Alterations in cellular metabolism, such as dysregulation in glycolysis, lipid metabolism, and glutaminolysis in response to hypoxic and low-nutrient conditions within the tumor microenvironment, are ...well-recognized hallmarks of cancer. Therefore, understanding the interplay between aerobic glycolysis, lipid metabolism, and glutaminolysis is crucial for developing effective metabolism-based therapies for cancer, particularly in the context of colorectal cancer (CRC). In this regard, the present review explores the complex field of metabolic reprogramming in tumorigenesis and progression, providing insights into the current landscape of small molecule inhibitors targeting tumorigenic metabolic pathways and their implications for CRC treatment.
Aberrant accumulation of β-catenin in the cell nucleus as a result of deregulation of the Wnt/β-catenin pathway is found in various types of cancer. Direct β-catenin targeting agents are being ...researched despite obstacles; however, specific β-catenin drugs for clinical treatments have not been approved so far. We focused on direct β-catenin targeting of potential therapeutic value as anticancer agents. This review provides recent advances on small molecule β-catenin agents. Structure-activity relationships and biological activities of reported inhibitors are discussed. This work provides useful knowledge in the discovery of β-catenin agents.
Triple-negative breast cancer (TNBC) is one of the most heterogeneous and aggressive breast cancer subtypes with a high risk of death on recurrence. To date, TNBC is very difficult to treat due to ...the lack of an effective targeted therapy. However, recent advances in the molecular characterization of TNBC are encouraging the development of novel drugs and therapeutic combinations for its therapeutic management. In the present review, we will provide an overview of the currently available standard therapies and new emerging therapeutic strategies against TNBC, highlighting the promises that newly developed small molecules, repositioned drugs, and combination therapies have of improving treatment efficacy against these tumors.
•Rubiscolin-6 is a linear peptide isolated by the spinach Rubisco.•New analogues have been prepared via SPPS with high purity and good overall yields.•Their activity on opioid receptors has been ...detected in vitro and in vivo.•Some of them possess a strong antioxidant and tyrosinase inhibitor activity.•Peptide LMAS6 exerts also a significant anti-inflammatory in vivo.
Rubiscolin-6 (amino acid sequence: YPLDLF) is a selective δ-opioid receptor peptide isolated from spinach Rubisco. Its synthetic analogue, peptide YPMDIV is the most potent described so far for its increased opioid activity, thus in this work it was considered as lead compound for the design of twelve new analogues e.g.LMAS1-12. Firstly all the novel compounds have been tested for their antinociceptive and anti-inflammatory capacity in vitro and in vivo in order to evaluate their ability to maintain or loss the original activity. Among them peptides LMAS5-8 gave the best results, thus their antioxidant properties have been investigated along with their enzymatic inhibitory ability. Peptide LMAS6 shows a strong antioxidant (154.25 mg TE/g CUPRAC) and inhibitor activity on tyrosinase (84.49 mg KAE/g), indicating a potential role in food industry as anti-browning agent, while peptides LMAS5 and LMAS7 possess a modest cholinesterase inhibitory activity suggesting a conceivable use for nutraceuticals production.
We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs. Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = ...<0.7 nM; Y181C EC50 = <0.7 nM; Y188L EC50 = 21.3 nM; K103N–Y181C EC50 = 6.2 nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs. Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N–Y181C RTs clarified a general binding mode that was consistent with biological results. Kinetic experiments disclosed that derivative 12 preferentially binds WT and K103N–Y181C RTs to binary and ternary complexes, respectively.
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•We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs.•IAS 12 exhibited a remarkable antiviral activity against K103N–Y181C mutant strain.•Binding mode of IAS 12 was consistent with biological data.•IAS 12 was able to bind K103N–Y181C RT to ternary complex.
Rapeseed meal (RSM) is a by-product of rapeseed oil extraction and is a rich source of bioactive compounds, including proteins and antioxidants. This study compared two methods for extracting ...antioxidants from RSM: conventional ethanol Soxhlet extraction and supercritical CO2 extraction. These procedures were applied to both native RSM and RSM after protein removal to evaluate their bio-compound composition and potential applications. HPLC-DAD, NMR, and GC/MS analyses revealed a rich polyphenolic profile in the extracts, including the presence of sinapic acid. The concentration of sinapic acid varied depending on the extraction method used. The anti-radical activity of the extracts was also analysed using the DPPH assay, which confirmed the potential of RSM as a source of antioxidants for use in cosmetics, food, and pharmaceutical formulations.
Dengue virus (DENV) is the leading mosquito-transmitted viral infection in the world. With more than 390 million new infections annually, and up to 1 million clinical cases with severe disease ...manifestations, there continues to be a need to develop new antiviral agents against dengue infection. In addition, there is no approved anti-DENV agents for treating DENV-infected patients. In the present study, we identified new compounds with anti-DENV replication activity by targeting viral replication enzymes - NS5, RNA-dependent RNA polymerase (RdRp) and NS3 protease, using cell-based reporter assay. Subsequently, we performed an enzyme-based assay to clarify the action of these compounds against DENV RdRp or NS3 protease activity. Moreover, these compounds exhibited anti-DENV activity in vivo in the ICR-suckling DENV-infected mouse model. Combination drug treatment exhibited a synergistic inhibition of DENV replication. These results describe novel prototypical small anti-DENV molecules for further development through compound modification and provide potential antivirals for treating DENV infection and DENV-related diseases.
Wingless/integrase-11 (WNT)/β-catenin pathway is a crucial upstream regulator of a huge array of cellular functions. Its dysregulation is correlated to neoplastic cellular transition and cancer ...proliferation. Members of the Dishevelled (DVL) family of proteins play an important role in the transduction of WNT signaling by contacting its cognate receptor, Frizzled, via a shared PDZ domain. Thus, negative modulators of DVL1 are able to impair the binding to Frizzled receptors, turning off the aberrant activation of the WNT pathway and leading to anti-cancer activity. Through structure-based virtual screening studies, we identified racemic compound RS4690 (1), which showed a promising selective DVL1 binding inhibition with an EC50 of 0.74 ± 0.08 μM. Molecular dynamic simulations suggested a different binding mode for the enantiomers. In the in vitro assays, enantiomer (S)-1 showed better inhibition of DVL1 with an EC50 of 0.49 ± 0.11 μM compared to the (R)-enantiomer. Compound (S)-1 inhibited the growth of HCT116 cells expressing wild-type APC with an EC50 of 7.1 ± 0.6 μM and caused a high level of ROS production. These results highlight (S)-1 as a lead compound for the development of new therapeutic agents against WNT-dependent colon cancer.
An exploration of the chemical space around a 2,5-dimethylpyrrole scaffold of antitubercular hit compound 1 has led to the identification of new derivatives active against Mycobacterium tuberculosis ...and multidrug-resistant clinical isolates. Analogues incorporating a cyclohexanemethyl group on the methyleneamine side chain at C3 of the pyrrole core, including 5n and 5q, exhibited potent inhibitory effects against the M. tuberculosis strains, substantiating the essentiality of the moiety to their antimycobacterial activity. In addition, selected derivatives showed promising cytotoxicity profiles against human pulmonary fibroblasts and/or murine macrophages, proved to be effective in inhibiting the growth of intracellular mycobacteria, and elicited either bactericidal effects, or bacteriostatic activity comparable to 1. Computational studies revealed that the new compounds bind to the putative target, MmpL3, in a manner similar to that of known inhibitors BM212 and SQ109.
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•New antitubercular 2,5-dimethylpyrroles identified from a hit expansion study are reported.•Originally designed as molecular hybrids of BM212 and SQ109.•Highly active against wild-type, multidrug-resistant and intracellular M. tuberculosis.•Selective against murine macrophages and human pulmonary fibroblasts.•Bactericidal and bacteriostatic in action against M. tuberculosis.
The biocatalytic aromatization of indolines into indole derivatives exploiting monoamine oxidase (MAO-N) enzymes is presented. Indoline substrates were prepared via photocatalytic cyclization of ...arylaniline precursors or via arylative dearomatization of unsubstituted indoles and in turn chemoselectively aromatized by the MAO-N D11 whole cell biocatalyst. Computational docking studies of the indoline substrates in the MAO-N D11 catalytic site allowed for the rationalization of the biocatalytic mechanism and experimental results of the biotransformation. This methodology represents an efficient example of biocatalytic synthesis of indole derivatives and offers a facile approach to access these aromatic heterocycles under mild reaction conditions.
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