QSAR prediction, synthesis, anticancer evaluation, and mechanistic investigations of novel sophoridine derivatives as topoisomerase I inhibitors.

Sophoridine, which is derived from the Leguminous plant Sophora alopecuroides L., has certain pharmacological activity as a new anticancer drug. Herein, a series of novel N-substituted sophoridine derivatives was designed, synthesized and evaluated with anticancer activity. Through QSAR prediction models, it was discovered that the introduction of a benzene ring as a main pharmacophore and reintroduced into a benzene in para position on the phenyl ring in the novel sophoridine derivatives improved the anticancer activity effectively. In vitro, 28 novel compounds were evaluated for anticancer activity against four human tumor cell lines (A549, CNE-2, HepG-2, and HEC-1-B). In particular, Compound 26 exhibited remarkable inhibitory effects, with an IC50 value of 15.6 µM against HepG-2 cells, surpassing cis-Dichlorodiamineplatinum (II). Molecular docking studies verified that the derivatives exhibit stronger binding affinity with DNA topoisomerase I compared to sophoridine. In addition, 26 demonstrated significant inhibition of DNA Topoisomerase I and could arrest cells in G0/G1 phase. This study provides valuable insights into the design and synthesis of N-substituted sophoridine derivatives with anticancer activity.

Evaluation of Microwave-Assisted Extraction Method for Preparation and Assessment of Thai Herbal Medicine Oral Tablets With Enriched Phytochemical Compounds.

In developing countries, populations have employed herbal medicines for primary health care because they are believed to be more appropriate to the human body and have less side effects than chemically synthesized drugs. The present study aimed to develop and evaluate herbal tablets incorporated with a Thai traditional medicinal extract, U-pa-ri-waat (URW), using microwave-assisted extraction (MAE). The extraction efficiency for URW using MAE and traditional solvent extraction was compared based on the percent yield after spray drying. URW tablets were prepared using the dry granulation method. The optimized products were assessed using standard characterization methods based on the United States and British Pharmacopeias. DPPH and ABTS radical scavenging assays were performed to analyze the antioxidant capacity of the microwave-assisted extracts. The results revealed that the flowability of the dry granule with added maltodextrin was improved compared to a granule without additives, as indicated by an angle of repose of 33.69 ± 2.0°, a compressibility index of 15.38 ± 0.66, and a Hausner's ratio of 1.18 ± 0.06. The resulting formulation produced flat tablets with uniform weight variation, hardness, thickness, friability, and optimum disintegration time. The URW extracts showed antioxidant activity and MAE with maltodextrin carrier displayed the strongest DPPH and ABTS radical activities with IC50 values of 1.60 ± 0.02 µg/mL and 4.02 ± 0.24 µg/mL, respectively. The URW tablet formulation passed the quality control tests. Storage of the formulation tablets for 90 days under accelerated conditions had minimal effects on tablet characteristics.

Flow Biocatalysis: A Challenging Alternative for the Synthesis of APIs and Natural Compounds.

Biocatalysts represent an efficient, highly selective and greener alternative to metal catalysts in both industry and academia. In the last two decades, the interest in biocatalytic transformations has increased due to an urgent need for more sustainable industrial processes that comply with the principles of green chemistry. Thanks to the recent advances in biotechnologies, protein engineering and the Nobel prize awarded concept of direct enzymatic evolution, the synthetic enzymatic toolbox has expanded significantly. In particular, the implementation of biocatalysts in continuous flow systems has attracted much attention, especially from industry. The advantages of flow chemistry enable biosynthesis to overcome well-known limitations of "classic" enzymatic catalysis, such as time-consuming work-ups and enzyme inhibition, as well as difficult scale-up and process intensifications. Moreover, continuous flow biocatalysis provides access to practical, economical and more sustainable synthetic pathways, an important aspect for the future of pharmaceutical companies if they want to compete in the market while complying with European Medicines Agency (EMA), Food and Drug Administration (FDA) and green chemistry requirements. This review focuses on the most recent advances in the use of flow biocatalysis for the synthesis of active pharmaceutical ingredients (APIs), pharmaceuticals and natural products, and the advantages and limitations are discussed.

Recent Developments in Nano-Drug Delivery Systems Loaded by Phytochemicals for Wound Healing.

Wound healing is a multi-stage process during which a cascade of molecular and cellular events collaborate to restore the damaged tissue to its healthy state. The inability of the available therapies to effectively heal the wounds has imposed major problems on healthcare systems. Therefore, developing novel therapeutic modalities capable of enhancing wound healing process with no/or limited scar formation is of more importance. Different studies have investigated the potential of phytochemicals on the wound healing process. They have shown to exert anti-inflammatory, antioxidant, and antibacterial activities as well as promoting collagen synthesis and deposition, leading to enhancing wound healing. Nanotechnology, as an applicable knowledge, has provided versatile means to improve the efficiency and effectiveness of wound treatment. The application of nanoparticles has conferred various advantages in the field of wound treatment. They protect the therapeutics from degradation, release the cargo in a controlled fashion, possess healing properties, and can act as extracellular matrix (ECM) mimic. In this review, we discuss the naturally-occurring compounds with wound healing properties and their nano-formulation for skin wound therapy.

Effect of prohydrojasmon on total phenolic content, anthocyanin accumulation and antioxidant activity in komatsuna and lettuce.

Prohydrojasmon has been reported to improve the quality of crops. However, most previous studies have investigated its application on fruits. Here, we evaluated the effect of prohydrojasmon on the growth and total phenolic content, anthocyanin content, and antioxidant activity in komatsuna (Brassica rapa var. periviridis) and lettuce (Lactuca sativa L.). Prohydrojasmon did not show any serious inhibitory effect. Prohydrojasmon applied to komatsuna at a concentration of 0.5 µM significantly increased the total phenolic content and anthocyanin content, and a concentration of 1 µM increased the antioxidant activity. In lettuce, prohydrojasmon at a concentration of 400 µM significantly increased the total phenolic content and anthocyanin content, while a concentration of 0.5 µM significantly increased the antioxidant activity. These results suggest that prohydrojasmon positively affects the phenolic compound and anthocyanin accumulation and antioxidant activity in komatsuna and lettuce without adversely affecting growth.

Correlation between Antioxidant/Antimutagenic and Antiproliferative Activity of Some Phytochemicals.

BACKGROUND: Chemotherapeutic drugs have high toxicity associated with undesirable side-effects. Now, natural products are the most important anti-cancer agents because of their low toxicity and potential effectiveness. METHODS: The half maximal inhibitory concentration (IC50) of amygdalin, naringenin and ellagic acid against breast, colon, and liver cell lines was estimated. The antimutagenic, free radical-, superoxide radical-, and hydroxyl radical- scavenging activities of these phytochemicals were measured. The expression of p53, bid, bax, bcl2, and caspases 9, 3, and 7 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in breast and liver cells. In addition, the active Caspase 3 protein was estimated in liver cells. RESULTS: Ellagic acid showed the highest antioxidant and antiproliferative activities. Amygdalin and naringenin with low and moderate antioxidant profiles showed a corresponding low and moderate cytotoxicity against cancer cell lines, respectively. Naringenin and ellagic acid had a significant antimutagenic activity which was detected by the Salmonella test. Ellagic acid offered a much better antimutagenic activity than naringenin. The apoptotic pathway evoked by ellagic acid in HepG2 and MCF-7 cells was investigated. The results showed that a caspase-dependent and a caspase-independent apoptosis occurred in MCF-7 and HepG2, respectively. CONCLUSION: The antimutagenic/antioxidant properties are well correlated with the antiproliferative activity of the phytochemicals investigated. This study proved that some easy, quick and cheap assays could predict the antiproliferative activity of many nutraceuticals. Finally, this platform could help in the discovery of new anticancer agents where hundreds of compounds are investigated in the pipeline of drug discovery.

Advances in Rosin-Based Chemicals: The Latest Recipes, Applications and Future Trends.

A comprehensive review of the publications about rosin-based chemicals has been compiled. Rosin, or colophony, is a natural, abundant, cheap and non-toxic raw material which can be easily modified to obtain numerous useful products, which makes it an excellent subject of innovative research, attracting growing interest in recent years. The last extensive review in this research area was published in 2008, so the current article contains the most promising, repeatable achievements in synthesis of rosin-derived chemicals, published in scientific literature from 2008 to 2018. The first part of the review includes low/medium molecule weight compounds: Especially intermediates, resins, monomers, curing agents, surfactants, medications and biocides. The second part is about macromolecules: mainly elastomers, polymers for biomedical applications, coatings, adhesives, surfactants, sorbents, organosilicons and polysaccharides. In conclusion, a critical evaluation of the publications in terms of data completeness has been carried out with an indication of the most promising directions of rosin-based chemicals development.

Beneficial effects and potential risks of tomato consumption for human health: An overview.

Tomato and its derived products have a very interesting nutritional value in addition to prominent antioxidant, anti-inflammatory, and anticancer activities. Tomatoes are generally quite safe to eat. However, overall consumption varies from individual to individual. Indeed, either beneficial or harmful effects of plants or their derived products are closely related to quality, including the presence of biologically active compounds. On the other hand, the synthesis and accumulation of these bioactive molecules depends on many other factors, such as environmental conditions. In this sense, this review briefly highlights the relationship between the chemistry of tomato and its derived products and their beneficial or harmful effects on human health, such as gastroesophageal reflux disease or heartburn, allergies, kidney and cardiovascular disorders, prostate cancer, irritable bowel syndrome, lycopenodermia, body aches, arthritis, and urinary problems.

Synthesis and biological evaluation of quercetin and resveratrol peptidyl derivatives as potential anticancer and antioxidant agents.

Quercetin and resveratrol are polyphenolic compounds, members of the flavonoid and the stilbene family, respectively, both medicinally important as dietary anticancer and antioxidant agents. They are present in a variety of foods-including fruits, vegetables, tea, wine, as well as other dietary supplements-and are responsible for various health benefits. Different quercetin and resveratrol esters of Leu/Met-enkephalin and tetrapeptide Leu-Ser-Lys-Leu (LSKL) were synthesized as model systems for monitoring the influence of the peptides on biological activity of resveratrol and quercetin. General formula of the main peptidyl-quercetin derivatives is 2-[3-(aa)n-4-hydroxyphenyl]-3,5,7-tri-hydroxy-4H-1-benzopyran-4-on, and the general formula of the main peptidyl-resveratrol derivatives is (E)-5-[4-(aa)n)styryl]benzene-1,3-diol. The antioxidant and anticancer activities of prepared compounds were investigated. Significant anticancer activity was obtained for the LSKL-based both quercetin and resveratrol derivatives. All prepared compounds exhibit antioxidant activity, in particular quercetin derivative containing Met-enkephalin.

Recent Studies on Cyclic 1,7-Diarylheptanoids: Their Isolation, Structures, Biological Activities, and Chemical Synthesis.

Diarylheptanoids are a family of plant secondary metabolites with a 7 carbon skeleton possessing two phenyl rings at the 1- and 7-positions. They can be subdivided into acyclic and cyclic diarylheptanoids where the latter are further divided into meta,meta-bridged biphenyls ([7.0]metacyclophanes) and meta,para-bridged diphenyl ether heptanoids (oxa[7.1]metapara-cyclophanes). Since the isolation of curcumin from the rhizomes of turmeric (Curcuma longa) in 1815 which was named curcumin, a variety of diarylheptanoids have been isolated from a number of plant families such as Aceraceae, Actinidiaceae, Betulaceae, Burseraceae, Casuarinaceae, Juglandaceae, Leguminosae, Myricaceae, and Zingiberaceae. Earlier studies on these diarylheptanoids have been summarized on several occasions, of which the main themes only focus on isolation, structure elucidation, and the biological properties of linear types. Only a few have covered cyclic diarylheptanoids and their chemical synthesis has been covered lastly by Zhu et al. in 2000. The present paper has, therefore, covered recent progress in cyclic diarylheptanoids focusing on the isolation, structural and biological features, and chemical synthesis.

Ethnobotany and Medicinal Plant Biotechnology: From Tradition to Modern Aspects of Drug Development.

Secondary natural products from plants are important drug leads for the development of new drug candidates for rational clinical therapy and exhibit a variety of biological activities in experimental pharmacology and serve as structural template in medicinal chemistry. The exploration of plants and discovery of natural compounds based on ethnopharmacology in combination with high sophisticated analytics is still today an important drug discovery to characterize and validate potential leads. Due to structural complexity, low abundance in biological material, and high costs in chemical synthesis, alternative ways in production like plant cell cultures, heterologous biosynthesis, and synthetic biotechnology are applied. The basis for any biotechnological process is deep knowledge in genetic regulation of pathways and protein expression with regard to todays "omics" technologies. The high number genetic techniques allowed the implementation of combinatorial biosynthesis and wide genome sequencing. Consequently, genetics allowed functional expression of biosynthetic cascades from plants and to reconstitute low-performing pathways in more productive heterologous microorganisms. Thus, de novo biosynthesis in heterologous hosts requires fundamental understanding of pathway reconstruction and multitude of genes in a foreign organism. Here, actual concepts and strategies are discussed for pathway reconstruction and genome sequencing techniques cloning tools to bridge the gap between ethnopharmaceutical drug discovery to industrial biotechnology.

Synthesis of phytochemicals-stabilized gold nanoparticles and their biological activities against bacteria and Leishmania.

Nanoscale materials have shown promising results in the field of medicine as therapeutic agents and drugs delivery vehicles. In the current study, gold nanoparticles (AuNPs) were prepared by a green and facile method using the aqueous extract of Rhazya stricta decne as a source of reducing and stabilizing agents. The bio-fabricated AuNPs were characterized by UV-visible spectroscopy, X-ray diffraction (XRD), Transmission electron microscopy (TEM) and FTIR spectroscopy. Antimicrobial activities of the biosynthesized AuNPs were tested against Leishmania tropica (HTD7), E. coli and S. aureus. AuNPs were the most effective agents in inhibiting the growth of intra-THP-1 amastigotes at 100 µg/mL concentration (IC50 = 43 µg/mL) after 48-h incubation. In addition, the prepared AuNPs also displayed good activity against E. coli (MIC = 25.0 µg/mL) and Bacillus subtilis (50.0 µg/mL). Interestingly, biogenic AuNPs did not exhibit cytotoxic effect against the THP-1 cells after 24 h exposure. The findings of this study conclude that phytochemicals-stabilized AuNPs could be a safe and effective source of antimicrobial agents.

Facile and green synthesis of phytochemicals capped platinum nanoparticles and in vitro their superior antibacterial activity.

The increase in the severe infectious diseases and resistance of the majority of the bacterial pathogens to the available drug is a serious problem now a day. In order to overcome this problem it is necessary to develop new therapeutic agents which are non-toxic and more effective to inhibit these microbial pathogens. For this purpose the plant extract of highly active medicinal plant, Taraxacum laevigatum was used for the synthesis of platinum nanoparticles (PtNPs) to enhance its bio-activities. The surface plasmon resonance peak appeared at 283nm clearly represent the formation of PtNPs. The results illustrate that the bio-synthesized PtNPs were uniformly dispersed, small sized (2-7nm) and spherical in shape. The green synthesized PtNPs were characterized by UV-vis spectroscopy, XRD, TEM, SEM, EDX, DLS and FTIR. These nanoparticles were tested against gram positive bacteria (Bacillus subtilis) and gram negative bacteria (Pseudomonas aeruginosa). The bio-synthesized PtNPs were examined to be more effective against both of the bacteria. The results showed, that the zone of inhibition of PtNPs against P. aeruginosa was 15 (±0.5) mm and B. subtilis was 18 (±0.8) mm. The most significant outcome of this examination is that PtNPs exhibited strong antibacterial activity against P. aeruginosa and B. subtilis which have strong defensive system against several antibiotics.

Challenges in the Development of Antifungal Agents Against Candida: Scope of Phytochemical Research.

BACKGROUND: Infections caused by Candida have become a major source of morbidity and mortality. Limited numbers of drugs are available to treat these infections. Phytochemicals can be the major source of antifungal compounds. The aim of this publication was to review the current literature to assess the challenges and scope of phytochemical research in the development of new antifungal drugs. METHODS: Literature describing cellular nature of Candida, the development of drug resistance and target sites for the new drugs were assessed. Publications reporting antifungal activities of crude extracts of plants, their essential oils and identified chemical constituents were also summarised. RESULTS: The results showed that the development of new antifungal agents from natural sources is a complex process due to the cellular nature of Candida and the types of infections caused, such as superficial to life threatening systemic mycosis which necessitate systemic and topical use of drugs. Efficacy of the drugs in the presence of body fluids, normal flora and medical devices can also pose a challenge. Synthetic, semi-synthetic and natural compounds can be screened for their antifungal activities against emerging target sites using new cost effective techniques to increase throughput. Their efficacy, substantivity and site specific desired drug delivery can be enhanced using nanotechnology, hydrogel formulation and bio-adhesive technology. Finally, partnership between academic research laboratories and pharmaceutical industries is also necessary. CONCLUSION: Many challenges are identified in the development of new antifungal drugs, however phytochemicals are still the major source of new antifungal drugs and should be strategically explored.

Phytochemicals as Prototypes for Pharmaceutical Leads Towards Drug Development Against Diabetic Cardiomyopathy.

Globally diabetes mellitus (DM) is swiftly reaching epidemic proportions and impose major health care and socio-economic challenges that are associated with its complications. DM is considered as the major risk factor for the development of debilitating micro & macro vascular complications. Clinical studies have revealed that development of diabetic cardiomyopathy (DCM) in subjects with diabetes can occur both- dependent and independent of pre-existing increased risk factors such as poor glycemic control, hyperlipidemia, and or hypertension. Therefore, DCM represents as a major challenge for the clinical community for the prompt diagnosis and devising the treatment paradigm to combat the diabetes induced cardiac dysfunction. In Chinese traditional medical practice, heart ailments have been coped with herbal extracts. Phytochemicals bioavailability and pharmacokinetic properties are to yet be established completely in human subjects. However, tremendous progress has been made to isolate, purify the phytochemicals and characterize their effects on mitigating the development of DCM in pre-clinical models. Currently there are no approved drugs available for the treatment of DCM. In this review, we have discussed the progress made in understanding the mechanisms for the phytochemicals cardio-protective actions in the diabetic milieu and their caveats and provide future perspectives for proposing these agents to serve as prototypes in the development of drugs for the management of DCM.

Phytochemical meanings of tetrahydro-ß-carboline moiety in strictosidine derivatives.

Synthesis of 13 different tetrahydro-ß-carbolines (THBC) was accomplished by applying the Pictet-Spengler reaction with seven aldehydes, which have been coupled with tryptamine (6) and l-tryptophan methyl ester (7), respectively. The resulting products represent analogues of strictosidine (1) and carboxystrictosidine (5). They were investigated with respect to possible effects on herbivores in feeding bioassays upon the generalist Spodoptera littoralis. Maximum inhibition averages were 42% after four and 46% after six days for the most effective product (19) at 1000ppm. Additionally, the frass of this particular bioassay was investigated via HPLC-UV for THBC digestion. All synthesized THBCs were also tested for their radical scavenger activity by monitoring their interaction with 2,2-diphenyl-1-picrylhydrazyl (DPPH). Compounds 16-20, 24 and 25 exhibited radical scavenging activity, ranging from 50% to 74% compared to that of α-tocopherol. All results were discussed with respect to possible contributions of tetrahydro-ß-carboline moieties in bioactivities of strictosidine (1) and its biodegradation products.

Actividad cicatrizante del cremigel elaborado a base del extracto atomizado de las hojas de Solanum nitidum R.&P. "ñuñunga", Ayacucho - 2014 / Cremigel healing activity based on the atomized extract of the leaves of Solanum nitidum R. & P. "ñuñunga", Ayacucho - 2014

La búsqueda e investigación de plantas medicinales con contenidos químicos y propiedades farmacológicas que contribuyen a la cicatrización, se extraen los metabolitos responsables de dicha acción y pueden ser presentadas en formulaciones magistrales como cremas, geles, jarabes etc. La investigación es básica experimental, Solanum nitidum R. & P. "ñuñunga", fue recolectada en la comunidad de Huaraca, distrito de Vinchos, provincia de Huamanga. El objetivo de la presente investigación fue demostrar la actividad cicatrizante del cremigel elaborado a base del extracto atomizado de Solanum nitidum R. & P. "ñuñunga", su ejecución se realizó en los laboratorios de la Escuela de Formación Profesional de Farmacia y Bioquímica. Para la determinación del efecto cicatrizante se utilizó el método de Montón J. Al extracto atomizado de las hojas Solanum nitidum R. & P. "ñuñunga", se realizo la marcha fitoquimico identificando la presencia de taninos, flavonoides, saponinas, catequinas, alcaloides y quinonas; mientras que sus parámetros fisicoquímicos evaluados fueron: polvo fino color verde, sabor amargo, 7,45% de humedad, 2,24% de cenizas totales, muy solubles en agua, con un rendimiento de 9,6%. El cremigel formulado fue elaborado cumpliendo con las técnicas y procedimientos en formulación magistral dermatológica. Según Fernandez, E. De los controles se obtuvo un cremigel de color crema a marrón claro de aspecto homogéneo, poder de evanescencia y extensibilidad alta, pH entre 6,30 a 7,43, no encontrando contaminación microbiológica. El experimento se realizó con ratas wistar, a los que después de provocarles la herida de un área de 1 cm2 en el lomo del animal se aplico diariamente el cremigel formulado para ayudar a la cicatrización, luego las heridas serán fotografiadas cada dos días bajo una escala medible, estas imágenes fueron pasadas al programa de AutoCAD para su cuantificación. Las ratas fueron divididas en cinco grupos de trabajo: tres ilevaluií l.ui'ltentraciones al1%, 2% y 4% ud I,(Cilli~cl, otro grupo fue tr&táuú CÜII un estándar (Dermaclín plus®) y la última con un blanco que mostro una cicatrización normal, l. Mediante el análisis de varianza se determinó la diferencia significativa que existe entre los grupos de tratamientos (p<0.05) y con la prueba de Duncan se determinó específicamente que pruebas fueron diferentes. Se concluye que el cremigel elaborado al 1%, 2% y 4% tuvo un mejor efecto cicatrizante en comparación al estándar empleado.