Xanthones as potential α-glucosidase non-competition inhibitors: Synthesis, inhibitory activities, and in silico studies.

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.

Insight on Structural Modification, Cytotoxic or Anti-Proliferative Activity, Structure-Activity Relationship of Berberine Derivatives.

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.

Design, Synthesis, and Activity Assays of Cyclin-Dependent Kinase 1 Inhibitors With Flavone Scaffolds.

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.

Structural modifications of berberine and their binding effects towards polymorphic deoxyribonucleic acid structures: A review.

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.

Characteristic profiling of Aconiti Lateralis Radix for distinguishing it from compatible herbal pair using UPLC-Q-TOF-MS coupled with chemometrics.

A method combining ultra-high-performance liquid chromatograph/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and chemometrics was established to evaluate the differences in chemical composition between Aconiti Lateralis Radix (Fuzi in Chinese) before and after combination with Glycyrrhizae Radix et Rhizoma (Gancao in Chinese). UPLC-Q-TOF-MS was used to characterize the chemical components before and after the combination of Fuzi with Gancao, and genetic algorithm selection variables were applied to extract important variables. Partial least square discriminant analysis was used to verify the reliability of the variables obtained by genetic algorithm selection in differentiating Fuzi and combinations with Gancao, and nine potential chemical markers were obtained. The changes in content of chemical markers in Fuzi before and after combination were visualized using a heat map and hierarchical cluster analysis. Based on the chemical markers, characteristic profiling of UPLC-Q-TOF-MS data was developed, then unsupervised principal components analysis and a supervised counter-propagation artificial neural network were used to validate the characteristic profiling approach and showed that it performed well in differentiating between Fuzi and combinations with Gancao.

Comparative Investigation of the Stems, Leaves, Flowers, and Roots of Centipeda Minima Based on Fingerprinting-Multivariate Classification Techniques.

BACKGROUND: 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. OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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. HIGHLIGHTS: 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.

Design, synthesis, and primary activity assays of baicalein derivatives as cyclin-dependent kinase 1 inhibitors.

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.

Polygonum multiflorum: Recent updates on newly isolated compounds, potential hepatotoxic compounds and their mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thunb.(PM), (known as Heshouwu () in China) is one of the most important and well mentioned Chinese medicinal herbs in the literature for its use in blackening hair, nourishing liver and kidney, anti-aging, anti-hyperlipidemia, antioxidant, anti-inflammatory, anticancer, hepatoprotection, cardio-protection and improving age-related cognitive dysfunction. The purpose of this review is to give a comprehensive and recent update on PM: new compounds or isolated for the first time, potential hepatotoxic compounds and their mechanisms. Moreover, future perspectives and challenges in the future study of this plant are conversed which will make a new base for further study on PM. MATERIALS AND METHODS: A comprehensive review of relevant published literature on PM using the scientific databases SCOPUS, PubMed, and Science Direct was done. RESULTS: PM is broadly produced in many provinces of China and well known in other Eastern Asian Countries for its ethno-medical uses. Previous phytochemical investigation of PM had led to the isolation of more than 175 compounds including recently isolated 70 new compounds. Most of the new compounds isolated after 2015 are majorly dianthrone glycosides and stilbene glycosides. Processing has also a significant effect on chemical composition, pharmacological activities, and toxicity of PM. PM-induced liver injury is increasing after the first report in Hong Kong in 1996. Hepatotoxicity of PM was constantly reported in Japan, Korea, China, Australia, Britain, Italy, and other countries although its toxicity is related to idiosyncratic hepatotoxicity. More interestingly, although there is indispensable interest to predict idiosyncratic hepatotoxicity of PM and understand its mechanisms, the responsible hepatotoxic compounds and mechanisms of liver damage induced by PM are still not clear. There is a big controversy on the identification of the most responsible constituent. Anthraquinone and stilbene compounds in PM, mainly emodine and TSG are mentioned in the literature to be the main responsible hepatotoxic compounds. However, comparing the two compounds, which one is the more critical toxic agent for PM-induced hepatotoxicity is not well answered. Affecting different physiological and metabolic pathways such as oxidative phosphorylation and TCA cycle pathway, metabolic pathways, bile acid excretion pathway and genetic polymorphisms are among the mechanisms of hepatotoxicity of PM. CONCLUSION: Deeper and effective high throughput experimental studies are still research hotspots to know the most responsible constituent and the mechanism of PM-induced hepatotoxicity.

Inhibitors of Cyclin-Dependent Kinase 1/2 for Anticancer Treatment.

BACKGROUND: The cell cycle is regulated by cyclin-dependent kinases (CDKs) and their cognate cyclins, along with their endogenous inhibitors (CDKIs). CDKs act as central regulators in this process. Different CDKs play relevant roles in different phases. Among all CDKs, CDK1 is indispensible, which can drive all events that are required in the cell cycle in the absence of interphase CDKs (CDK2, CDK3, CDK4 and CDK6). So, CDK1 is an attractive target for anticancer drug development. METHODS: CDK1 and CDK2 have 89.19% similar residues and 74.32% identical residues, their structures especially the ATP-binding sites are of great similarity. So, it is difficult to inhibit CDK1 and CDK2 individually. In this review, recent advances about CDK1/2 inhibitors were summarized. The chemical structures of different classes of CDK1/2 inhibitors and their structure activity are presented. RESULTS: 19 kinds of CDK1/2 or CDK1 inhibitors with different scaffolds, including CDK2 allosteric inhibitors, were summarized. Some inhibitors are nature derived, for example, phenanthrene derivatives, nortopsentin derivatives, variolin B derivatives and meridians. CONCLUSION: Nature products, especially marine ones are potential resources for CDK1 inhibitors development. The findings of CDK2 allosteric inhibitors open an avenue to the discovery of novel selective CDK1 or other CDKs allosteric inhibitors.

Design, synthesis, and activity evaluation of a new 5-fluorouracil prodrug containing an Asn-Gly-Arg(NO2)COOCH3 tripeptide.

Aminopeptidase N (APN/CD13) of the M1 family is a broad specificity enzyme that is intimately involved in tumor angiogenesis and metastasis. Asparagine-glycine-arginine (NGR) is a tumor-homing tripeptide, which can selectively combine with APN/CD13 that is overexpressed on the surface of some tumor cells. Various anti-tumor drugs can be conjugated to NGR to improve selectivity, efficacy, and to decrease drug toxicity. In this study, a tripeptide NGR(NO2) was synthesized and conjugated with 5-fluorouracil. The anti-tumor activities of this new prodrug were evaluated in vivo. More significant anti-tumor effects were observed over the parent 5-fluorouracil.

Synthesis and activity evaluation of a new bestatin derivative LYP2 as an aminopeptidase N inhibitor.

As a ubiquitous enzyme overexpressed on the epithelium of the tumor, aminopeptidase N (APN) plays important roles in the angiogenesis and metastasis of the tumor. Bestatin as an effective inhibitor against APN is used in the ancillary treatment of various cancers. In this study, we modified the structure of a bestatin derivative LYP reported in our former study to provide a new bestatin derivative LYP2 with enhanced stability. We also tested the inhibitive activity of LYP2, which retained good efficacy in vitro and in vivo towards APN.

Design, synthesis and preliminary activity evaluation of novel L-lysine derivatives as aminopeptidase N/CD13 inhibitors.

A novel class of L-lysine derivatives as aminopeptidase N (APN) inhibitors was designed and synthesized. Activity evaluation showed that compound C7 (IC(50) = 9.6 +/-1.3 microM) and C20 (IC(50) = 13.6 +/- 1.9 microM) were equivalent to the positive control Bestatin (IC(50) = 11.3 +/- 1.6 microM).

Design, synthesis and primary activity assay of bi- or tri-peptide analogues with the scaffold l-arginine as amino-peptidase N/CD13 inhibitors.

A series of bi- or tri-peptide analogues with the scaffold l-arginine were designed, synthesized and evaluated for their inhibitory activities against amino-peptidase N (APN) and metalloproteinase-2 (MMP-2). The primary activity assay showed that all the compounds exhibited higher inhibitory activities against APN than MMP-2. Within this series, compounds C6 and C7 (IC(50)=4.2 and 4.3microM) showed comparable APN inhibitory activities with the positive control bestatin (IC(50)=3.8microM).

Design, synthesis and primary activity evaluation of L-arginine derivatives as amino-peptidase N/CD13 inhibitors.

A series of L-arginine derivatives were designed, synthesized and assayed for their activities against amino-peptidase N (APN)/CD13 and metalloproteinase-2 (MMP-2). The results showed that most compounds exhibited high inhibitory activities against APN and low activities against MMP-2. Within this series, two compounds 5q and 5s (IC(50)=5.3 and 5.1 microM) showed similar inhibitory activities compared with bestatin (IC(50)=3.8 microM), which could be used as novel lead compounds for the future APN inhibitors development as anticancer agents.