNA structures. But its poor lipophilicity and fast metabolism limited its clinical utility. Structural modification of BBR is an effective approach to improve its DNA binding activity and bioavailability in vivo. A large number of studies dedicated to improving the binding affinities of BBR towards different DNA structures have been carried out and achieved tremendous advancements. In this article, the main achievements of BBR derivatives in polymorphic DNA structures binding researches in recent 20 years were reviewed. The structural modification strategy of BBR, the DNA binding effects of its derivatives, and the structure activity relationship (SAR) analysis have also been discussed.

Cyclin-dependent kinase 1 (CDK1) plays an indispensable role in the whole cell cycle. It has become a new target for cancer therapy. According to the binding mode of a pan-CDK inhibitor, flavopiridol with CDK1, and our previous work, a new series of flavone derivatives were discovered. Among them, compound 2a showed the best CDK1 inhibitory and anti-proliferative potencies in the in vitro activity investigation. The IC₅₀ of 2a against CDK1 was 36.42 ± 1.12 μM vs. 11.49 μM ± 0.56 of flavopiridol. In the anti-proliferation activity assays, 2a exhibited better activity toward RAW264.7 than MCF-7 cells. The results indicated that flavone derivatives, besides inhibiting the growth of tumor cells, can also antagonize inflammatory response. Molecular docking results showed that conformation of 2a can form hydrogen bonds and various hydrophobic interactions with the key amino acid residues of CDK1. It can be used as a promising lead compound for CDK1 inhibitor development.

Centipeda minima (L.) A. Br. et Aschers, known as Ebushicao (EBSC) in Chinese, has long been used in traditional Chinese medicine for dispelling wind, clearing orifices, detoxification, and swelling. Although the traditional use of EBSC involves the whole plant, during harvesting and processing, separation of the stems, leaves, flowers, and roots often occurs. However, there are few studies on its medicinal parts. A strategy combining high-performance liquid chromatography (HPLC) fingerprinting and multivariate classification techniques are here proposed for the comparison of roots, stems, leaves, and flowers of EBSC. The roots, stems, leaves, and flowers of EBSC samples were analyzed and compared based on HPLC fingerprints combined with chemometrics, including hierarchical cluster analysis (HCA), principal component analysis (PCA), partial least-squares discriminant analysis (PLS-DA), and back propagation artificial neural network (BP-ANN). Chemical markers were screened using PLS-DA, and the contents of representative ingredients were determined by an HPLC method. The HCA and PCA provided clear discrimination of roots, stems, leaves, and flowers. Moreover, the PLS-DA model and BP-ANN were established to verify the classification results and showed a greater ability to predict new samples. Four representative chemical markers were screened out, and the content of these markers in flowers and leaves was higher than that in stems and roots, and the difference was significant. Combining HPLC fingerprinting and multicomponent chemical pattern recognition technology can be used to distinguish different parts of EBSC. The results indicated that brevilin A, quercetin, rutin, and chlorogenic acid, the important active components of EBSC, were mainly present in the leaves and flowers. This is of great significance for the differentiation and identification of the different medicinal parts of EBSC, as well as for the effectiveness of drug usage in clinical practice. HP LC was used to quickly obtain chemical for fingerprint analysis. HCA, P CA, P LS-DA were used to visualize the discrimination of roots, stems, leaves and flowers of EBSC. P LS-DA model was established to verify the classification results and obtained the chemical marker. BP-ANN model was used to further improve the discrimination accuracy.

Twelve baicalein derivatives, derivatized with 7‐ester and 8‐aminomethylene groups, were synthesized as cyclin‐dependent kinase 1 (CDK1) inhibitors, by the addition of one of four secondary amines to C‐8, using the Mannich reaction, followed by mono‐esterification with one of three carboxylic acids. Analysis by ¹H‐, ¹³C‐NMR, and HMBC spectra, as well as a chemical test, confirmed that the esterification occurred at the 7‐phenolic hydroxyl position of baicalein but not at the 5‐ or 6‐positions.

Malignant tumor is a disease with high mortality. Traditional treatment methods have many disadvantages, such as side‐effects, drug resistance. Because cyclin‐dependent kinase 1 (CDK1) plays an indispensable role in cell cycle regulation, it became an attractive target in rational anti‐cancer drug discovery. Herein, we reported a series of baicalein derivatives, which remarkably repressed the proliferation of MCF‐7 tumor cells and the activity of CDK1/cyclin B kinase. Among them, compound 4a displayed better inhibition rate than flavopiridol against MCF‐7 proliferation at the concentration of 50 μg/ml, comparable to compound CGP74514A, while compound 3o possessed the best activity against CDK1/cyclin B kinase (IC₅₀ = 1.26 μM). The inhibitory activities toward the kinase well correlated with anti‐proliferative activities. Molecular docking results suggested that compound 3o can interact with the key amino acid residues, E81, L83, and D146, of CDK1 through hydrogen bond just like flavopiridol does. And it can also form an extra hydrogen bond with D146 by its introduced 7‐acrylate group, which flavopiridol does not have. These findings proved that baicalein derivatives can be used as CDK1 inhibitors fighting against cancer.

The 2,3,5,4’-tetrahydroxy-stilbene-2-O-β-D-glucoside (THSG) is a main active ingredient of Polygoni Multiflori Radix (PMR). In this study, THSG was found to be a differential chemical composition between PMR and its compatible herb pairs through chemometrics techniques. The effects of the herb pairs Codonopsis Radix-PMR, Astragali Radix-PMR, and Ophiopogonis Radix (OR)-PMR on the stability and absorption behavior of THSG were investigated by simulating the digestive environment in vitro and using an everted gut sac model. The results indicated that the compatible pairs were able to significantly increase the stability of THSG in the gastrointestinal tract and delay the absorption of THSG in the small intestine. OR had the most obvious influence on THSG as the t_0.9 values of THSG increased by 14.74- and 6.68-fold in simulated gastric juice and small intestinal fluid, and the apparent permeability coefficient of THSG were 2.07- and 1.97-fold lower for OR-PMR in the ileum and duodenum, respectively. Thus, the compatibility could potentially be used to change the biopharmaceutical properties of THSG. Moreover, the present study established a research method for describing the compatibilities of traditional Chinese medicine based on stability-intestinal absorption, which may provide important reference values for the compatibilities of traditional Chinese medicine. Graphical Abstract