Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.

Sulfur-Directed α-C(sp3)-H Amidation of Pyrrolidines with Dioxazolones under Rhodium Catalysis.

Site-selective functionalization of saturated N-heterocycles such as pyrrolidines is a central topic in organic synthesis and drug discovery. We herein report the sulfur-assisted rhodium(III)-catalyzed sp3 C-H amidation of pyrrolidines with dioxazolones as amidating agents. The amenability of the thioamide directing group is elucidated by a series of control experiments.

Design and synthesis of 4th generation EGFR inhibitors against human triple (Del19/T790M/C797S) mutation.

Epidermal growth factor receptor (EGFR)-targeted therapy is used to treat EGFR mutation-induced non-small cell lung cancer (NSCLC). However, its efficacy does not last beyond a certain period due to the development of primary and secondary resistance. First and second-generation inhibitors (e.g., gefitinib, erlotinib, and afatinib) induce EGFR T790M mutations, while third-generation inhibitors (e.g., osimertinib) induce C797S as a major target resistance mutation. Therefore, the C797S mutation is being actively researched. In this study, we investigated the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against the C797S mutation. We identified a compound 13k that displayed nanomolar potency and high selectivity. Moreover, we used a triple mutant xenograft mouse model to evaluate the in vivo efficacy of 13k in inhibiting EGFR C797S, which demonstrated exceptional profiles and satisfactory EGFR C797S inhibition efficacy. Based on its excellent in vitro and in vivo profiles, compound 13k can be considered a promising candidate for treating EGFR C797S mutations.

Target protein degradation by protacs: A budding cancer treatment strategy.

Cancer is one of the most common causes of death. So, its lethal effect increases with time. Near about hundreds of cancers are known in humans. Cancer treatment is done to cure or prolonged remission, and shrinkage of the tumor. Cytotoxic agents, biological agents/targeted drugs, hormonal drugs, surgery, radiotherapy/proton therapy, chemotherapy, immunotherapy, and gene therapy are currently used in the treatment of cancer but their cost is high and cause various side effects. Seeing this, some new targeted strategies such as PROTACs are the need of the time. Proteolysis targeting chimera (PROTAC) has become one of the most discussed topics regarding cancer treatment. Few of the PROTAC molecules are in the trial phases. PROTACs have many advantages over other strategies such as modularity, compatibility, sub-stoichiometric activity, acting on undruggable targets, molecular design, and acts on intracellular targets, selectivity and specificity can be recruited for any cancer, versatility, and others. PROTACs are having some unclear questions on their pharmacokinetics, heavy-molecular weight, etc. PROTACs are anticipated to bring about a conversion in current healthcare and will emerge as booming treatments. In this review article we summarize PROTACs, their mechanism of action, uses, advantages, disadvantages, challenges, and future aspects for the successful development of potent PROTACs as a drug strategy.

Catalyst-Controlled C-H Allylation and Annulation of 2-Aryl Quinazolinones with 2-Methylidene Cyclic Carbonate.

The site-selective modification of quinazolinone as a privileged bicyclic N-heterocycle is an attractive topic in medicinal chemistry and material science. We herein report the ruthenium(II)-catalyzed C-H allylation of 2-aryl quinazolinones with 2-methylidene cyclic carbonate. In addition, tandem C-H allylation and annulation are achieved under rhodium(III) catalysis, resulting in the formation of tetracyclic quinazolinones including a tertiary carbon center. Post-transformations of the synthesized products demonstrate the potential of the developed methodology. A series of mechanistic investigations were also performed.

Unravelling a trichloroacetic acid-catalyzed cascade access to benzo[f]chromeno[2,3-h]quinoxalinoporphyrins.

A facile one-pot four-component synthetic methodology is evolved to construct novel copper(II) benzo[f]chromeno[2,3-h]quinoxalinoporphyrins in good yields via a sequential reaction of copper(II) 2,3-diamino-5,10,15,20-tetraarylporphyrins, 2-hydroxynaphthalene-1,4-dione, aromatic aldehydes, and dimedone in the presence of a catalytic amount of trichloroacetic acid in chloroform at 65 °C. Further, the newly prepared copper(II) porphyrins were transformed to the corresponding free base and zinc(II) benzo[f]chromeno[2,3-h]quinoxalinoporphyrins under standard demetallation and zinc insertion conditions. The absorption and emission properties of the obtained porphyrins were investigated by using UV-visible and fluorescence spectroscopy. The preliminary photophysical results revealed a significant red-shift in their absorption and emission spectra as compared to the meso-tetrakis(4-methylphenyl)porphyrins due to the extended π-conjugation.

Rh(III)-Catalyzed C8-Spiroannulation of 1-Aminonaphthalenes with Maleimides.

The rhodium(III)-catalyzed C8-spiroannulation of 1-aminonaphthalenes with maleimides is described herein. Initially formed C8-alkenylated 1-aminonaphthalenes can intercept nucleophilic 1-amino groups through the intramolecular aza-Michael reaction, resulting in the formation of spirofused tetracyclic frameworks. This protocol displayed a wide substrate scope and a broad functional group compatibility. The synthetic utility of this process is demonstrated by the gram-scale synthesis, late-stage modification, and synthetic transformations.

Cascade Amination and Aza-6π-Annulation-Aromatization Strategy for the Synthesis of ß-Pyrimidine-Fused Porphyrins.

Novel nickel(II) and copper(II) complexes of 2-(N,N-dimethylformamidine)-3-formyl-5,10,15,20-tetraarylporphyrins have been synthesized for the first time from 2-aminoporphyrins under Vilsmeier-Haack conditions. These porphyrins are utilized as new building blocks to construct diverse ß-pyrimidine-fused 5,10,15,20-tetraarylporphyrins in good yields via a cascade ammonia-mediated condensation and intramolecular aza-6π-annulation/aromatization in 1,2-dichloroethane at 80 °C. Furthermore, copper(II) ß-pyrimidine-fused porphyrins underwent demetallation in the presence of conc. H2SO4 to afford free-base porphyrins, which on zinc insertion using Zn(OAc)2 in CHCl3-MeOH provided zinc(II) ß-pyrimidine-fused porphyrins in appreciable yields. Notably, these newly synthesized π-extended porphyrins displayed a modest bathochromic shift in their electronic absorption and emission spectra as compared to the traditional meso-tetraarylporphyrins. However, the protonated porphyrins (2a) and (3g) displayed a significant red-shifted absorption.

Bifunctionalized nanobioprobe based rapid color-shift assay for typhoid targeting Vi capsular polysaccharide.

Typhoid fever is an acute illness caused by Salmonella Typhi and the current diagnostic gap leads to inaccurate, over-diagnosis of typhoid leading to excessive use of antibiotics. Herein, to address the challenges we describe a new rapid color-shift assay based on a novel bifunctional nanobioprobe (Vi-AgNP probe) that is functionalized with specific biomarker Vi polysaccharide and also has the co-presence of Ag as urease inhibitor. The immunoreactions between the Vi with specific antibodies (Abs) present in typhoid patient sample forms a shielding barrier over Vi-AgNP probe rendering the urease to be active, generating colored output. Vi polysaccharide coating on the AgNP was visualized using HRTEM. TEM was performed to get insight into shielding barrier formation by the Abs. MST (microscale thermophoresis) data showed less binding Kd of 7.43 µM in presence of Abs whereas probe with urease showed efficient binding with Kd 437 nM. The assay was validated using 53 human sera samples and proven effective with 100% sensitivity. The assay showed relative standard deviation (RSD) of 4.3% estimated using rabbit anti-Vi Abs. The entire procedure could be completed within 15 min. Unlike lateral flow based assays, our assay does not require multiple combination of Abs for detection. The assay format was also found compatible in paper strip test that provides promising opportunities to develop low-cost on-spot assay for clinical diagnostics.

Rhodium(III)-Catalyzed Conjugate Addition of ß-CF3-Enones with Quinoline N-Oxides.

The site-selective incorporation of a trifluoromethyl group into biologically active molecules and pharmaceuticals has emerged as a central topic in medicinal chemistry and drug discovery. Herein, we demonstrate the rhodium(III)-catalyzed conjugate addition of ß-trifluoromethylated enones with quinoline N-oxides, which result in the generation of ß-trifluoromethyl-ß'-quinolinated ketones. The reaction proceeds under mild conditions with complete functional group tolerance. The synthetic applicability was showcased by successful gram-scale experiments and valuable synthetic transformations of coupling products.

Tandem C-S Coupling and Debrominative Cyclization Enables an Easy Access to ß-Thiazole-Fused Porphyrins.

A catalyst-free synthetic approach to ß-thiazole-fused 5,10,15,20-tetraarylporphyrins via a cascade reaction of nickel(II) or copper(II) 2-amido-3-bromo-5,10,15,20-tetraarylporphyrins and Lawesson's reagent is described. During the course of the reaction, 3-bromo-2-thioamido-5,10,15,20-tetraarylporphyrins formed in situ undergo debrominative cyclization in refluxing toluene to provide novel ß-thiazole-fused porphyrin macrocycles in good yields. Furthermore, free-base and zinc(II) ß-thiazole-fused porphyrins have also been constructed in excellent yields by using standard demetalation and zinc metal insertion procedures. The preliminary photophysical studies revealed a significant bathochromic shift in the electronic absorption and emission spectra of new porphyrins as compared to meso-tetraarylporphyrin precursors.

Targeting dendritic cells with TLR-2 ligand-coated nanoparticles loaded with Mycobacterium tuberculosis epitope induce antituberculosis immunity.

Novel vaccination strategies are crucial to efficiently control tuberculosis, as proposed by the World Health Organization under its flagship program "End TB Strategy." However, the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), particularly in those coinfected with HIV-AIDS, constitutes a major impediment to achieving this goal. We report here a novel vaccination strategy that involves synthesizing a formulation of an immunodominant peptide derived from the Acr1 protein of Mtb. This nanoformulation in addition displayed on the surface a toll-like receptor-2 ligand to offer to target dendritic cells (DCs). Our results showed an efficient uptake of such a concoction by DCs in a predominantly toll-like receptor-2-dependent pathway. These DCs produced elevated levels of nitric oxide, proinflammatory cytokines interleukin-6, interleukin-12, and tumor necrosis factor-α, and upregulated the surface expression of major histocompatibility complex class II molecules as well as costimulatory molecules such as CD80 and CD86. Animals injected with such a vaccine mounted a significantly higher response of effector and memory Th1 cells and Th17 cells. Furthermore, we noticed a reduction in the bacterial load in the lungs of animals challenged with aerosolized live Mtb. Therefore, our findings indicated that the described vaccine triggered protective anti-Mtb immunity to control the tuberculosis infection.

PROTACs: A Hope for Breast Cancer Patients?

BACKGROUND: Breast Cancer (BC) is the most widely occurring disease in women. A massive number of women are diagnosed with breast cancer, and many lose their lives every year. Cancer is the leading cause of death worldwide, posing a formidable challenge to the current medication difficulties. OBJECTIVES: The main objective of this study is to examine and explore novel therapy (PROTAC) and its effectiveness against breast cancer. METHODS: The literature search was conducted across Medline, Cochrane, ScienceDirect, Wiley Online, Google Scholar, PubMed, and Bentham Sciences from 2001 to 2020. The articles collected were screened, segregated, and selected papers were included for writing the review article. RESULTS AND CONCLUSION: A novel innovation emerged around two decades ago that has great potential to overcome the limitations and provide future direction for the treatment of many diseases, which has presently not many therapeutic options available and are regarded as incurable with traditional techniques. That innovation is called PROTAC (Proteolysis Targeting Chimera), which can efficaciously ubiquitinate and debase cancer, encouraging proteins through noncovalent interaction. PROTACs constituted of two active regions isolated by a linker are equipped for eliminating explicit undesirable protein. It is empowering greater sensitivity to "drugresistant targets" and a more prominent opportunity to influence non-enzymatic function. PROTACs have been demonstrated to show better target selectivity contrasted with traditional small-molecule inhibitors. So far, the most investigation into PROTACs mainly concentrated on cancer treatment applications, including breast cancer. The treatment of different ailments may benefit the patients from this blossoming innovation.

Gene Expression and Proteomics Studies Suggest an Involvement of Multiple Pathways Under Day and Day-Night Combined Heat Stresses During Grain Filling in Wheat.

Recent weather fluctuations imposing heat stress at the time of wheat grain filling cause frequent losses in grain yield and quality. Field-based studies for understanding the effect of terminal heat stress on wheat are complicated by the effect of multiple confounding variables. In the present study, the effect of day and day-night combined heat stresses during the grain-filling stage was studied using gene expression and proteomics approaches. The gene expression analysis was performed by using real-time quantitative PCR (RT-qPCR). The expression of genes related to the starch biosynthetic pathway, starch transporters, transcription factors, and stress-responsive and storage proteins, at four different grain developmental stages, indicated the involvement of multiple pathways. Under the controlled conditions, their expression was observed until 28 days after anthesis (DAA). However, under the day stress and day-night stress, the expression of genes was initiated earlier and was observed until 14 DAA and 7 DAA, respectively. The protein profiles generated using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy (MALDI-TOF MS/MS) showed a differential expression of the proteins belonging to multiple pathways that included the upregulation of proteins related to the translation, gliadins, and low-molecular-weight (LMW) glutenins and the downregulation of proteins related to the glycolysis, photosynthesis, defense, and high-molecular-weight (HMW) glutenins. Overall, the defense response to the day heat stress caused early gene expression and day-night heat stress caused suppression of gene expression by activating multiple pathways, which ultimately led to the reduction in grain-filling duration, grain weight, yield, and processing quality.

Remdesivir and Hydroxychloroquine: A Compassionate Use in Covid-19.

OBJECTIVE: Early in December 2019, mass sufferers due to Novel Coronavirus Pneumonia (SARS-CoV-2) in Wuhan (China) roused worldwide concern. Hardly any drugs showed the light of hope concerning the depletion in the period of treatment, and virological suppression became ineffective. Furthermore, numerous sufferers have undergone off-label use or compassionate use treatments as well as antiretroviral, antiparasitic agents, anti-inflammatory compounds, and convalescent plasma in either oral/parenteral route. This study aims to compile and analyze the effectiveness of Remdesivir and Hydroxychloroquine and give an insight into their drug profile in the treatment and management of COVID-19 patients. METHODS: Relevant literature was searched from PubMed, Crossref, Springer, Bentham Sciences, Google Scholar, DOAJ, ScienceDirect, and MEDLINE by using keywords like COVID-19, SARS-- COV-2, Remdesivir, and Hydroxychloroquine. Appropriate peer-reviewed articles were studied and compiled for this review paper. The figures were prepared by using ChemOffice 2016 (Chem- Draw Professional 2016) and Microsoft Office. RESULTS: This study indicates that 5 out of 10 works of literature find that Remdesivir leads to a reduction in recovery time, and the remaining 5 pieces of literature found Remdesivir to have no variance and have limitations. However, 6 out of 12 articles presented an increased chance of survival or reduction in recovery time due to hydroxychloroquine, while the remaining 6 presented hydroxychloroquine having no effect. CONCLUSION: There is a need to assess more pharmacokinetics and randomized controlled trials (RCT) for Remdesivir and Hydroxychloroquine. Studies should be conducted in different combinations along with Hydroxychloroquine and Remdesivir to obtain better results.

Malaria transmission-blocking drugs: implications and future perspectives.

As the world gets closer to eliminating malaria, the scientific community worldwide has begun to realize the importance of malaria transmission-blocking interventions. The onus of breaking the life cycle of the human malaria parasite Plasmodium falciparum predominantly rests upon transmission-blocking drugs because of emerging resistance to commonly used schizonticides and insecticides. This third part of our review series on malaria transmission-blocking entails transmission-blocking potential of preclinical transmission-blocking antimalarials and other non-malaria drugs/experimental compounds that are not in clinical or preclinical development for malaria but possess transmission-blocking potential. Collective analysis of the structure and the activity of these experimental compounds might pave the way toward generation of novel prototypes of next-generation transmission-blocking drugs.

Construction of coumarin-fused pyrido[2,3-b]porphyrins through a trichloroacetic acid-accelerated domino approach.

The first synthesis to construct coumarin-fused pyrido[2,3-b]porphyrins has been accomplished via a cascade reaction of 2-amino-meso-tetraphenylporphyrins, aromatic aldehydes and 4-hydroxycoumarin in o-dichlorobenzene containing a stoichiometric amount of trichloroacetic acid under reflux conditions. The methodology presented herein provides a direct access to a new series of π-extended nickel(ii) and copper(ii) porphyrin analogues in 58-69% isolated yields under one-pot operation. Furthermore, coumarin-fused copper(ii) pyrido[2,3-b]porphyrin underwent demetalation under the influence of concentrated sulfuric acid to produce free-base porphyrin which on zinc metal insertion using zinc acetate in a chloroform-methanol mixture afforded coumarin-fused zinc(ii) pyrido[2,3-b]porphyrin in good yield. The structures of the newly prepared coumarin-fused pyrido[2,3-b]porphyrins were established on the basis of spectral data analysis. In comparison with meso-tetraphenylporphyrin precursors, these porphyrinoids demonstrated a significant red-shift in their electronic absorption and emission spectra.

Recent advances in transmission-blocking drugs for malaria elimination.

The scientific community worldwide has realized that malaria elimination will not be possible without development of safe and effective transmission-blocking interventions. Primaquine, the only WHO recommended transmission-blocking drug, is not extensively utilized because of the toxicity issues in G6PD deficient individuals. Therefore, there is an urgent need to develop novel therapeutic interventions that can target malaria parasites and effectively block transmission. But at first, it is imperative to unravel the existing portfolio of transmission-blocking drugs. This review highlights transmission-blocking potential of current antimalarial drugs and drugs that are in various stages of clinical development. The collective analysis of the relationships between the structure and the activity of transmission-blocking drugs is expected to help in the design of new transmission-blocking antimalarials.

Gold nanoparticle triggered siloxane formation for polymerization based amplification in enzyme free visual immunoassay.

Herein, we report a new signal amplification scheme for quantitative biochemical analysis based on gold nanoparticle (GNPs) catalyzed polymerization of transparent silane solution to milky white and turbid siloxane. Using immunoassay as a proof of concept, GNP labeled immunoprobe was used to bind captured antigen and catalyse the polymerization reaction allowing sensitive biochemical investigation. The polymerization reaction was optimized for standard 96 well polystyrene microtiter plates and we discovered that sodium lactate acts as an enhancer in the polymerization reaction as it reduces detection time to merely 30 min. The sensing strategy was applied to detection and quantification of Salmonella Typhimurium in water and egg samples and the platform showed excellent visibly quantifiable analytical response up to 100 cells mL-1. Furthermore, clinical utility and potential of the method was validated by detecting Vi capsular polysaccharide (Vi antigen) responsible for typhoidal Salmonellosis in human serum in sandwich format with a detection limit of 1 ng mL-1. The method serves as the first report towards nanoparticle triggered polymerization for development of rapid and low cost quantitative biochemical assay.

Rapid and sensitive colorimetric detection of pathogens based on silver-urease interactions.

Herein, we demonstrate a facile and economic approach for colorimetric detection of microbial pathogens in drinking water, employing silver-urease interactions. In the presence of harmful pathogens, receptor coated silver nanoparticles (AgNPs) preferentially bind to the bacterial surface and urease catalytically elevates the pH of the solution, which is sensed by a pH responsive chromogenic dye. The assay demarcates bacterial contamination levels up to 102 cells mL-1 in a field-friendly method.