Development and characterization of edible and active coating based on xanthan gum nanoemulsion incorporating betel leaf extract for fresh produce preservation.

Developing an edible and active coating, incorporating environmentally-friendly antimicrobial agents into edible polymers, provides an eco-friendly alternative to conventional packaging and exhibits significant potential in preserving the quality of postharvest food. Herein, we aim to develop a novel edible and active coating based on xanthan gum (XG) nanoemulsion (NE) incorporating betel leaf extract (BLE) for the preservation of fresh produce. The total phenolic content, total flavonoid content, and antioxidant capacity of the methanol extract of BLE at various concentrations were characterized. Further development of the active coating at different formulations of Tween 80 (1 % and 3 % w/v), XG (0.1 % to 0.5 % w/v), and BLE (1 % to 5 % w/v) was characterized by physical stability, viscosity, and antimicrobial properties. Results showed that the active coating at 1 % BLE showed significant antimicrobial properties against diverse bacterial and fungal foodborne pathogens (e.g., B. cereus, S. aureus) and fungal cultures (e.g., C. albicans). The study also examined the shelf-life of tomatoes coated with the BLE-XG NE solution, stored at 4 °C for 27 days. Analyses of weight retention, soluble solids, pH, texture, sensory attributes, and microbial populations showed that the coating effectively preserved tomato quality, highlighting its potential to preserve fresh produce and enhance food security.

Unveiling the Potential of Marine Biopolymers: Sources, Classification, and Diverse Food Applications.

Environmental concerns regarding the usage of nonrenewable materials are driving up the demand for biodegradable marine biopolymers. Marine biopolymers are gaining increasing attention as sustainable alternatives in various industries, including the food sector. This review article aims to provide a comprehensive overview of marine biopolymers and their applications in the food industry. Marine sources are given attention as innovative resources for the production of sea-originated biopolymers, such as agar, alginate, chitin/chitosan, and carrageenan, which are safe, biodegradable, and are widely employed in a broad spectrum of industrial uses. This article begins by discussing the diverse source materials of marine biopolymers, which encompass biopolymers derived from seaweed and marine animals. It explores the unique characteristics and properties of these biopolymers, highlighting their potential for food applications. Furthermore, this review presents a classification of marine biopolymers, categorizing them based on their chemical composition and structural properties. This classification provides a framework for understanding the versatility and functionality of different marine biopolymers in food systems. This article also delves into the various food applications of marine biopolymers across different sectors, including meat, milk products, fruits, and vegetables. Thus, the motive of this review article is to offer a brief outline of (a) the source materials of marine biopolymers, which incorporates marine biopolymers derived from seaweed and marine animals, (b) a marine biopolymer classification, and (c) the various food applications in different food systems such as meat, milk products, fruits, and vegetables.

Value Addition Employing Waste Bio-Materials in Environmental Remedies and Food Sector.

Overall, combating food waste necessitates a multifaceted approach that includes education, infrastructure, and policy change. By working together to implement these strategies, we can help reduce the negative impacts of food waste and create a more sustainable and equitable food system. The sustained supply of nutrient-rich agrifood commodities is seriously threatened by inefficiencies caused by agricultural losses, which must be addressed. As per the statistical data given by the Food and Agriculture Organisation (FAO) of the United Nations, nearly 33.33% of the food that is produced for utilization is wasted and frittered away on a global level, which can be estimated as a loss of 1.3 billion metric tons per annum, which includes 30% cereals, 20% dairy products 35% seafood and fish, 45% fruits and vegetables, and 20% of meat. This review summarizes the various types of waste originating from various segments of the food industry, such as fruits and vegetables, dairy, marine, and brewery, also focusing on their potential for developing commercially available value-added products such as bioplastics, bio-fertilizers, food additives, antioxidants, antibiotics, biochar, organic acids, and enzymes. The paramount highlights include food waste valorization, which is a sustainable yet profitable alternative to waste management, and harnessing Machine Learning and Artificial Intelligence technology to minimize food waste. Detail of sustainability and feasibility of food waste-derived metabolic chemical compounds, along with the market outlook and recycling of food wastes, have been elucidated in this review.

Recent advances in the preservation of postharvest fruits using edible films and coatings: A comprehensive review.

In recent years, there has been considerable growth in the creation of edible films and coatings, which is predicted to have a major impact on fruit quality in the coming years. Consumers want fresh fruits that are pesticide-free, good quality, high nutritional value, and a long shelf life. The use of edible coatings and films on fruits is an environmentally dependable approach to a creative solution to this problem. The application, recent trends, and views of coatings and edible films, as well as their impact on fruit quality, are presented in this article, along with a knowledge of their key roles and benefits. According to numerous studies, natural polymers are highly suited for use as packaging material for fresh fruits and can often be a viable alternative to synthetic chemicals. Plasticisers, surfactants, cross-linkers, antimicrobial agents, functional additives, nanoparticles, and fruit and vegetable residues can be used to alter the properties of edible coatings.

Structural Modifications and Strategies for Native Starch for Applications in Advanced Drug Delivery.

Pharmaceutical excipients are compounds or substances other than API which are added to a dosage form, these excipients basically act as carriers, binders, bulk forming agents, colorants, and flavouring agents, and few excipients are even used to enhance the activity of active pharmaceutical ingredient (API) and various more properties. However, despite of these properties, there are problems with the synthetic excipients such as the possibility of causing toxicity, inflammation, autoimmune responses, lack of intrinsic bioactivity and biocompatibility, expensive procedures for synthesis, and water solubility. However, starch as an excipient can overcome all these problems in one go. It is inexpensive, there is no toxicity or immune response, and it is biocompatible in nature. It is very less used as an excipient because of its high digestibility and swelling index, high glycemic index, paste clarity, film-forming property, crystalline properties, etc. All these properties of starch can be altered by a few modification processes such as physical modification, genetic modification, and chemical modification, which can be used to reduce its digestibility and glycemic index of starch, improve its film-forming properties, and increase its paste clarity. Changes in some of the molecular bonds which improve its properties such as binding, crystalline structure, and retrogradation make starch perfect to be used as a pharmaceutical excipient. This research work provides the structural modifications of native starch which can be applicable in advanced drug delivery. The major contributions of the paper are advances in the modification of native starch molecules such as physically, chemically, enzymatically, and genetically traditional crop modification to yield a novel molecule with significant potential for use in the pharmaceutical industry for targeted drug delivery systems.

Carica papaya L. Leaves: Deciphering Its Antioxidant Bioactives, Biological Activities, Innovative Products, and Safety Aspects.

The prevalence of viral infections, cancer, and diabetes is increasing at an alarming rate around the world, and these diseases are now considered to be the most serious risks to human well-being in the modern period. There is a widespread practice in Asian countries of using papaya leaves (C. papaya L.) as herbal medicine, either alone or in combination with prescribed medications, to treat a variety of ailments. The importance of conducting the necessary descriptive studies in order to determine the safety of papaya leaf consumption is also emphasized in the context of their application in the healthcare sector. Electronic databases such as Google Scholar, Scopus, and PubMed were used to gather information on papaya leaves, their therapeutic potential, and clinical evidence-based studies. The literature was gathered from publications on papaya leaves, their therapeutic potential, and clinical evidence-based studies. The antidengue, anticancer, antidiabetic, neuroprotective, and anti-inflammatory effects of papaya leaves discussed in this article are supported by evidence from preclinical, in vivo, in vitro, and clinical trial studies, as well as from other sources. Leaves have been investigated for their mechanism of action as well as their potential to be used in the development of novel herbal products for the health business. According to the reports gathered, only a small number of research demonstrated that leaf extract at high concentrations was hazardous to certain organs. The collective literature reviewed in this review provides insights into the use of papaya leaves as a cure for epidemic diseases, highlighting the phytochemical composition and pharmacological attributes of papaya leaves, as well as the results of various preclinical and clinical studies that have been conducted so far on the subject. The review clearly demonstrates the successful medical evidence for the use of papaya leaf extracts in the healthcare system as a supplemental herbal medication in a variety of clinical settings.

Barley-based probiotic food mixture: health effects and future prospects.

Consumers around the globe are increasingly aware of the relation between nutrition and health. In this sense, food products that can improve gastrointestinal health such as probiotics, prebiotics and synbiotics are the most important segment within functional foods. Cereals are the potential substrates for probiotic products as they contain nutrients easily assimilated by probiotics and serve as the transporters of Lactobacilli through the severe conditions of gastrointestinal tract. Barley is one of the important substrates for the probiotic formulation because of its high phenolic compounds, ß-glucans and tocols. The purpose of this review is to examine recent information regarding barley-based probiotic foods with a specific focus on the potential benefits of barley as a substrate for probiotic microorganisms in the development of dairy and nondairy based food products, and to study the effects of food matrices containing barley ß-glucans on the growth and features of Lactobacillus strains after fermentation.

Formulation, Characterization, and In Vitro Mineral Absorption of Ficus Palmata Fruit Extract Nanoemulsion.

OBJECTIVE: Loss of vital bioactive components of Ficus palmata fruit extract during food processing is a major issue. Therefore, to retain the antioxidant potential and to increase the mineral bioavailability, gum arabic stabilized nanoemulsion of Fig fruit extract was prepared. METHOD: . Nanoemulsion was formulated using three different levels (1, 3, and 5%) of fig extract, however, to optimize the fig extract concentration, the amount of gum arabic and linoleic acid was kept constant. RESULTS: The average droplet size of nanoemulsion was observed in the range of 22.88-37.87 nm, whereas the Fourier Transform Infrared (FTIR) Spectroscopy confirmed the presence of functional groups in the emulsion system. Also, increased ionic concentration significantly (p < 0.05) increased the average droplet size and zeta potential of nanoemulsion during storage. Increased shear rate and temperature unveiled a slight decrease in apparent viscosity of the nanoemulsion. Non-significant (p < 0.05) difference in TBA value confirmed the oxidative stability of the emulsion. Significantly (p < 0.05) higher mineral bioavailability for calcium was observed as compared to iron and zinc. CONCLUSION: Our results manifested improved anti-oxidant activity, mineral bioavailability, and oxidative stability of Fig extract nanoemulsion, suggesting its potential use as a therapeutic alternative.

Phytochemistry, Pharmacology, and Nutraceutical Profile of Carissa Species: An Updated Review.

Carissa, a genus of the Apocynaceae family, consists of evergreen species, such as shrubs as well as small trees that are native to Asia, Africa, and Oceania's subtropical and tropical regions. Most of the Carissa species are traditionally used to treat various diseases, such as chest pain, headaches, gonorrhoea, rheumatism, syphilis, oedema, rabies, stomach pain, hepatitis, cardiac diseases, and asthma. The pharmacological studies on Carissa species revealed its antioxidant, antimicrobial, anticancer, cardioprotective, antipyretic, analgesic, wound healing, anticonvulsant, antiarthritic, adaptogenic, anti-inflammatory, and antidiabetic activities, thus validating its use in indigenous medicine systems. The review article summarised the comprehensive literature available, including morphology, indigenous uses, bioactive composition, nutraceutical, and pharmacological activities of Carissa species. A total of 155 research papers were cited in this review article. The Carissa fruits are rich in dietary fibre, lipids, proteins, carbohydrates, vitamin C, and macro- and micro-elements. A total of 121 compounds (35 polyphenols (flavonoids and phenolic acids), 30 lignans, 41 terpenoids, 7 steroids, 2 coumarins, and 6 cardiac glycosides) have been extracted from C. spinarum, C. carandas, and C. macrocarpa. Among all chemical constituents, lupeol, carissol, naringin, carisssone, scopoletin, carissaeduloside A, D, J, carandinol, sarhamnoloside, carissanol, olivil, carinol, 3ß-hydroxyolean-11-en-28,13ß-oilde, ursolic acid, and carissone are the key bioactive constituents responsible for pharmacological activities of genus Carissa. The gathered ethnopharmacological information in the review will help to understand the therapeutic relevance of Carissa as well as paving a way for further exploration in the discovery of novel plant-based drugs.

Effect of Alginate-Microencapsulated Hydrogels on the Survival of Lactobacillus rhamnosus under Simulated Gastrointestinal Conditions.

Thanks to the beneficial properties of probiotic bacteria, there exists an immense demand for their consumption in probiotic foods worldwide. Nevertheless, it is difficult to retain a high number of viable cells in probiotic food products during their storage and gastrointestinal transit. Microencapsulation of probiotic bacteria is an effective way of enhancing probiotic viability by limiting cell exposure to extreme conditions via the gastrointestinal tract before releasing them into the colon. This research aims to develop a new coating material system of microencapsulation to protect probiotic cells from adverse environmental conditions and improve their recovery rates. Hence, Lactobacillus rhamnosus was encapsulated with emulsion/internal gelation techniques in a calcium chloride solution. Alginate-probiotic microbeads were coated with xanthan gum, gum acacia, sodium caseinate, chitosan, starch, and carrageenan to produce various types of microcapsules. The alginate+xanthan microcapsules exhibited the highest encapsulation efficiency (95.13 ± 0.44%); they were simulated in gastric and intestinal juices at pH 3 during 1, 2, and 3 h incubations at 37 °C. The research findings showed a remarkable improvement in the survival rate of microencapsulated probiotics under simulated gastric conditions of up to 83.6 ± 0.89%. The morphology, size, and shape of the microcapsules were analyzed using a scanning electron microscope. For the protection of probiotic bacteria under simulated intestinal conditions; alginate microbeads coated with xanthan gum played an important role, and exhibited a survival rate of 87.3 ± 0.79%, which was around 38% higher than that of the free cells (49.4 ± 06%). Our research findings indicated that alginate+xanthan gum microcapsules have a significant potential to deliver large numbers of probiotic cells to the intestines, where cells can be released and colonized for the consumer's benefit.

The Wonderful Activities of the Genus Mentha: Not Only Antioxidant Properties.

Medicinal plants and their derived compounds have drawn the attention of researchers due to their considerable impact on human health. Among medicinal plants, mint (Mentha species) exhibits multiple health beneficial properties, such as prevention from cancer development and anti-obesity, antimicrobial, anti-inflammatory, anti-diabetic, and cardioprotective effects, as a result of its antioxidant potential, combined with low toxicity and high efficacy. Mentha species are widely used in savory dishes, food, beverages, and confectionary products. Phytochemicals derived from mint also showed anticancer activity against different types of human cancers such as cervix, lung, breast and many others. Mint essential oils show a great cytotoxicity potential, by modulating MAPK and PI3k/Akt pathways; they also induce apoptosis, suppress invasion and migration potential of cancer cells lines along with cell cycle arrest, upregulation of Bax and p53 genes, modulation of TNF, IL-6, IFN-γ, IL-8, and induction of senescence phenotype. Essential oils from mint have also been found to exert antibacterial activities against Bacillus subtilis, Streptococcus aureus, Pseudomonas aeruginosa, and many others. The current review highlights the antimicrobial role of mint-derived compounds and essential oils with a special emphasis on anticancer activities, clinical data and adverse effects displayed by such versatile plants.

ANT2681: SAR Studies Leading to the Identification of a Metallo-ß-lactamase Inhibitor with Potential for Clinical Use in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae.

The clinical effectiveness of the important ß-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-ß-lactamase (MBL) enzymes. To address this resistance issue, multiple ß-lactam/ß-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development.

Fruit and Vegetable Peels: Utilization of High Value Horticultural Waste in Novel Industrial Applications.

Fruits and vegetables are the highly used food products amongst the horticultural crops. These items are consumed uncooked, nominally cooked or fully cooked, according to their nature and cooking process. With the change in diet habits and rising population, the production, as well as the processing of horticultural crops, has exponentially improved to meet its increasing demand. A large amount of peel waste is generated from fruit and vegetable-based industries and household kitchen and has led to a big nutritional and economic loss and environmental problems. Processing of fruits and vegetables alone generates a significant waste, which amounts to 25-30% of the total product. Most common wastes include pomace, peels, rind and seeds, which are highly rich in valuable bioactive compounds such as carotenoids, enzymes, polyphenols, oils, vitamins and many other compounds. These bioactive compounds show their application in various industries such as food to develop edible films, food industries for probiotics and other industries for valuable products. The utilization of these low-cost waste horticultural wastes for producing the value-added product is a novel step in its sustainable utilization. The present review intends to summarize the different types of waste originating from fruits as well as vegetables peels and highlight their potential in developing edible films, probiotics, nanoparticles, carbon dots, microbial media, biochar and biosorbents.

Review on essential oils, chemical composition, extraction, and utilization of some conifers in Northwestern Himalayas.

Essential oils (EOs) are regarded as alternative therapeutic agents for many diseases. In phytotherapy research areas, it is now well reported that conifers are the rich source of EOs. This review aims to update information on the biological sources and the best extraction processes of the significant constituents along with the traditional and therapeutic properties of the EOs from selected conifers of Himachal Pradesh, Northwestern Himalaya. In the present review, ten conifer species of high values have been selected. Results from several studies suggest that the conifers contain monoterpenes, sesquiterpenes, diterpenes, ketones, alcohols, and esters, which are used in medicines, food products, and cosmetics as well as other commercial and industrial products. Traditionally, the EOs from the conifers have been reported to be used against fever, cough, bronchitis, skin diseases, gastrointestinal disorders, and asthma. The pharmacological studies suggest that these EOs can be used as antirheumatic, antiseptic, antispasmodic, anticancer, anti-inflammatory, antitoxic, aphrodisiac, and astringent agents. It is, therefore, concluded that the EOs from the conifers might be one of the promising tools for the treatment of various diseases. Extensive research is required to ascertain the efficacy of the EOs from unstudied conifers.

The Disappearing Director: The Case of Directed N-Arylation via a Removable Hydroxyl Group.

A facile and broadly applicable method for the regiospecific N-arylation of benzotriazoles is reported. Copper-mediated reactions of diverse 1-hydroxy-1H-benzotriazoles with aryl boronic acids lead to 1-aryl-1H-benzotriazole 3-oxides. A N1-OH → N3 prototropy in the 1-hydroxy-1H-benzotriazoles is plausibly the underlying basis, where the tautomer is captured by the boronic acid, leading to C-N (not C-O) bond formation. Because the N-O bond in amine N-oxides and 1-hydroxy-1H-benzotriazoles can be easily reduced by diboron reagents such as (pinB)2 and B2(OH)4, exposure of the 1-aryl-1H-benzotriazole 3-oxides to B2(OH)4 then leads to facile reduction of the N-O bond resulting in diverse, regiospecifically-arylated benzotriazoles. Thus, the N-hydroxyl group in 1-hydroxy-1H-benzotriazoles acts as a disposable arylation director.

Synthesis and biological evaluation of novel quinazoline-sulfonamides as anti-cancer agents.

A robust economic approach to N-(quinazoline-4-yl)sulfonamides was developed and synthesized different aryl, hetero aryl, alkyl and cyclopropyl sulfonamides in excellent yields. All the compounds were evaluated for cytotoxic affinity to SKOV3, DU145, THP1, U937, and COLO205 cell lines. Interesting to find that the bulkiness of substituent at C-2 position of quinazoline forces the molecule to flip around in order to bind in the active site, when compared to the binding preference of previously known quinazoline compounds. Among the 21 compounds synthesized 2b, 2d, 2e, 2h, 2i, 3c, 3d, 3f, 3g and 3h found to be active on all the cell lines tested with IC50 values <10µg/mL. Performed docking simulations to understand the binding preference of various C-2 substituted quinazoline sulfonamides.

Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides.

Cladribine, 2-chloro-2'-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2'-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.

A novel anti-inflammatory natural product from Sphaeranthus indicus inhibits expression of VCAM1 and ICAM1, and slows atherosclerosis progression independent of lipid changes.

A large body of evidence suggests that atherosclerosis is an inflammatory disease, in which cytokines and growth factors play a major role in disease progression. The methanolic extracts of Sphaeranthus indicus as well as its active ingredient, 7-hydroxy frullanoide (7-HF), are shown to suppress LPS-induced cytokine production from mononuclear cells, and inhibit the expression of VCAM1, ICAM1 and E-selectin by TNF-α- stimulated HUVECs in a concentration-dependent manner. We tested the hypothesis that the inhibition of cytokines and adhesion molecules should attenuate the progression of atherosclerosis, independent of changes in the lipid profile. Studies were carried out in two animal models: a high fat-fed LDLr(-/-) mouse and a high fat-fed hyperlipidemic hamster. Methanolic extract of S. indicus was dosed to hyperlipidemic LDLr(-/-) at 100 and 300 mg (equivalent to 20 and 60 mg 7-HF)/kg body weight/ day for 8 weeks, and plasma lipids as well as aortic lesion area were quantitated. Hyperlipidemic hamsters were treated with one dose of 200 mg/kg/day. S. indicus extract treatment did not alter the lipid profile in both animal models, but reduced aortic lesion area in LDLr(-/-) mice and hyperlipidemic hamsters by 22 % and 45 %, respectively. Fenofibrate, included as a reference agent, decreased aortic lesions by 26 % in LDLr (-/-) mice and 84 % in hyperlipidemic hamsters, respectively, which was driven by massive reductions in proatherogenic lipoproteins. The lipid-independent anti-atherosclerotic activity of S. indicus was associated with the reductions in the circulating levels of MCP-1, TNF-α, and IL-6 via phosphorylation and degradation of IkB-α that prevents translocation of NF-kB in the nucleus to induce proinflammatory cytokines. Our findings demonstrate that anti-inflammatory agents that lower pro-inflammatory proteins inhibit the progression of atherosclerosis. The methanolic extract of S. inducus, currently being used to treat psoriasis, offer promise to benefit individuals who have high circulating pro-inflammatory cytokines, and predisposed to coronary artery disease.

In vitro starch digestibility, pasting and textural properties of mung bean: effect of different processing methods.

Mung bean was subjected to different processing conditions (soaking, germination, cooking and autoclaving) and their textural, pasting and in vitro starch digestibility characteristics were studied. A significant reduction in textural properties (hardness, cohesiveness, gumminess and chewiness) after cooking and autoclaving treatment of mung bean was observed. Flours made from differently processed mung bean showed significant differences (P < 0.05) in their pastin g characteristics. Peak and final viscosity were the highest for flour from germinated mung bean whereas those made from autoclaved mung bean showed the lowest value. in vitro starch digestibility of mung bean flours was assessed enzymatically using modified Englyst method and the parameters studied were readily digestible starch (RDS), slowly digestible starch (SDS), resistant starch (RS) and total starch (TS) content. Various processing treatments increased the RDS contents of mung bean, while the SDS content was found to be the highest for soaked and the lowest for the autoclaved sample. Germinated sample showed higher amount of digestible starch (RDS + SDS) as compared to raw and soaked samples. Flours from raw and soaked samples showed significantly low starch hydrolysis rate at all the temperatures with total hydrolysis of 29.9 and 31.2 %, respectively at 180 min whereas cooked and autoclaved samples showed high hydrolysis rates with 50.2 and 53.8 % of these hydrolyzing within 30 min of hydrolysis.

P7170: A Novel Molecule with Unique Profile of mTORC1/C2 and Activin Receptor-like Kinase 1 Inhibition Leading to Antitumor and Antiangiogenic Activity.

The mTOR pathway is often upregulated in cancer and thus intensively pursued as a target to design novel anticancer therapies. Approved and emerging drugs targeting the mTOR pathway have positively affected the clinical landscape. Recently, activin receptor-like kinase 1 (ALK1), belonging to the TGFß receptor family, has been reported as an emerging target for antiangiogenic cancer therapy. Here, we describe a novel orally efficacious compound, P7170, that inhibits mTORC1/mTORC2/ALK1 activity with a potent cell growth inhibition. In cell-based assays, P7170 strongly inhibited (IC50 < 10 nmol/L) the phosphorylation of p70S6K (T389) and pAKT (S473). In many cancer cell lines, such as prostate, ovarian, colon, and renal, P7170 treatment resulted in marked cell growth inhibition. Furthermore, it induced G1-S cell-cycle arrest and autophagy. In vitro HUVEC tube formation, in vivo Matrigel plug, and rat aorta ring assays demonstrated that P7170 exhibited significant antiangiogenic activity. In addition, ALK1 knockdown studies in HUVEC confirmed that the antiangiogenic activity of P7170 was primarily due to ALK1 inhibition. Strong inhibition of ALK1 in addition to mTORC1/mTORC2 differentiates P7170 in its mechanism of action in comparison with existing inhibitors. In vivo mouse xenograft studies revealed P7170 to exhibit a significant dose-dependent tumor growth inhibition in a broad range of human tumor types when administered orally at 10 to 20 mg/kg doses. The distinctive pharmacological profile with favorable pharmacokinetic parameters and in vivo efficacy makes P7170 an attractive candidate for clinical development. It is currently being tested in phase I clinical studies.