Corrigendum: Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity.

[This corrects the article DOI: 10.3389/fonc.2022.972372.].

Research progress of indole-fused derivatives as allosteric modulators: Opportunities for drug development.

Allosteric modulation is a direct and effective method for regulating the function of biological macromolecules, which play vital roles in various cellular activities. Unlike orthosteric modulators, allosteric modulators bind to sites distant from the protein's orthosteric/active site and can have specific effects on the protein's function or activity without competing with endogenous ligands. Compared to traditional orthosteric modulators, allosteric modulators offer several advantages, including reduced side effects, greater specificity, and lower toxicity, making them a promising strategy for developing novel drugs. Indole-fused architectures are widely distributed in natural products and bioactive drug leads, displaying diverse biological activities that attract the interest of both chemists and biologists in drug discovery. Currently, an increasing number of indole-fused compounds have exhibited potent activities in allosteric modulation. In this review, we provide a brief summary of examples of allosteric modulators based on the indole-fused complex architecture, highlighting the strategies for drug design/discovery and the structure-activity relationships of allosteric modulators from the perspective of medicinal chemistry.

Discovery of tetrahydrofuranyl spirooxindole-based SMYD3 inhibitors against gastric cancer via inducing lethal autophagy.

SMYD3 is a histone methyltransferase involved in transcriptional regulation, and its overexpression in various forms of cancer justifies that blocking SMYD3 functions can serve as a novel therapeutic strategy in cancer treatment. Herein, a series of novel tetrahydrofuranyl spirooxindoles were designed and synthesized based on a structure-based drug design strategy. Subsequent biochemical analysis suggested that these novel SMYD3 inhibitors showed good anticancer activity against stomach adenocarcinoma both in vitro and in vivo. Among them, compound 7r exhibited potent inhibitory capacities against SMYD3 and BGC823 cells with IC50 values of 0.81 and 0.75 µM, respectively. Mechanistic investigations showed that 7r could suppress Akt methylation and activation by SMYD3 and trigger lethal autophagic flux inhibition via the Akt-mTOR pathway. Collectively, our results may bridge the rational discovery of privileged structures, epigenetic targeting of SMYD3, and regulation of autophagic cell death.

Unraveling the structures, functions and mechanisms of epithelial membrane protein family in human cancers.

Peripheral myelin protein 22 (PMP22) and epithelial membrane proteins (EMP-1, -2, and -3) belong to a small hydrophobic membrane protein subfamily, with four transmembrane structures. PMP22 and EMPs are widely expressed in various tissues and play important roles in cell growth, differentiation, programmed cell death, and metastasis. PMP22 presents its highest expression in the peripheral nerve and participates in normal physiological and pathological processes of the peripheral nervous system. The progress of molecular genetics has shown that the genetic changes of the PMP22 gene, including duplication, deletion, and point mutation, are behind various hereditary peripheral neuropathies. EMPs have different expression patterns in diverse tissues and are closely related to the risk of malignant tumor progression. In this review, we focus on the four members in this protein family which are related to disease pathogenesis and discuss gene mutations and post-translational modification of them. Further research into the interactions between structural alterations and function of PMP22 and EMPs will help understand their normal physiological function and role in diseases and might contribute to developing novel therapeutic tools.

Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity.

Simultaneous inhibition of more than one target is considered to be a novel strategy in cancer therapy. Owing to the importance of histone deacetylases (HDACs) and p53-murine double minute 2 (MDM2) interaction in tumor development and their synergistic effects, a series of MDM2/HDAC bifunctional small-molecule inhibitors were rationally designed and synthesized by incorporating an HDAC pharmacophore into spirooxindole skeletons. These compounds exhibited good inhibitory activities against both targets. In particular, compound 11b was demonstrated to be most potent for MDM2 and HDAC, reaching the enzyme inhibition of 68% and 79%, respectively. Compound 11b also showed efficient antiproliferative activity towards MCF-7 cells with better potency than the reference drug SAHA and Nutlin-3. Furthermore, western blot analysis revealed that compound 11b increased the expression of p53 and Ac-H4 in MCF-7 cells in a dose-dependent manner. Our results indicate that dual inhibition of HDAC and MDM2 may provide a novel and efficient strategy for the discovery of antitumor drug in the future.

Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies.

Triple-negative breast cancer (TNBC) is a subtype of human breast cancer with one of the worst prognoses, with no targeted therapeutic strategies currently available. Regulated cell death (RCD), also known as programmed cell death (PCD), has been widely reported to have numerous links to the progression and therapy of many types of human cancer. Of note, RCD can be divided into numerous different subroutines, including autophagy-dependent cell death, apoptosis, mitotic catastrophe, necroptosis, ferroptosis, pyroptosis and anoikis. More recently, targeting the subroutines of RCD with small-molecule compounds has been emerging as a promising therapeutic strategy, which has rapidly progressed in the treatment of TNBC. Therefore, in this review, we focus on summarizing the molecular mechanisms of the above-mentioned seven major RCD subroutines related to TNBC and the latest progress of small-molecule compounds targeting different RCD subroutines. Moreover, we further discuss the combined strategies of one drug (e.g., narciclasine) or more drugs (e.g., torin-1 combined with chloroquine) to achieve the therapeutic potential on TNBC by regulating RCD subroutines. More importantly, we demonstrate several small-molecule compounds (e.g., ONC201 and NCT03733119) by targeting the subroutines of RCD in TNBC clinical trials. Taken together, these findings will provide a clue on illuminating more actionable low-hanging-fruit druggable targets and candidate small-molecule drugs for potential RCD-related TNBC therapies.

Indole-Based Small Molecules as Potential Therapeutic Agents for the Treatment of Fibrosis.

Indole alkaloids are widely distributed in nature and have been particularly studied because of their diverse biological activities, such as anti-inflammatory, anti-tumor, anti-bacterial, and anti-oxidant activities. Many kinds of indole alkaloids have been applied to clinical practice, proving that indole alkaloids are beneficial scaffolds and occupy a crucial position in the development of novel agents. Fibrosis is an end-stage pathological condition of most chronic inflammatory diseases and is characterized by excessive deposition of fibrous connective tissue components, ultimately resulting in organ dysfunction and even failure with significant morbidity and mortality. Indole alkaloids and indole derivatives can alleviate pulmonary, myocardial, renal, liver, and islet fibrosis through the suppression of inflammatory response, oxidative stress, TGF-ß/Smad pathway, and other signaling pathways. Natural indole alkaloids, such as isorhynchophylline, evodiamine, conophylline, indirubin, rutaecarpine, yohimbine, and vincristine, are reportedly effective in organ fibrosis treatment. In brief, indole alkaloids with a wide range of pharmacological bioactivities are important candidate drugs for organ fibrosis treatment. The present review discusses the potential of natural indole alkaloids, semi-synthetic indole alkaloids, synthetic indole derivatives, and indole-contained metabolites in organ fibrosis treatment.

Design, Synthesis, and Biological Evaluation of Tetrahydro-α-carbolines as Akt1 Inhibitors That Inhibit Colorectal Cancer Cell Proliferation.

A series of densely functionalized THαCs were designed and synthesized as Akt1 inhibitors. Organocatalytic [3+3] annulation between indolin-2-imines 1 and nitroallylic acetates 2 provided rapid access to this pharmacologically interesting framework. In vitro kinase inhibitory abilities and cytotoxicity assays revealed that compound 3 af [(3S*,4S*)-4-(4-bromo-2-fluorophenyl)-9-methyl-3-nitro-1-tosyl-2,3,4,9-tetrahydro-1H-pyrido[2,3-b]indole] was the most potent Akt1 inhibitor, and mechanistic study indicated that compound 3 af suppressed the proliferation of colorectal cancer cells via inducing apoptosis and autophagy. Molecular docking suggested that the indole fragment of 3 af was inserted into the hydrophobic pocket of Akt1 protein, and the H-bond between 3 af and residue Lys179 also contributed to the stable binding. This article provides an efficient strategy to design and synthesize biologically important compounds as novel Akt1 inhibitors.

Advances in indole-containing alkaloids as potential anticancer agents by regulating autophagy.

Cancer is a leading cause of death worldwide, and cancer development is often associated with disturbances in the autophagy process. Autophagy is a catabolic process involved in many physiological processes, crucial for cell growth and survival. It is an intracellular lysosomal/vacuolar degradation system. In this system, inner cytoplasmic cell membrane is degraded by lysosomal hydrolases, and the products are released back into the cytoplasm. Indole alkaloids are natural products extensively found in nature and have been proven to possess various pharmacological activities. In recent years, pharmacological studies have demonstrated another potential of indole alkaloids, autophagy regulation. The regulation may contribute to the efficacy of indole alkaloids in preventing and treating cancer. This review summarizes the current understanding of indole alkaloids' effect on tumor cells and autophagy. Then, we focus on mechanisms by which indole alkaloids can target the autophagy process associated with cancer, including the PI3K/Akt/mTOR signaling pathway, MAPK signaling pathway, ROS signaling pathway, Beclin-1, and so on. Literature has been surveyed primarily from 2009 to Nov. 2021, and some semisynthetic or fully synthetic indole derivatives are also discussed.

Evodiamine alleviates lipopolysaccharide-induced pulmonary inflammation and fibrosis by activating apelin pathway.

Inflammation can cause a series of inflammatory lung disease, which seriously endangers human health. Pulmonary fibrosis is a kind of inflammatory disease with end-stage lung pathological changes. It has complicated and unknown pathogenesis and is still lack of effective therapeutic drugs. LPS-induced inflammation is a common feature of many infectious inflammations such as pneumonia, bacteremia, glomerulonephritis, etc. Evodiamine, one of the main components of Evodia rutaecarpa, is an alkaloid with excellent antiinflammatory effects. In this study, we evaluated the protective capacities of evodiamine on LPS-induced inflammatory damages in vitro and in vivo. MTT method, flow cytometry, immunofluorescence, and other methods were used for in vitro study to determine the protective capacities of evodiamine. The results suggest that evodiamine can protect murine macrophages from the LPS-nigericin-induced damages by (a) inhibiting cellular apoptosis, (b) inhibiting inflammatory cytokines releasing, and (c) activating the apelin pathway. We also used the exogenous apelin-13 peptide co-cultured with LPS-nigericin in RAW264.7 cells and found that apelin-13 contributes to protecting the effects of evodiamine. In vivo, the ELISA method and immunohistochemistry were used to examine inflammatory cytokines, apelin, and histological changes. BALB/c mice were exposed to LPS and subsequent administration of evodiamine （p.o.）for some time, the results of the alveolar lavage fluid and the tissue slices showed that evodiamine treatment alleviated the pulmonary inflammation and fibrosis, stimulated apelin expression and inhibited the inflammatory cytokines. These results provide a basis for the protective effect and mechanism of evodiamine in LPS-induced inflammation and suggest that it might be potential therapeutics in human pulmonary infections.

Regulation of the Ras-Related Signaling Pathway by Small Molecules Containing an Indole Core Scaffold: A Potential Antitumor Therapy.

The Ras-Related signaling pathway plays an important role in cell development and differentiation. A growing body of evidence collected in recent years has shown that the aberrant activation of Ras is associated with tumor-related processes. Several studies have indicated that indole and its derivatives can target regulatory factors and interfere with or even block the aberrant Ras-Related pathway to treat or improve malignant tumors. In this review, we summarize the roles of indole and its derivatives in the isoprenylcysteine carboxyl methyltransferase-participant Ras membrane localization signaling pathway and Ras-GTP/Raf/MAPK signaling pathway through their regulatory mechanisms. Moreover, we briefly discuss the current treatment strategies that target these pathways. Our review will help guide the further study of the application of Ras-Related signaling pathway inhibitors.

Novel HSP90-PI3K Dual Inhibitor Suppresses Melanoma Cell Proliferation by Interfering with HSP90-EGFR Interaction and Downstream Signaling Pathways.

Melanoma is the deadliest form of skin cancer, and its incidence has continuously increased over the past 20 years. Therefore, the discovery of a novel targeted therapeutic strategy for melanoma is urgently needed. In our study, MTT-based cell proliferation assay, cell cycle, and apoptosis assays through flow cytometry, protein immunoblotting, protein immunoprecipitation, designing of melanoma xenograft models, and immunohistochemical/immunofluorescent assays were carried out to determine the detailed molecular mechanisms of a novel HSP90-PI3K dual inhibitor. Our compound, named DHP1808, was found to suppress A375 cell proliferation through apoptosis induction by activating the Fas/FasL signaling pathway; it also induced cell-cycle arrest and inhibited the cell migration and invasion of A375 cells by interfering with Hsp90-EGFR interactions and downstream signaling pathways. Our results indicate that DHP1808 could be a promising lead compound for the Hsp90/PI3K dual inhibitor.

Organocatalytic diastereoselective [3+2] cyclization of MBH carbonates with dinucleophiles: synthesis of bicyclic imidazoline derivatives that inhibit MDM2-p53 interaction.

An efficient organocatalytic cyclization strategy was developed to synthesize pharmacologically interesting bicyclic imidazoline derivatives. Morita-Baylis-Hillman carbonates were applied as C3 electrophiles to react with N,C-dinucleophiles for the first time, yielding the desired products in good to excellent yields with outstanding diastereoselectivities. The optically pure bicyclic imidazolines were expeditiously prepared by utilizing the readily available chiral ketene aminals as building blocks. The products were found to inhibit MDM2-p53 binding and cell proliferation. The most potent compound 5c induced the accumulation of MDM2, p53 and p21 proteins in HCT116 cells and blocked interaction between MDM2 and p53.

Protecting Group-Directed Diastereodivergent Synthesis of Chiral Tetrahydronaphthalene-Fused Spirooxindoles via Bifunctional Tertiary Amine Catalysis.

A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids bearing a quaternary carbon center at the ß-position of THN has been developed. The diastereodivergent direct catalytic Michael-aldol reaction between 3-ylideneoxindole and 2-methylbenzaldehyde was accomplished by using bifunctional tertiary amine. Simply changing the protecting group on the substrate in the organocatalytic cascade reaction led to inverted diastereoselectivity in good yields with a high ee value. To explain the diastereodivergence of the organocatalytic Michael-aldol cascade, we also proposed plausible transition-state models for [4 + 2] annulation based on the observed stereochemistry of the products.

Highly diastereoselective synthesis of cyclopropane-fused spiro-pseudoindoxyl derivatives through [2 + 1] annulation of 2-ylideneoxindoles and sulfonium bromides.

Compared with the intensively studied C3 spirooxindoles, limited reliable approaches are reported for synthesizing structurally analogous C2-spiropseudoindoxyl derivatives. Here, we developed an efficient method for highly diastereoselective synthesis of cyclopropane-fused spiropseudoindoxyl derivatives (up to 88% yield and >20 : 1 dr in all cases) through [2 + 1] annulation of (Z)-2-ylideneoxindoles with sulfur ylides.

Probabilistic Damage Detection of a Steel Truss Bridge Model by Optimally Designed Bayesian Neural Network.

Excellent pattern matching capability makes artificial neural networks (ANNs) a very promising approach for vibration-based structural health monitoring (SHM). The proper design of the network architecture with the suitable complexity is vital to the ANN-based structural damage detection. In addition to the number of hidden neurons, the type of transfer function used in the hidden layer cannot be neglected for the ANN design. Neural network learning can be further presented in the framework of Bayesian statistics, but the issues of selection for the hidden layer transfer function with respect to the Bayesian neural network has not yet been reported in the literature. In addition, most of the research works in the literature for addressing the predictive distribution of neural network output is only for a single target variable, while multiple target variables are rarely involved. In the present paper, for the purpose of probabilistic structural damage detection, Bayesian neural networks with multiple target variables are optimally designed, and the selection of the number of neurons, and the transfer function in the hidden layer, are carried out simultaneously to achieve a neural network architecture with suitable complexity. Furthermore, the nonlinear network function can be approximately linear by assuming the posterior distribution of network parameters is a sufficiently narrow Gaussian, and then the input-dependent covariance matrix of the predictive distribution of network output can be obtained with the Gaussian assumption for the situation of multiple target variables. Structural damage detection is conducted for a steel truss bridge model to verify the proposed method through a set of numerical case studies.

Direct Sulfide-Catalyzed Diastereoselective [4+1] Annulations of ortho-Quinone Methides and Bromides.

Direct sulfide organocatalysis is an emerging topic in research on synthetic chemistry. Here, an unprecedented sulfide-catalyzed diastereoselective [4+1] annulation of (in situ generated) ortho-quinone methides and bromides is reported. Notably, the robustness of such sulfide organocatalysis was demonstrated by performing the catalytic reaction under oxidative conditions without significantly affecting the reaction outcome. Various dihydrobenzofurans with diverse substituents were obtained with high isolated yields of up to 98% and remarkable diastereoselectivity (>19:1 dr in general).

Asymmetric synthesis of bicyclic dihydropyrans via organocatalytic inverse-electron-demand oxo-Diels-Alder reactions of enolizable aliphatic aldehydes.

A highly enantioselective organocatalytic inverse-electron-demand oxo-Diels-Alder reaction involving aqueous acetaldehyde has been discovered. The reaction, in which cyclic enones serve as dienes in the presence of readily available secondary amine catalysts, allows facile construction of optically active bicyclic dihydropyrans. Other typical enolizable aliphatic aldehydes can also serve as competent dienophiles in the reaction.

Surface-enhanced Raman spectroscopic study of p-aminothiophenol.

p-aminothiophenol (PATP) is an important molecule for surface-enhanced Raman spectroscopy (SERS). It can strongly interact with metallic SERS substrates and produce very strong SERS signals. It is a molecule that has often been used for mechanistic studies of the SERS mechanism as the photon-driven charge transfer (CT) mechanism is believed to be present for this molecule. Recently, a hot debate over the SERS behavior of PATP was triggered by our finding that PATP can be oxidatively transformed into 4,4'-dimercaptoazobenzene (DMAB), which gives a SERS spectra of so-called "b2 modes". In this perspective, we will give a general overview of the SERS mechanism and the current status of SERS studies on PATP. We will then demonstrate with our experimental and theoretical evidence that it is DMAB which contributes to the characteristic SERS behavior in the SERS spectra of PATP and analyze some important experimental phenomena in the framework of the surface reaction instead of the contribution "b2 modes". We will then point out the existing challenges of the present system. A clear understanding of the reaction mechanism for nitrobenzene or aromatic benzene will be important to not only understand the SERS mechanism but to also provide an economic way of producing azo dyes with a very high selectivity and conversion rate.