Structural and functional investigation on stem and peel polysaccharides from different varieties of pitaya.

Varieties of plant species may affect the composition and structures of the polysaccharides, thus have an impact on their chemical properties and biological activities. Herein, the present study comparatively evaluated the differences in the chemical composition, morphological structures, antioxidant activity, and anti-inflammatory activity of the stem and peel polysaccharides from different varieties of pitaya. The FT-IR and NMR spectra indicated that the six polysaccharides had similar structural features, whereas the physicochemical characterization showed that they differed significantly in terms of the monosaccharide composition, molecular weight, and surface morphology. In addition, different varieties of pitaya polysaccharides exhibited different antioxidant activities and similar anti-inflammatory activities. These data suggested that varietal differences resulted in pitaya stem and peel polysaccharides with different monosaccharide compositions and molecular weights, thus led to different antioxidant activities and protection against oxidative damage, while similar structural features were closely related to their similar anti-inflammatory activities. Therefore, the study of the stem and peel polysaccharides from different varieties of pitaya can help us to better understand the relationship between their composition and structure and their biological activities. In addition, pitaya stem and peel polysaccharides have the potential to act as antioxidants or to treat inflammatory damage.

Molecular simulations required to target novel and potent inhibitors of cancer invasion.

INTRODUCTION: Computer-aided drug design (CADD) is a computational approach used to discover, develop, and analyze drugs and active molecules with similar biochemical properties. Molecular simulation technology has significantly accelerated drug research and reduced manufacturing costs. It is an optimized drug discovery method that greatly improves the efficiency of novel drug development processes. AREASCOVERED: This review discusses the development of molecular simulations of effective cancer inhibitors and traces the main outcomes of in silico studies by introducing representative categories of six important anticancer targets. The authors provide views on this topic from the perspective of both medicinal chemistry and artificial intelligence, indicating the major challenges and predicting trends. EXPERT OPINION: The goal of introducing CADD into cancer treatment is to realize a highly efficient, accurate, and desired approach with a high success rate for identifying potent drug candidates. However, the major challenge is the lack of a sophisticated data-filtering mechanism to verify bottom data from mixed-quality references. Consequently, despite the continuous development of algorithms, computer power, and interface optimization, specific data filtering mechanisms will become an urgent and crucial issue in the future.

A selective fluorescent probe for hydrogen sulfide from a series of flavone derivatives and intracellular imaging.

In this work, through the orthogonal design of two fluorophores and two recognition groups, a series of fluorescent probes were developed from the flavone derivatives for hydrogen sulfide (H2S). The probe FlaN-DN stood out from the primarily screening on the selectivity and response intensities. It could respond to H2S with both the chromogenic and fluorescent signals. Among the recent reported probes for the H2S detection, FlaN-DN indicated the most highlighted advantages including the rapid response (within 200 s) and the high response multiplication (over 100 folds). FlaN-DN was sensitive to the pH condition, thus could be applied to distinguish the cancer micro-environment. Moreover, FlaN-DN suggested practical capabilities including a wide linear range (0-400 µM), a relatively high sensitivity (limit of detection 0.13 µM), and high selectivity towards H2S. As a low cytotoxic probe, FlaN-DN achieved the imaging in living HeLa cells. FlaN-DN could detect the endogenous generation H2S and visualize the dose-dependent responses to the exogenous H2S level. This work provided a typical case of natural-sourced derivatives as functional implements, which might inspire the future investigations.

Discovery of pyrazole-carbohydrazide with indole moiety as tubulin polymerization inhibitors and anti-tumor candidates.

In this work, a series of indole-containing pyrazole-carbohydrazide derivatives A1-A25 were synthesized, and their biological activity on tubulin polymerization inhibition and mitotic catastrophe was evaluated. For introducing indole group to CA-4 pattern, the carbohydrazide linker was used for the first time. As the top hit, A18 suggested notable antiproliferation efficacy and tubulin polymerization inhibitory activity. Inferring comparable antitubulin effect with the positive control Colchicine, A18 indicated obviously lower cyto-toxicity. The cell scratch test showed that A18 could block the cell migration, while the confocal imaging depicted that A18 could induce the mitotic catastrophe via a Colchicine-like approach. The docking simulation visualized the probable binding pattern of A18. With the information in this work, some new hints on modification might be involved in further tubulin-related investigations.

Discussion on the Structural Modification and Anti-tumor Activity of Flavonoids.

Flavonoids are secondary metabolites of plants. In general，most flavonoids are combined with glucosides and have extremely complex molecular structures. In nature, these flavonoids have a variety of biological activities, such as anti-oxidation，anti-virus, anti-tumor, scavenging free radicals, etc.; however，due to poor solubility and stability of flavonoids，their bioavailability is limited. The drug design method is used to modify the structure of flavonoids to give them special properties. At present, flavonoids have shown broad application prospects in treating tumors, inhibiting proliferation, migration, invasion, angiogenesis, and multi-drug resistance of tumors and have become a research hotspot.

A fluorescent probe derived from Berberrubine for detecting hydrogen polysulfide in food samples.

In this work, we chose the fluorophore Berberrubine to develop a selective probe for hydrogen polysulfide (H2Sn), and applied it into the detection in both food samples and living cells. The developed probe, HER9SS, suggested practical steadiness and serviceability, especially for multi-scene detection. The detecting system was stable in relatively wide pH (7.0-11.0) and temperature (25-45 °C) ranges. Both the storage of BER9SS in solid or in solution could maintain the steadiness over 7 d. BER9SS also indicated advantages including rapid response (within 15 min), high sensitivity (LOD = 0.02 µM; LOQ = 0.01 µM), long linear range (0-15.0 equivalent) and high selectivity among competing analytes. The recovery ranging in 95.23% - 104.8% in the applications in food sources samples (including water and plants) and food samples inferred the practical potential of BER9SS. In biological imaging, BER9SS could achieve both the dose-dependent monitoring and the ß-lapachone-induced generation of H2Sn. Therefore, the information in this work might be useful for the development of fluorescent probes from natural products for multi-scene applications in future, especially with the corresponding attentions on the practicability and serviceability.

A novel selective probe for detecting glutathione from other biothiols based on the concept of Fluorescence Fusion.

Biological thiols importantly regulate the intracellular redox activity and metabolic level, but many of the developed probes for biothiols are facing difficulty in effectively distinguishing GSH from Cys/Hcy due to the similarity in mechanism. In this work, despite the previous pattern of "Logic Gate", we reported the concept of "Fluorescence Fusion" for the first time to achieve only one excitation-emission process. The exploited the probe, MZ-NBD, could quickly measure GSH in 10 min with a large Stokes shift (130 nm). Though the reacting mechanism was similar, only GSH could cause the "Fluorescence Fusion" with only one strong fluorescence response while Cys/Hcy caused two peaks. Adjusting the excitation wavelength could hardly split the fused peak into two. Though image recognition by artificial intelligence could easily distinguish the patterns of peaks, here we used the signal-treating method to realize the high selectivity towards GSH. Moreover, MZ-NBD could be utilized for rapid detection of GSH in living MCF-7 cells, which was more suitable for GSH than using the "Logic Gate" strategy. More than introducing a novel probe with the new concept, this work was meaningful as the linker of traditional reaction-based fluorescent probes and potential image recognition by artificial intelligence, thus led to various future researches in inter-disciplines.

A berberrubine-derived fluorescent probe for hydrazine and its practical application in water and food samples.

In this work, we attempted to develop a fluorescent probe for hydrazine in real samples. Accordingly, we designed BER9-HZ to fulfill the set rules as solubility, anti-interference capability and functional compatibility. The selected reporting group BER9 dissolved 100% within 10 min, which indicated much better solubility than Berberine. The 615 nm reporting signal was in the Near-Infrared region. BER9-HZ presented advantages including wide linear range (0-20 equivalent), high sensitivity (detection limit 0.076 µM), steadiness (pH 7.0-13.0, temperature 25-45 °C), rapid response (within 20 min) and high selectivity in both independent and co-existing systems. Significantly, BER9-HZ could work steadily in real environmental, plant and food samples, thus be used in the detection of hydrazine (directly incubated or pre-treated with real sample) in living cells. Therefore, this work marched one step further to the systematic managing of hydrazine in real samples, and raised useful information for future investigations on Nitrogen circulation.

A Novel Fluorescent Probe for Selective Detection of Hydrazine and Its Application in Imaging.

In this work, a novel fluorescent probe with first-time-selected thiazepine backbone, TZPzine-1, was developed for selective detection of hydrazine in water samples and living cells. Chosen from our recent anti-cancer agents, TZPzine-1 inferred structurally based advantages of the optical adjustability and the hydrazine-trapping approach. It also showed applicable properties including high sensitivity (LOD = 50 nM), wide linear range (0-15 equiv.), high selectivity (especially from competing species), rapid response (within 20 min), and practical steadiness in various pH (6.0-11.0) and temperature (15-50 °C) conditions. To satisfy the interdisciplinary requirements in environmental toxicology, TZPzine-1 was successfully applied in water samples and living cells. We hope that the information in this work, as well as the concept of monitoring the nitrogen cycle, may be referable for future research on systematic management.

Monitoring of Fe (II) ions in living cells using a novel quinoline-derived fluorescent probe.

Physiologically, Fe(III) and Fe(II) is the most important redox pairs in a variety of biological and environmental procedures with its capability of transition. The detection of physiological iron, especially Fe(II), has become the recent research focus of investigations on revealing the mechanism of iron-related metabolism. In this work, we exploited a novel quinoline-derived fluorescent probe, YTP, for the detection of Fe(II). It could monitor the level of Fe(II) with a linear range of 0-2.0 equivalent and the detection limit of 0.16 µM. High selectivity from other analytes including Fe(III) and steadiness for over 24 h confirmed the practicability of YTP. YTP was further applied in real buffer systems and in cellular imaging. The probe could achieve the semi-quantitative monitoring of Fe(II) in living cells. This work provided a potential implement for the detection of Fe(II), and raised important information for further researches on the redox pairs of iron, in mechanism and in practice.

Discovery of novel indole-1,2,4-triazole derivatives as tubulin polymerization inhibitors.

A series of novel indole-1,2,4-triazole derivatives have been designed, synthesized, and evaluated as potential tubulin polymerization inhibitors. The top hit 12, bearing the 3,4,5-trimethoxyphenyl moiety, exhibited substantial anti-proliferative activity against HepG2, HeLa, MCF-7, and A549 cells in vitro with IC50 values of 0.23 ± 0.08 µM, 0.15 ± 0.18 µM, 0.38 ± 0.12 µM, and 0.30 ± 0.13 µM, respectively. It also inhibited tubulin polymerization with the IC50 value of 2.1 ± 0.12 µM, which was comparable with that of the positive controls. Furthermore, compound 12 regulated the expression of cell cycle-related proteins (Cyclin B1, Cdc25c, and Cdc2) and apoptosis-related proteins (Bcl-2, Bcl-x, and Mcl-1). Mechanistically, compound 12 could arrest cell cycle at the G2/M phase, thus induce an increase of apoptotic cell death. In addition, molecular docking hinted the possible interaction mode of compound 12 into the colchicine binding site of tubulin heterodimers. According to the applications of microtubule-targeting agents in both direct and synergistic cancer therapies, we hope this work might be of significance for future researches.

Recent Progress in Small Molecular Inhibitors of DNA Gyrase.

BACKGROUND: In the past few decades, with the abuse of antibiotics, bacterial resistance has enhanced constantly. More and more super species of bacteria, which are seriously threatening human health, have been discovered. Developing novel antibacterial agents to overcome the drug-resistance is an urgent duty. We all know that blocking the information-transfer of bacterial DNA and RNA is one of the effective ways to inhibit bacterial growth. Therefore, as the indispensable enzyme for DNA replication and transcription, DNA gyrase is one of the important targets for bacterial inhibitors. Accordingly, many inhibitors of DNA gyrase have also been developed. METHODS: In this review, to highlight the recent progress in DNA gyrase inhibitors, the study in this field over the past three years (2017-2019) was summarized and organized based on their backbones or core moieties. Both of the subunits of DNA gyrase were taken into consideration. RESULTS: These DNA gyrase inhibitors have been classified based on their backbones or core moieties. After the comparison of the divided 14 categories, we could achieve some clues for future modification. In particular, we found that benzodiazepines and naphthalene heterocycles were the most common structures in the drug design. On the other hand, isopropyl and cyclopropyl have also been used in drug design, which provides more inspiration for the investigations. Except for GSK2140944, which has entered the phase III clinical trial stage, other compounds here were not fully promulgated with their optimal pharmacokinetic activity. CONCLUSION: We briefly summed up the current situation and future challenges on this topic. Through the discussion of the design strategies and drug effect, we hope that this review can provide a focused direction for future researches.

A novel series of benzothiazepine derivatives as tubulin polymerization inhibitors with anti-tumor potency.

In this work, a series of diaryl benzo[b][1,4]thiazepine derivatives D1-D36 were synthesized and screened as tubulin polymerization inhibitors with anti-tumor potency. They were designed by introducing the seven-member ring benzothiazepine as the linker for CA-4 modification for the first time. Among them, the hit compound D8 showed potential on inhibiting the growth of several cancer cell lines (IC50 values: 1.48 µM for HeLa, 1.47 µM for MCF-7, 1.52 µM for HT29 and 1.94 µM for A549), being comparable with the positive controls Colchicine and CA-4P. The calculated IC50 value of D8 as an tubulin polymerization inhibitor was 1.20 µM. The results of the flow cytometry assay revealed that D8 could induce the mitotic catastrophe and the death of living cancer cells. D8 also indicated the anti-vascular activity. The possible binding pattern was implied by docking simulation, inferring the possibility of introducing interactions with the nearby tubulin chain. Since the novel structural trial has been conducted with preliminary discussion, this work might stimulate new ideas in further modification of tubulin-related anti-cancer agents and therapeutic approaches.

Recent Progress in the Development of Quinoline Derivatives for the Exploitation of Anti-Cancer Agents.

BACKGROUND: Along with the progress in medicine and therapies, the exploitation of anti-cancer agents focused more on the vital signaling pathways and key biological macromolecules. With rational design and advanced synthesis, quinoline derivatives have been utilized frequently in medicinal chemistry, especially in developing anti-cancer drugs or candidates. METHODS: Using DOI searching, articles published before 2020 all over the world have been reviewed as comprehensively as possible. RESULTS: In this review, we selected the representative quinoline derivate drugs in market or clinical trials, classified them into five major categories with detailed targets according to their main mechanisms, discussed the relationship within the same mechanism, and generated a summative discussion with prospective expectations. For each mechanism, the introduction of the target was presented, with the typical examples of quinoline derivate drugs. CONCLUSION: This review has highlighted the quinoline drugs or candidates, suited them into corresponding targets in their pathways, summarized and discussed. We hope that this review may help the researchers who are interested in discovering quinoline derivate anti-cancer agents obtain considerable understanding of this specific topic. Through the flourishing period and the vigorous strategies in clinical trials, quinoline drugs would be potential but facing new challenges in the future.

Synthesis, anticancer activity and molecular docking studies on 1,2-diarylbenzimidazole analogues as anti-tubulin agents.

Twenty-four 1,2-diarylbenzimidazole derivatives were designed, synthesized and biologically evaluated. It turned out that most of them were potential anticancer drugs. Among them, compound c24 showed the highest anti-tumor activity (GI50 = 0.71-2.41 µM against HeLa, HepG2, A549 and MCF-7 cells), and low toxicity to normal cells (CC50 > 100 µM against L02 cells). In the microtubule binding assay, c24 showed the most potent inhibition of microtubule polymerization (IC50 = 8.47 µM). The binding ability of compound c24 to tubulin crystal was verified by molecular docking simulation experiment. Further studies on HepG2 and HeLa cells showed that compound c24 could cause mitotic arrest of tumor cells to G2/M phase then inducing apoptosis. To sum up, compound c24 is a promising microtubule assembly inhibitor.

A patent review of RAF kinase inhibitors (2010-2018).

Introduction: RAF kinase inhibitors block and regulate RAS/RAF/MEK/ERK signaling, which is a key to tumor treatment. At present, although RAF kinase inhibitors have good efficacy, there are few such drugs with low toxicity, and thus, it is urgent to find novel RAF kinase inhibitors associated with higher activity and fewer adverse reactions. This review highlights the anti-tumor effects of several published RAF kinase inhibitors and might be helpful in providing new ideas for the development of novel drug candidates in the future. Areas covered: This article covers the pertinent literature published on RAF kinase inhibitors from 2010 to 2018, as well as the potential use of these compounds as therapeutics for cancer. Expert opinion: To date, many RAF kinase inhibitors with different structures have been studied, many of which have prominent inhibitory activities toward RAF kinase. Further, the specificity of these drugs offers hope for the targeted therapy of tumors. Although RAF kinase inhibition has achieved promising results for the treatment of many cancers, overcoming limitations associated with drug resistance and safety comprises a new direction for the optimization and improvement of RAF kinase inhibitors.

Design, synthesis, and biological evaluation of 2,3-diphenyl-cycloalkyl pyrazole derivatives as potential tubulin polymerization inhibitors.

Several novel cycloalkyl-fused 2,3-diaryl pyrazole derivatives were designed, synthesized, and evaluated as potential anti-tubulin agents. Compound A10 exhibited the most potent antiproliferative activity against a panel of cancer lines (IC50  = 0.78-2.42 µM) and low cytotoxicity against 293T & L02 (CC50 values of 131.74 and 174.89 µM, respectively). Moreover, A10 displayed inhibition of tubulin polymerization in vitro, arrested the G2/M phase of the cell cycle, changed morphology of tubulin, increased intracellular reactive oxygen species, and induced apoptosis of HeLa cells. Docking simulation and 3D-QSAR models were performed to elaborate on the anti-tubulin mechanism of the derivatives. The inhibition of monoclonal colony formation provided more intuitional data to verify the possibility of A10 as a novel tubulin assembling inhibitor.

Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX.

In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50=0.23±0.16µM for COX-2, IC50=0.87±0.07µM for 5-LOX, IC50=4.48±0.57µM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50=0.41±0.28µM for COX-2, IC50=7.68±0.55µM against A549) and Zileuton (IC50=1.35±0.24µM for 5-LOX). Further investigation confirmed that 11g could induce human non-small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents.

Design, synthesis and biological evaluation of novel benzo-α-pyrone containing piperazine derivatives as potential BRAFV600E inhibitors.

The increasingly acquired resistance to vemurafenib and side effects of known inhibitors motivate the search for new and more effective anti-melanoma drugs. In this Letter, virtual screening and scaffold growth were combined together to achieve new molecules as BRAFV600E inhibitors. Along with docking simulation, a primary screen in vitro was performed to filter the modifications for the lead compound, which was then substituted, synthesized and evaluated for their inhibitory activity against BRAFV600E and several melanoma cell lines. Out of the obtained compounds, derivative 3l was identified as a potent BRAFV600E inhibitor and exerted an anticancer effect through BRAFV600E inhibition. The following biological evaluation assays confirmed that 3l could induce cell apoptosis and marked DNA fragmentation. Furthermore, 3l could arrest the cell cycle at the G0/G1 phase in melanoma cells. The docking simulation displayed that 3l could tightly bind with the crystal structure of BRAFV600E at the active site. Overall, the biological profile of 3l suggests that this compound may be developed as a potential anticancer agent.

Coumarin sulfonamides derivatives as potent and selective COX-2 inhibitors with efficacy in suppressing cancer proliferation and metastasis.

Cyclooxygenase-2 is frequently overexpression in malignant tumors and the product PGE2 promotes cancer cell progression and metastasis. We designed novel series of coumarin sulfonamides derivatives to improve biological activities of COX-2 inhibition and anticancer. Among them, compound 7t showed most powerful selective inhibitory and antiproliferative activity (IC50=0.09µM for COX-2, IC50=48.20µM for COX-1, IC50=0.36µM against HeLa cells), comparable to the control positive compound Celecoxib (0.31µM, 43.37µM, 7.79µM). Cancer cell apoptosis assay were performed and results indicated that compound 7t effectively fuels HeLa cells apoptosis in a dose and time-dependent manner. Moreover, 7t could significantly suppress cancer cell adhesion, migration and invasion which were essential process of cancer metastasis. Docking simulations results was further indicated that compound 7t could bind well to the COX-2 active site and guided a reasonable design of selective COX-2 inhibitor with anticancer activities in future.