Natural Product-derived Compounds Research Articles

Natural products with SGLT2 inhibitory activity: Possibilities of application for the treatment of diabetes.

Diabetes mellitus currently affects as many as 400 million people worldwide, creating a heavy economic burden and stretching health care resources. A dysfunction of glucose homeostasis underlies the disease. Despite advances in the treatment of diabetes, many patients still suffer from complications and side effects; hence, development of more effective treatments for diabetes is still desirable. SGLT2 is the principle cotransporter involved in glucose reabsorption in the kidney. SGLT2 inhibition reduces glucose reabsorption by the kidney and ameliorates plasma glucose concentration. The interest in natural products that can be used for the inhibition of SGLT2 is growing. The flavonoid phlorizin, which can be isolated from the bark of apple trees, has been used as lead structure due to its inhibitory activity of SGLT1 and SGLT2. Some phlorizin-derived synthetic compounds, including canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and ertugliflozin, are approved by the food and drug administration to treat type 2 diabetes mellitus (T2DM), whereas others are under clinical trials investigation. In addition, other natural product-derived compounds have been investigated for their ability to improve blood glucose control. The present review summarizes the natural products with SGLT2 inhibitory activity, and the synthetic compounds obtained from them, and discusses their application for the treatment of diabetes.

A novel potent autophagy inhibitor ECDD-S27 targets vacuolar ATPase and inhibits cancer cell survival

Autophagy is a conserved lysosomal-dependent cellular degradation process and its dysregulation has been linked to numerous diseases including neurodegeneration, infectious diseases, and cancer. Modulation of autophagy is therefore considered as an attractive target for disease intervention. We carried out a high-content image analysis screen of natural product-derived compounds to discover novel autophagy modulating molecules. Our screen identified ECDD-S27 as the most effective compound for increasing the number of autophagic vacuoles inside cells. The structure of ECDD-S27 revealed that it is a derivative of cleistanthin A, a natural arylnaphthalene lignan glycoside found in plants. ECDD-S27 increases the number of autophagic vacuoles by inhibiting the autophagic flux and is able to restrict the survival of different cancer cells at low nanomolar concentrations. Molecular docking and SERS analysis showed that ECDD-S27 may potentially target the V-ATPase. Upon treatment of various cancer cells with ECDD-S27, the V-ATPase activity is potently inhibited thereby resulting in the loss of lysosomal acidification. Taken together, these data indicated that ECDD-S27 retards the autophagy pathway by targeting the V-ATPase and inhibits cancer cell survival. The observed antitumor activity without cytotoxicity to normal cells suggests the therapeutic potential warranting further studies on lead optimization of the compound for cancer treatment.

Exogenous interference detection in urine proteinograms

Recently, much attention has been paid to natural product-derived compounds for antidiabetic drug discovery. More recent studies are being focused on clarifying the bioactivity of plants and derived products. The aim of the present study was to investigate the anti-oxidant and antidiabetic activities of Clerodendrum inerme leaf extract (CILE) in streptozotocin-induced diabetic mice.C. inerme leaves were analyzed for preliminary phytochemical properties and the content of total phenolic and flavonoid were determined. In vitro anti-oxidant activity was measured using DPPH assay. Streptozotocin-induced diabetic model in mice was applied for in vivo study by the effect of CILE at two dose levels (343 and 686 mg/kg b.w.).The results showed that C. inerme leaves contained the major constituents of flavonoids, alkaloids, tannins, triterpenes, and saponins. CILE exhibited the total polyphenol and flavonoid content with 120.458 mg gallic acid equivalent/g dry weight and 4.494 mg hispidulin equivalent/g dry weight, respectively. The anti-oxidant activity of CILE was expressed with IC50 = 25.28 µg/mL. CILE at the doses of 343 mg/kg and 686 mg/kg after 7 d administration exerted a decrease in plasma glucose, protected the liver, kidneys against oxidation stress via increasing glutathione content in the liver, and reduced malondialdehyde content in the liver and kidneys. Pancreatic histological analysis in diabetic mice treated with CILE also showed the pancreatic β-cells regeneration via increasing the size and number of pancreatic islets.These findings suggested that C. inerme leaves had potent antidiabetic and anti-oxidant activities. The results provide reliable scientific base, which is the premise for further research and development of CILE as supplements.

High-throughput screening campaigns against a PI3Kα isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds.

The phosphatidylinositol 3-kinase (PI3K) pathway is involved in many cellular functions including cell growth, metabolism, and transformation. Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3Kα isoform is implicated mostly in cancer, we conducted a high-throughputscreening (HTS) campaign using a 3-step PI3K homogenous time-resolved fluorescence assay against this isoform bearing the H1047R mutation. A total of 288,000 synthetic and natural product-derived compounds were screened and of which, we identified 124 initial hits that were further selected by considering the predicted binding mode, relationship to known pan-assay interference compounds and previous descriptions as a lipid kinase inhibitor. A total of 24 compounds were then tested for concentration-dependent responses. These hit compounds provide novel scaffolds that can potentially be optimized to create novel PI3K inhibitors.

In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa.

Buruli ulcer (BU) is caused by Mycobacterium ulcerans and is predominant in both tropical and subtropical regions. The neglected debilitating disease is characterized by chronic necrotizing skin lesions attributed to a mycolactone, which is a macrolide toxin secreted by M. ulcerans. The preferred treatment is surgical excision of the lesions followed by a prolonged combination antibiotic therapy using existing drugs such as rifampicin and streptomycin or clarithromycin. These antibiotics appear not to be adequately potent and efficacious against persistent and late stage ulcers. In addition, emerging drug resistance to treatment poses great challenges. There is a need to identify novel natural product-derived lead compounds, which are potent and efficacious for the treatment of Buruli ulcer. Natural products present a rich diversity of chemical compounds with proven activity against various infectious diseases, and therefore, are considered in this study. This study sought to computationally predict natural product-derived lead compounds with the potential to be developed further into potent drugs with better therapeutic efficacy than the existing anti-buruli ulcer compounds. The three-dimensional (3D) structure of Isocitrate lyase (ICL) of Mycobacterium ulcerans was generated using homology modeling and was further scrutinized with molecular dynamics simulations. A library consisting of 885 compounds retrieved from the AfroDb database was virtually screened against the validated ICL model using AutoDock Vina. AfroDb is a compendium of “drug-like” and structurally diverse 3D structures of natural products originating from different geographical regions in Africa. The molecular docking with the ICL model was validated by computing a Receiver Operating Characteristic (ROC) curve with a reasonably good Area Under the Curve (AUC) value of 0.89375. Twenty hit compounds, which docked firmly within the active site pocket of the ICL receptor, were assessed via in silico bioactivity and pharmacological profiling. The three compounds, which emerged as potential novel leads, comprise ZINC38143792 (Euscaphic acid), ZINC95485880, and ZINC95486305 with reasonable binding energies (high affinity) of −8.6, −8.6, and −8.8 kcal/mol, respectively. Euscaphic acid has been reported to show minimal inhibition against a drug-sensitive strain of M. tuberculosis. The other two leads were both predicted to possess dermatological activity while one was antibacterial. The leads have shown promising results pertaining to efficacy, toxicity, pharmacokinetic, and safety. These leads can be experimentally characterized to assess their anti-mycobacterial activity and their scaffolds may serve as rich skeletons for developing anti-buruli ulcer drugs.

Molecular Mechanisms of Breast Cancer Metastasis and Potential Anti-metastatic Compounds.

Throughout the world, breast cancer is among the major causes of cancer-related death and is the most common cancer found in women. The development of cancer molecular knowledge has surpassed the novel concept of cancer biology and unraveled principle targets for anticancer drug developments and treatment strategies. Metastatic breast cancer cells acquire their aggressive features through several mechanisms, including augmentation of survival, proliferation, tumorigenicity, and motility-related cellular pathways. Clearly, natural product-derived compounds have since long been recognized as an important source for anticancer drugs, several of which have been shown to have promising anti-metastasis activities by suppressing key molecular features supporting such cell aggressiveness. This review provides the essential details of breast cancer, the molecular-based insights into metastasis, as well as the effects and mechanisms of potential compounds for breast cancer therapeutic approaches. As the abilities of cancer cells to invade and metastasize are addressed as the hallmarks of cancer, compounds possessing anti-metastatic effects, together with their defined molecular drug action could benefit the development of new drugs as well as treatment strategies.

The Role of Saikosaponins in Therapeutic Strategies for Age-Related Diseases.

As life expectancy increases, elderly populations tend to spend an increasing number of years in poor health, with chronic age-related diseases and disability. Therefore, the development of therapeutic strategies to treat or prevent multiple pathophysiological conditions in the elderly may improve health-adjusted life expectancy and alleviate the potential economic and social burdens arising from age-related diseases. Bioactive natural products might represent promising new drug candidates for the treatment of many chronic age-related diseases, including cancer, Alzheimer's disease, cardiovascular disease, obesity, and liver disease. Here, we discuss a therapeutic option using saikosaponins, which are triterpene saponins isolated from Bupleurum, against a variety of age-related diseases. Understanding the underlying mechanisms of natural products like saikosaponins in the treatment of age-related diseases may help in the development of diverse natural product-derived compounds that may be effective against a number of chronic health problems.

Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR) and display trypanocidal activity

Crassiflorone is a natural product with anti-mycobacterial and anti-gonorrhoeal properties, isolated from the stem bark of the African ebony tree Diospyros crassiflora. We noticed that its pentacyclic core possesses structural resemblance to the quinone-coumarin hybrid 3, which we reported to exhibit a dual-targeted inhibitory profile towards Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR). Following this basic idea, we synthesized a small library of crassiflorone derivatives 15-23 and investigated their potential as anti-trypanosomatid agents. 19 is the only compound of the series showing a balanced dual profile at 10 μM (% inhibitionTbGAPDH = 64% and % inhibitionTcTR = 65%).In phenotypic assay, the most active compounds were 18 and 21, which at 5 μM inhibited Tb bloodstream-form growth by 29% and 38%, respectively. Notably, all the newly synthesized compounds at 10 μM did not affect viability and the status of mitochondria in human A549 and 786-O cell lines, respectively. However, further optimization that addresses metabolic liabilities including solubility, as well as cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, and CYP2D6) inhibition, is required before this class of natural product-derived compounds can be further progressed.

Review of Natural Product-Derived Compounds as Potent Antiglioblastoma Drugs.

Common care for glioblastoma multiforme (GBM) is a surgical resection followed by radiotherapy and temozolomide- (TMZ-) based chemotherapy. Unfortunately, these therapies remain inadequate involving severe mortality and recurrence. Recently, new approaches discovering combinations of multiple inhibitors have been proposed along with the identification of key driver mutations that are specific to each patient. To date, this approach is still limited by the lack of effective therapy. Hopefully, novel compounds derived from natural products are suggested as potential solutions. Inhibitory effects of natural products on angiogenesis and metastasis and cancer suppressive effect of altering miRNA expression are provident discoveries. Angelica sinensis accelerates apoptosis by their key substances influencing factors of apoptosis pathways. Brazilin displays antitumor features by making influence on reactive oxygen species (ROS) intensity. Sargassum serratifolium, flavonoids, and so on have antimetastasis effect. Ficus carica controls miRNA that inhibits translation of certain secretory pathway proteins during the UPR. Serratia marcescens and patupilone (EPO 906) are physically assessed materials through clinical trials related to GBM progression. Consequently, our review puts emphasis on the potential of natural products in GBM treatment by regulating multiple malignant cancer-related pathway solving pending problem such as reducing toxicity and side effect.

Potential Anti-metastasis Natural Compounds for Lung Cancer.

As lung cancer is the most common malignancy worldwide and high mortalities are the result of metastasis, novel information surpassing the treatment strategies and therapeutic agents focusing on cancer dissemination are of interest. Lung cancer metastasis involves increased motility, survival in circulation and ability to form new tumors. Metastatic cells increase their aggressive features by utilizing several mechanisms to overcome hindrances of metastasis, including epithelial to mesenchymal transition (EMT), increased in cellular survival and migratory signals. Sufficient amounts of natural product-derived compounds have been shown to have promising anti-metastasis activities by suppressing key molecular features upholding such cell aggressiveness. The knowledge regarding molecular mechanisms rendering cell dissemination together with the anti-metastasis information of natural product-derived compounds may lead to development of novel therapeutic strategies.

Corrigendum: Natural product-derived quaternary ammonium compounds with potent antimicrobial activity.

Correction to: The Journal of Antibiotics (2016) 69, 344–347; doi:10.1038/ja.2015.107; published online 18 November 2015 The authors of the above article noted an error in publication of this paper in Figures 1 and 2, whereby the wrong bond was used to show the configuration of C9 in (-)-quinine andderivatives thereof.

Natural Product-Derived Spirooxindole Fragments Serve as Privileged Substructures for Discovery of New Anticancer Agents.

The utility of natural products for identifying anticancer agents has been highly pursued in the last decades and over 100 drug molecules in clinic are natural products or natural product-derived compounds. Natural products are believed to be able to cover unexplored chemical space that is normally not occupied by commercially available molecule libraries. However, the low abundance and synthetic intractability of natural products have limited their applications in drug discovery. Recently, the identification of biologically relevant fragments derived from biologically validated natural products has been recognized as a powerful strategy in searching new biological probes and drugs. The spirocyclic oxindoles, as privileged structural scaffolds, have shown their potential in designing new drugs. Several anticancer drug candidates such as SAR405838, RO8994, CFI-400945 and their bioisosteres are undergoing clinical trials or preclinical studies. To highlight the significant progress, we focus on illustrating the discovery of SAR405838, RO8994, CFI-400945 and their bioisosteres for cancer therapy using substructure-based strategies and discussing modes of action, binding models and preclinical data.

Invitro and invivo anti-Vibrio vulnificus activity of psammaplin A, a natural marine compound.

Vibrio vulnificus is known to induce severely fulminant and fatal septicemia in susceptible hosts. In the present study, the antimicrobial activity of natural marine product-derived compounds against V. vulnificus, were investigated invitro and invivo. Twelve pure compounds were isolated from natural marine products and their inhibitory effects on V.vulnificus-induced cytotoxicity were determined in INT‑407 cells. Among the 12 pure compounds tested, treatment with psammaplinA significantly suppressed V.vulnificus‑induced cytotoxicity in INT‑407 cells. Notably, treatment with psammaplinA (5-50µg) had improved survival rates compared with that in the untreated mice, when the mice were infected with V. vulnificus intraperitoneally. In addition, the bacterial load of V.vulnificus in several tissues (spleen, liver and small intestine) was significantly lower in psammaplinA‑treated mice than in untreated mice. Furthermore, psammaplinA treatment significantly suppressed the growth of V. vulnificus. Taken together, these results indicate that psammaplin A may be a potential agent for the prevention and treatment of V.vulnificus infections.

Small-molecule inhibitors of the tuberculosis target, phenylalanyl-tRNA synthetase from Penicillium griseofulvum CPCC-400528

AbstractPhenylalanyl-tRNA synthetase (PheRS), a member of aminoacyl-tRNA synthetase family, was the new target of anti-tubercular drug discovery. In an attempt to fully exploit the new potential anti-tuberculosis drugs presented in micro-organisms, we developed a high-throughput screening assay against Mycobacterium tuberculosis (Mtb) PheRS and then screened a library consisting of 32,000 strains and 1500 natural product-derived compounds. One potent hit extract of Penicillium griseofulvum CPCC-400528 was identified. In this study, isopatulin (1), (+)-epiepoformin (2) and gentisyl alcohol (3), three patulin-producing intermediates, together with three indole-tetramic acids, α-cyclopiazonic acid (4), β-cyclopiazonic acid (5) and iso-α-cyclopiazonic acid (6), were isolated and identified as bioactive constituents from P. griseofulvum CPCC-400528. Their structures were elucidated on the basis of spectroscopic data. Compounds 1, 3, 4, and 5 exhibited Mtb PheRS-inhibiting activities, as well as moderate to wea...

Natural Product-Based Antibiotics: Synthesis and SAR-Studies.

Efficient control of the infectious diseases in the era of the emerging bacterial resistance demands consistent development of new antibiotic agents with novel modes of action. With some notable exceptions, the majority of the currently used antibiotics are natural product-derived compounds which were elaborated upon lead structures discovered by screening of various isolates. In this review, we summarized some selected examples of recent advances in the area of natural product based antibiotic development with particular emphasis on the synthetic and SAR-elucidation aspects.

Natural product-derived quaternary ammonium compounds with potent antimicrobial activity.

Natural product-derived quaternary ammonium compounds with potent antimicrobial activity.

Oxyesterol-binding protein family (OSBP/ORP) ligand binding and natural product drug development

A structurally-diverse class of potent anti-cancer natural product compounds – cephalostatin 1, OSW-1, ritterazine B and schweinfurthin A -exert their anti-proliferative activity through binding to members of the oxysterol-binding protein (OSBP) and OSBP-related protein (ORP) family. Based on their shared OSBP/ORP cellular targets, these natural products are referred to as the ORPphilins. The ORPphilin compounds have been shown to bind with high affinity (Ki values = 20 – 70 nM) to two members of the OSBP/ORP family; namely OSBP and ORP4. This shared tight binding is remarkable due to the structurally-diversity of the ORPphilin natural product class of molecules, and the fact these compounds were isolated from very different biological sources. The cellular function(s) of the OSBP/ORPs are yet to be fully determined, but some of the family members apparently serve as sterol sensors and/or sterol transporting proteins. There are twelve different OSBP/ORPs in humans that show very different tissue distribution patterns. The expression levels and function of many different OSBP/ORPs have been implicated in in many disease-states, including different cancers, diabetes and cardiovascular disease. Despite their connections to disease, the OSBP/ORPs remain understudied with respect to their ligand binding and resulting biological function. The OSBP/ORP have been shown to experimentally bind oxysterols and phospholipids, but the physiological ligands for the OSBP/ORP members have not been identified. We have launched a systematic study of class-wide OSBP/ORP ligand binding, which includes understanding the binding interactions of the OSBP/ORPs with the ORPphilin natural products. Our 96-well OSBP/ORP ligand binding assay allows screening of many ligands against the complete panel of OSBP/ORP proteins, and the screen will incorporate a diverse set of oxysterols, phospholipids and ORPphilin-derived compounds. Through these comprehensive binding assays and subsequent biochemical studies, we will identify putative physiological ligands for individual OSBP/ORP family members. We will also begin to develop natural product-derived anti-cancer compounds, based on the ORPphilin compound OSW-1, that selectively target the anti-cancer target protein ORP4 over the other members of the OSBP/ORPs family.

Natural products with antischistosomal activity.

In recent years, natural product groups have been gaining prominence as possible sources of new drugs for schistosomiasis. This review attempts to update the antischistosomal natural compounds, or natural product-derived compounds, from the mid-1980s. Some of the main metabolites obtained from plants (e.g., terpenes, alkaloids, phenolic compounds and peptides) with in vitro and/or in vivo antischistosomal properties are discussed. Less thoroughly, due to scarcity of data in the literature, molecules from animals (e.g., peptides) are also described. Special mention of the anthelmintic activity against different parasitic stages of schistosomes is made; the mechanism of action of most of the metabolites is discussed, and a number of bioassay procedures are listed.

Perspectives in Metabolic Engineering: Understanding Cellular Regulation Towards the Control of Metabolic Routes

Metabolic engineering seeks to redirect metabolic pathways through the modification of specific biochemical reactions or the introduction of new ones with the use of recombinant technology. Many of the chemicals synthesized via introduction of product-specific enzymes or the reconstruction of entire metabolic pathways into engineered hosts that can sustain production and can synthesize high yields of the desired product as yields of natural product-derived compounds are frequently low, and chemical processes can be both energy and material expensive; current endeavors have focused on using biologically derived processes as alternatives to chemical synthesis. Such economically favorable manufacturing processes pursue goals related to sustainable development and "green chemistry". Metabolic engineering is a multidisciplinary approach, involving chemical engineering, molecular biology, biochemistry, and analytical chemistry. Recent advances in molecular biology, genome-scale models, theoretical understanding, and kinetic modeling has increased interest in using metabolic engineering to redirect metabolic fluxes for industrial and therapeutic purposes. The use of metabolic engineering has increased the productivity of industrially pertinent small molecules, alcohol-based biofuels, and biodiesel. Here, we highlight developments in the practical and theoretical strategies and technologies available for the metabolic engineering of simple systems and address current limitations.

Anticancer compounds from plants.

Cancer is a leading cause of death all over the world and represents a major public health burden. Natural plant products have been historically used for the treatment of various diseases. The earnest search for plant-derived anticancer agents began in the 1950s with the discovery and development of the vinca alkaloids–vinblastine and vincristine, and with the isolation of the cytotoxic podophyllotoxins (Cragg and Newman, 2005). A good number of the current– day commercially approved anticancer drugs as well as the natural product-derived compounds in various stages of clinical development as anticancer agents originate from plants. Natural products still serve as an excellent source for the discovery and development of modern drugs for cancer treatment. The present work reviews the most recent information in the field of natural anticancer substances, and in this regard we have summarized the key information published in 2012 on plant derived anticancer compounds (Table 1).