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Background: The heat shock response (HSR) is a highly conserved mechanism that maintains intracellular homeostasis in response to various environmental and physiological stresses. Heat shock proteins (HSPs), particularly HSP70, play a pivotal role in this process as molecular chaperones. Although HSP70 inhibitors have demonstrated anti-cancer activity, their therapeutic potential has been limited by the negative feedback mechanism between HSP70 and heat shock factor 1 (HSF1). The combination of HSP70 inhibitors with HSF1 inhibitors has been proposed to overcome this limitation and enhance anti-cancer effects., Methods: We combined HSP70 inhibitors (VER-155008 and YK-5) with an HSF1 inhibitor (DTHIB) in CRC cells and evaluated their effects on cell survival, apoptosis, and protein homeostasis., Results: Strong synergistic effects were observed (combination index <0.5, ZIP score > 10) with the combination treatment, leading to decreased cell survival and increased apoptosis in CRC cells. Mechanistic studies revealed that HSP70 inhibitors activated the phosphorylation of HSF1, inducing HSP70 expression, and that the combination therapy resulted in more pronounced HSR inhibition and protein homeostasis disturbances., Conclusion: The combination therapy of HSP 70 and HSF 1 inhibitors showed significant synergistic antitumor activity., General Significance: Combining HSP70 and HSF1 inhibitors may be a promising anti-cancer strategy, offering a potential solution to overcome the negative feedback mechanism and enhance anti-cancer effects., Competing Interests: Declaration of competing interest Zhi-Shu Huang reports financial support was provided by Sun Yat-Sen University. Shi-Liang Huang reports financial support was provided by Sun Yat-Sen University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The biological function against obesity of heat shock protein Hsp72 in adipose tissue has remained unclear. Our findings demonstrated that the expression levels of Hsp72 increased during the triglyceride (TG) accumulation process both in adipose tissue and 3T3-L1 cells. A significant decrease in adipogenic gene expression and TG levels was observed upon Hsp72 knockdown in 3T3-L1 cells, suggesting that Hsp72 promoted adipogenic differentiation and lipid synthesis processes. Encouraged by these findings, we further confirmed the allosteric Hsp72 inhibitors YK5 and MKT-077 also exhibited inhibition of both these processes. Further evaluation revealed that Hsp72 played a key role in interacting with numerous novel metabolic and cytomorphologic-related client proteins, thereby mediating the adipogenesis and lipogenesis process. Hsp72 inhibitors had the potential to disrupt these interactions, leading to the downregulation of adipogenic and lipogenic gene expression, as well as the suppression of TG accumulation. These findings suggested that inhibiting Hsp72 to disrupt adipogenic differentiation and lipid synthesis in adipocytes may be a promising anti-obesity strategy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

c-MYC is a proto-oncogene ubiquitously overexpressed in various cancers. The formation of G-quadruplex (G4) structures within the c-MYC promoter region can regulate its transcription by interfering with protein binding. Consequently, small molecules targeting c-MYC G4 have emerged as promising anticancer agents. Herein, we report that sanguinarine (SG) and its analogs exhibit a high affinity for c-MYC G4 and potently modulate G4-protein interactions within a natural product library. Notably, SG uniquely enhances NM23-H2 binding to c-MYC G4, both in vitro and in cellular contexts, leading to c-MYC transcriptional repression and subsequent inhibition of cancer cell growth in an NM23-H2-dependent manner. Mechanistic studies and molecular modeling suggest that SG binds to the c-MYC G4/NM23-H2 interface, acting as an orthosteric stabilizer of the DNA-protein complex and preventing c-MYC transcription. Our findings identify SG as a potent c-MYC transcription inhibitor and provide a novel strategy for developing G4-targeting anticancer therapeutics through modulation of G4-protein interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is a global public health problem with its pathogenesis not fully understood. Excessive apoptosis of renal tubular epithelial cells is an important feature of AKI patients, and therefore an anti-apoptotic approach could be used in the treatment for AKI. Up-regulation of B-cell lymphoma-2 ( BCL-2 ) gene and protein has been found to be correlated with anti-apoptosis of cells. It has been found that the presence of the C-rich sequence on the upstream region of the BCL-2 gene promoter could form DNA secondary i-motif structure, and its stabilization by small molecules could up-regulate gene transcription and translation. In the present study, we constructed AKI models through folic acid (FA) induction. With these in vitro and in vivo models, we demonstrated that the acridone derivative A22 could up-regulate the expression of BCL-2 by targeting its gene promoter i-motif to reduce renal tubular epithelial cell apoptosis and improve renal function in many ways. A22 could alleviate FA-induced oxidative stress injury, inflammatory response, and endoplasmic reticulum stress in mouse kidneys. Our results provided a potentially new anti-apoptotic approach for the treatment of early stages of AKI. Our employed model focused on its short-term effect on AKI, while its long-term efficacy and safety, particularly regarding the regeneration of renal tubular epithelial cells, require further investigation before clinical application. This study further demonstrated that promoter i-motif could be targeted for up-regulating BCL-2 expression for the treatment of important diseases caused by excessive apoptosis.

Due to the emerging global epidemic of obesity, developing safe and effective agents for anti-obesity is urgently needed. Our previous study found that 2-pyrimidinylindole derivative Wd3d exhibited potential anti-obesity activity. Herein, to further optimize the potential moiety, structural modifications were proceeded for two rounds in this study. Firstly, we designed, synthesized, and evaluated 36 new derivatives of 2-pyrimidinylindole scaffold with different substituents on the indole ring and pyrimidine ring to investigate their structure-activity relationship (SAR). Then, analogs with potent activity had the aldehyde group replaced with the acylhydrazone group to reduce cytotoxicity and improve metabolic stability. Detailed SAR studies and animal evaluation experiments led to the discovery of the compound 9ga, which significantly reduced TG accumulation with an EC 50 value of 0.07 μM and showed relatively low cytotoxicity with an IC 50 value of around 24 μM. Oral administration of 9ga effectively prevented the excessive growth of body weight and lessened fat mass as well as liver mass, decreased lipid accumulation in the liver and blood, and improved the heart injury parameter in the diet-induced obesity mouse model significantly better than Wd3d. A mechanism study showed that 9ga regulated the lipid metabolism during early adipogenesis by inhibiting PPARγ pathway. In conclusion, our study further highlights the anti-obesity potential of 2-pyrimidinylindole derivatives in diet-induced obesity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Aims: Obesity always leads to profound perturbation of metabolome. Metabolome studies enrich the knowledge on associations between endogenous metabolites and obesity, potentially providing innovative strategies for the development of novel anti-obesity pharmacotherapy. This study aims to identify an endogenous metabolite that regulates energy expenditure and to explore its application for obesity treatment., Materials and Methods: C57BL/6 mice were fed with a high-fat and high-cholesterol (HFC) diet, comprising 60% fat and 1.2% cholesterol, for 12 weeks to induce obesity. Significant metabolites were identified in the livers of both health and obese mice through comparative hepatic metabolomics analysis. Correlation between serum or adipose L-aspartate level and body weight in obese mice, as well as human body mass index (BMI), was evaluated. In addition, saline or 200 mg/kg L-aspartate was orally administrated to HFC diet mice and HFC diet-induced obese mice for 6-7 weeks. Body weight, adipose tissue weight, glucose tolerance and liver damage were assessed to evaluate the effect on obesity prevention and treatment. Comprehensive lab animal monitoring system (CLAMS) and seahorse assay were employed to investigate the regulatory effect of L-aspartate on energy metabolism in vivo and in vitro, respectively. 3T3-L1 preadipocytes and murine white adipose tissue (WAT) were utilized to examine the impact of L-aspartate on adipocyte adipogenesis and lipogenesis and cellular signalling pathway in vitro and in vivo., Results: L-aspartate, an approved drug for liver injury and chronic fatigue, was identified as an endogenous inducer of energy expenditure. Serum or adipose L-aspartate levels were found to be negatively correlated with the severity of obesity in both humans and mice. Administration of L-aspartate to HFC diet mice led to a significant reduction in body weight, with decreases of 14.5% in HFC diet mice and 8.5% in HFC diet-induced obese mice, respectively. In addition, the treatment improved related metabolic syndrome (Figure 2 and Figure S3). These therapeutics were associated with enhancements in whole-body energy expenditure and suppression of adipocyte adipogenesis along with activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway., Conclusion: L-aspartate may serve as a novel endogenous inducer of energy expenditure and suppressor of adipogenesis and lipogenesis along with activation of AMPK, thereby offering a promising therapeutic strategy for obesity prevention and treatment., (© 2024 John Wiley & Sons Ltd.)

Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) have important regulatory roles in energy metabolism, yet their specific functions and underlying regulatory mechanisms have not been delineated. Using a chemical-genetic screening strategy, we demonstrated that the JAK/STAT3 pathway is the primary regulatory mechanism governing mtDNA G4 dynamics in hypoxic cancer cells. Further proteomic analysis showed that activation of the JAK/STAT3 pathway facilitates the translocation of RelA, a member of the NF-κB family, to the mitochondria, where RelA binds to mtDNA G4s and promotes their folding, resulting in increased mtDNA instability, inhibited mtDNA transcription, and subsequent mitochondrial dysfunction. This binding event disrupts the equilibrium of energy metabolism, catalyzing a metabolic shift favoring glycolysis. Collectively, the results provide insights into a strategy employed by cancer cells to adapt to hypoxia through metabolic reprogramming., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Both the pyrroloindoline core and N-CF 3 moiety hold significant importance in medicinal chemistry. However, to date, no instances of constructing N-CF 3 -containing pyrroloindolines have been reported. Herein, we present a robust and operationally simple approach to assembling such intriguing skeletons from tryptamine-derived isocyanides through a cascade sequence, which includes an oxidative trifluorination and a subsequent halogenative cyclization. Key to the success lies in the development of a facile conversion of isocyanides to N-CF 3 moiety with commercially available reagents N-halosuccinimide and Et 3 N·HF. The protocol features mild reaction conditions, broad functional group tolerance, good to excellent yields, and high diastereoselectivities. In addition, we demonstrate that the halide substituent within the products serves as a versatile functional handle for accessing diverse C3-quaternary-substituted N-CF 3 -pyrroloindolines., (© 2024. The Author(s).)

The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d , featuring an 8a- N -acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3 , but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N -acylhydrazone to enhance drug-like properties.

Background: Vascular endothelial growth factor (VEGF) is overexpressed in most malignant tumors, which has important impact on tumor angiogenesis and development. Its gene promoter i-motif structure formed by C-rich sequence can regulate gene expression, which is a promising new target for anti-tumor therapy., Methods: We screened various compounds and studied their effects on VEGF through extensive experiments, including SPR, MST, TO displacement, FRET, CD, ESI-MS, NMR, MTT, clone formation, qPCR, Western blot, dual-luciferase reporter assay, immunofluorescence, cell scrape, apoptosis, transwell assay, and animal model., Results: After extensive screening, bisacridine derivative B09 was found to have selective binding and stabilization to VEGF promoter i-motif, which could down-regulate VEGF gene expression. B09 showed potent inhibition on MCF-7 and HGC-27 cell proliferation and metastasis. B09 significantly inhibited tumor growth in xenograft mice model with HGC-27 cells, showing decreased VEGF expression analyzed through immunohistochemistry., Conclusion: B09 could specifically regulate VEGF gene expression, possibly through interacting with promoter i-motif structure. As a lead compound, B09 could be further developed for innovative anti-cancer agent targeting VEGF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

WRN helicase is a critical protein involved in maintaining genomic stability, utilizing ATP hydrolysis to dissolve DNA secondary structures. It has been identified as a promising synthetic lethal target for microsatellite instable (MSI) cancers. However, few WRN helicase inhibitors have been discovered, and their potential binding sites remain unexplored. In this study, we analyzed potential binding sites for WRN inhibitors and focused on the ATP-binding site for screening new inhibitors. Through molecular dynamics-enhanced virtual screening, we identified two compounds, h6 and h15, which effectively inhibited WRN's helicase and ATPase activity in vitro. Importantly, these compounds selectively targeted WRN's ATPase activity, setting them apart from other non-homologous proteins with ATPase activity. In comparison to the homologous protein BLM, h6 exhibits some degree of selectivity towards WRN. We also investigated the binding mode of these compounds to WRN's ATP-binding sites. These findings offer a promising strategy for discovering new WRN inhibitors and present two novel scaffolds, which might be potential for the development of MSI cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

c-MYC is a hallmark of various cancers, playing a critical role in promoting tumorigenesis. The formation of G-quadruplex (G4) in the c-MYC promoter region significantly suppresses its expression. Therefore, developing small-molecule ligands to stabilize c-MYC G4 formation and subsequentially suppress c-MYC expression is an attractive topic for c-MYC-driven cancer therapy. However, achieving selective ligands for c-MYC G4 poses challenges. In this study, we developed a series of triazole-modified quinazoline (TMQ) derivatives as potential c-MYC G4 ligands and c-MYC transcription inhibitors from 4-anilinoquinazoline lead 7a using click chemistry. Importantly, the c-MYC G4 stabilizing ability and antiproliferation activity were well correlated among these new derivatives, particularly in the c-MYC highly expressed colorectal cancer cell line HCT116. Among them, compound A6 exhibited good selectivity in stabilizing c-MYC G4 and in suppressing c-MYC transcription better than 7a. This compound induced G4 formation, selectively inhibited G4-related c-MYC transcription and suppressed the progression of HCT116 cells. These findings identify a new c-MYC transcription inhibitor and provide new insights for optimizing c-MYC G4-targeting ligands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hyperactivated KRAS mutations fuel tumorigenesis and represent attractive targets for cancer treatment. While covalent inhibitors have shown clinical benefits against the KRAS G12C mutant, advancements for non-G12C mutants remain limited, highlighting the urgent demand for pan-KRAS inhibitors. RNA G-quadruplexes (rG4s) in the 5'-untranslated region of KRAS mRNA can regulate KRAS translation, making them promising targets for pan-KRAS inhibitor development. Herein, we designed and synthesized 50 novel coumarin-quinolinium derivatives, leveraging our previously developed rG4-specific ligand, QUMA-1 . Notably, several compounds exhibited potent antiproliferative activity against cancer cells as pan-KRAS translation inhibitors. Among them, 15a displayed exceptional capability in stabilizing KRAS rG4s, suppressing KRAS translation, and consequently modulating MAPK and PI3K-AKT pathways. 15a induced cell cycle arrest, prompted apoptosis in KRAS-driven cancer cells, and effectively inhibited tumor growth in a KRAS mutant xenograft model. These findings underscore the potential of 15a as a pan-KRAS translation inhibitor, offering a novel and promising approach to target various KRAS-driven cancers.

Thirteen new Euphorbia diterpenoids, euphylonanes A-M ( 1 - 13 ), and eight known ones were isolated from the whole plants of Euphorbia hylonoma . Compounds 1 and 2 are two rearranged ingenanes bearing a rare 6/6/7/3-fused ring system. Compound 3 represents the first example of a 9,10-epoxy tigliane, while 4 - 21 are typical ingenanes varying with substituents. Structures were elucidated using a combination of spectroscopic, computational, and chemical methods. Most ingenanes exerted a significant antiadipogenic effect in 3T3-L1 adipocytes, among which 4 was the most active with an EC 50 value of 0.60 ± 0.27 μM. Mechanistic study revealed that 4 inhibited the adipogenesis and lipogenesis in adipocytes via activation of the AMPK signaling pathway.

Obesity, a global pandemic posing a growing threat to human health, necessitates the development of effective and safe anti-obesity agents. Our previous studies highlighted the lipid-lowering effects of indolylquinazoline Bouchardatine and its derivatives. In this study, we employed scaffold hopping and simplification strategies to design and synthesize two new series derivatives by modifying the D ring. Extensive discussions have been conducted regarding the structure-activity relationship between lipid-lowering activity and the new compounds. These discussions have resulted in the discovery of 2-pyrimidinylindole derivatives as a promising scaffold for anti-obesity treatment. The new 2-pyrimidinylindole derivatives exhibited comparable lipid-lowering activity to the previously reported indolylquinazoline derivatives, including SYSU-3d and R17, with reduced toxicity. The most potent compound, 5a, demonstrated a larger therapeutic index, improved aqueous solubility and oral bioavailability compared to the previous lead compounds. In vivo evaluation indicated that 5a effectively reduced lipid accumulation in adipose tissue, improved glucose tolerance, and mitigated insulin resistance and liver function damage caused by a high-fat and high-cholesterol diet. Mechanism studies indicated that 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. Overall, our study has identified a highly active compound 5a, and provided the basis for further development of 2-pyrimidinylindole as a promising scaffold for obesity treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Mitochondrion-lysosome interactions have garnered significant attention in recent research. Numerous studies have shown that mitochondrion-lysosome interactions, including mitochondrion-lysosome contact (MLC) and mitophagy, are involved in various biological processes and pathological conditions. Single fluorescent probes are termed a pivotal chemical tool in unraveling the intricate spatiotemporal interorganelle interplay in live cells. However, current chemical tools are insufficient to deeply understand mitochondrion-lysosome dynamic interactions and related diseases, Moreover, the rational design of mitochondrion-lysosome dual-targeting fluorescent probes is intractable. Herein, we designed and synthesized a pH-sensitive fluorescent probe called INSA , which could simultaneously light up mitochondria (red emission) and lysosomes (green emission) for their internal pH differences. Employing INSA , we successfully recorded long-term dynamic interactions between lysosomes and mitochondria. More importantly, the increasing mitochondrion-lysosome interactions in ferroptotic cells were also revealed by INSA . Further, we observed pH variations in mitochondria and lysosomes during ferroptosis for the first time. In brief, this work not only introduced a pH-sensitive fluorescent probe INSA for the disclosure of the mitochondrion-lysosome dynamic interplays but also pioneered the visualization of the organellar pH alternation in a specific disease model.

Electrophilic addition reaction to alkynes is of fundamental importance in organic chemistry, yet the regiocontrol when reacting with unsymmetrical 1,2-dialkyl substituted alkynes is often problematic. Herein, it is demonstrated that the rarely recognized β-boron effect can confer a high level of site-selectivity in several alkyne electrophilic addition reactions. A broad range of highly functionalized and complex organoborons are thus formed under simple reaction conditions starting from propargylic MIDA (N-methyliminodiacetic acid) boronates. These products are demonstrated to be valuable building blocks in organic synthesis. In addition to the regiocontrol, this study also observes a drastic rate enhancement upon B(MIDA) substitution. Theoretical calculation reveals that the highest occupied molecular obital (HOMO) energy level of propargylic B(MIDA) is significantly raised by 0.3 eV, and the preferential electrophilic addition to the γ position is due to its higher HOMO orbital coefficient and more negative natural bond orbital (NBO) charge compared to the β position. This study demonstrates the potential of utilizing the β-boron effect in stereoelectronic control of chemical transformations, which can inspire further research in this area., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Organofluorine compounds have been widely used in pharmaceutical, agrochemical, and material sciences. Reported herein are divergent fluorination reactions of vinylcyclopropanes with different electrophiles, which allow the facile synthesis of homoallylic monofluorides and vicinal-difluorides through ring-opening 1,5-hydrofluorination and ring-retaining 1,2-difluorination, respectively. Both protocols feature mild conditions, simple operations, good functional group tolerance, and generally good yields. The practicality of these reactions is demonstrated by their scalability, as well as the successful conversion of the formed homoallylic monofluorides into other complex fluorinated molecules., (© 2023 Wiley-VCH Verlag GmbH.)

MSN8C, an analog of mansonone E, has been identified as a novel catalytic inhibitor of human DNA topoisomerase II that induces tumor regression and differs from VP-16(etoposide). Treatment with MSN8C showed significant antiproliferative activity against eleven human tumor cell lines in vitro. It was particularly effective against the HL-60/MX2 cell line, which is resistant to Topo II poisons. The resistance factor (RF) of MSN8C for Topo II in HL-60/MX2 versus HL-60 was 1.7, much lower than that of traditional Topo II poisons. Furthermore, in light of its potent antitumor efficacy and low toxicity, as demonstrated in the A549 tumor xenograft model, MSN8C has been identified as a promising candidate for antitumor applications.

Two series of novel acridone derivatives were designed and synthesized, with their anticancer activity evaluated. Most of these compounds showed potent antiproliferative activity against cancer cell lines. Among them, compound C4 with dual 1,2,3-triazol moieties exhibited the most potent activity against Hep-G2 cells with IC 50 value determined to be 6.29 ± 0.93 μM. Subsequent experiments showed that C4 could bind to and destabilize Kras gene promoter i-motif structure without significant interaction with its corresponding G-quadruplex. C4 could down-regulate Kras expression in Hep-G2 cells, possibly due to its interaction with the Kras i-motif. Further cellular studies indicated that C4 could induce apoptosis of Hep-G2 cells, possibly related to its effect on mitochondrial dysfunction. These results indicated that C4 could be further developed as a promising anticancer agent., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Metabolic reprogramming is a crucial hallmark of tumorigenesis. Modulating the reprogrammed energy metabolism is an attractive anticancer therapeutic strategy. We previously found a natural product, bouchardatine , modulated aerobic metabolism and inhibited proliferation in the colorectal cancer cell (CRC). Herein, we designed and synthesized a new series of bouchardatine derivatives to discover more potential modulators. We applied the dual-parametric high-content screening (HCS) to evaluate their AMP-activated protein kinase (AMPK) modulation and CRC proliferation inhibition effect simultaneously. And we found their antiproliferation activities were highly correlated to AMPK activation. Among them, 18a was identified with nanomole-level antiproliferation activities against several CRCs. Interestingly, the evaluation found that 18a selectively upregulated oxidative phosphorylation (OXPHOS) and inhibited proliferation by modulating energy metabolism. Additionally, this compound effectively inhibited the RKO xenograft growth along with AMPK activation. In conclusion, our study identified 18a as a promising candidate for CRC treatment and suggested a novel anti-CRC strategy by AMPK activating and OXPHOS upregulating.

Background: c-Kit protein is a signal transduction protein involved in multiple signal pathways, which play an important role in a variety of cellular events such as cell proliferation, apoptosis and differentiation. Special DNA secondary structures on the promoter of c-Kit gene, including G-quadruplex and i-motif structures, could act as "molecular switch" for gene transcriptional regulation, which are potentially important target for development of new anti-cancer drugs., Methods: We screened and evaluated the effect of compounds on c-Kit through several experiments, including SPR, FRET, CD, MST, NMR, dual-luciferase reporter assay, Western blot, qPCR, immunofluorescence, MTT assay, colony formation, cell scrape, cell apoptosis, cell cycle analysis, and transwell assay., Results: After extensive screening, we found that bisacridine derivative B05 had selective binding and stabilization to dual i-motif structures on c-Kit gene promoter, which could down-regulate c-Kit gene transcription and translation, resulting in inhibition of cell proliferation and metastasis. B05 exhibited potent anti-tumor activity on HGC-27 cells, and strongly suppressed tumor growth in HGC-27 xenograft mice model., Conclusions: B05 could interact with c-Kit promoter dual i-motif structures with excellent selectivity, which make it possible for selective regulation of gene transcription and translation. B05 could be further developed for selective anti-cancer agent targeting c-Kit promoter i-motifs., General Significance: i-Motifs on different proto-oncogene promoters are diversified, and especially binding of dual i-motifs on the same promoter simultaneously could significantly down-regulate gene transcription with decreased dosage, and therefore increasing the selectivity. This new strategy shed bight light on development of selective DNA-targeting ligands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Helicases are crucial enzymes in DNA and RNA metabolism and function by unwinding particular nucleic acid structures. However, most convenient and high-throughput helicase assays are limited to the typical duplex DNA. Herein, we developed an immunosorbent assay to monitor the Werner syndrome (WRN) helicase unwinding a wide range of DNA structures, such as a replication fork, a bubble, Holliday junction, G-quadruplex and hairpin. This assay could sensitively detect the unwinding of DNA structures with detection limits around 0.1 nM, and accurately monitor the substrate-specificity of WRN with a comparatively less time-consuming and high throughput process. Remarkably, we have established that this new assay was compatible in evaluating helicase inhibitors and revealed that the inhibitory effect was substrate-dependent, suggesting that diverse substrate structures other than duplex structures should be considered in discovering new inhibitors. Our study provided a foundational example for using this new assay as a powerful tool to study helicase functions and discover potent inhibitors.

Developing c-MYC transcription inhibitors that target the G-quadruplex has generated significant interest; however, few compounds have demonstrated specificity for c-MYC G-quadruplex and cancer cells. In this study, we designed and synthesized a series of benzoazole derivatives as potential G-quadruplex ligand-based c-MYC transcription inhibitors. Surprisingly, benzoselenazole derivatives, which are rarely reported as G-quadruplex ligands, demonstrated greater c-MYC G-quadruplex selectivity and cancer cell specificity compared to their benzothiazole and benzoxazole analogues. The most promising compound, benzoselenazole m-Se3 , selectively inhibited c-MYC transcription by specifically stabilizing the c-MYC G-quadruplex. This led to selective inhibition of hepatoma cell growth and proliferation by affecting the MYC target gene network, as well as effective tumor growth inhibition in hepatoma xenografts. Collectively, our study demonstrates that m-Se3 holds significant promise as a potent and selective inhibitor of c-MYC transcription for cancer treatment. Furthermore, our findings inspire the development of novel selenium-containing heterocyclic compounds as c-MYC G-quadruplex-specific ligands and transcription inhibitors.

Raptor, a regulatory-associated protein of mTOR, has been genetically proved to be an important regulator in lipogenesis. However, its druggable potential is rarely investigated, largely due to the lack of an inhibitor. In this study, the antiadipogenic screening of a daphnane diterpenoid library followed by target fishing led to the identification of a Raptor inhibitor, 1c (5/7/6 carbon ring with orthoester and chlorine functionalities). Pharmacodynamic studies verified that 1c is a potent and tolerable antiadipogenic agent in vitro and in vivo. Mechanistic studies revealed that the targeting of Raptor by 1c could block the formation of mTORC1 and then downregulate the downstream S6K1- and 4E-BP1-mediated C/EBPs/PPARγ signaling, eventually retarding adipocyte cell differentiation at the early stage. These findings suggest that Raptor can be explored as a novel therapeutic target for obesity and its related complications, and 1c as the first Raptor inhibitor may provide a new therapeutic option for these conditions.

Mutations in NRAS promote tumorigenesis and drug resistance. As this protein is often considered an undruggable target, it is urgent to develop novel strategies to suppress NRAS for anticancer therapy. Recent reports indicated that a G-quadruplex (G4) structure formed in the untranslated region of NRAS mRNA can downregulate NRAS translation, suggesting a potential NRAS suppression strategy. Here, we developed a novel cell-based method for large-scale screening of NRAS G4 ligand using the G-quadruplex-triggered fluorogenic hybridization probe and successfully identified the clinically used agent Octenidine as a potent NRAS repressor. This compound suppressed NRAS translation, blocked the MAPK and PI3K-AKT signaling, and caused concomitant cell cycle arrest, apoptosis, and autophagy. It exhibited better antiproliferation effects over clinical antimelanoma agents and could inhibit the growth of NRAS -mutant melanoma in a xenograft mouse model. Our results suggest that Octenidine may be a prominent anti- NRAS -mutant melanoma agent and represent a new NRAS -mutant melanoma therapy option.

Mitochondria have a crucial role in regulating energy metabolism and their dysfunction has been linked to tumorigenesis. Cancer diagnosis and intervention have a great interest in the development of new agents that target biomolecules within mitochondria. However, monitoring and modulating mitochondria RNA (mtRNA), an essential component in mitochondria, in cells is challenging due to limited functional research and the absence of targeting agents. In this study, we designed and synthesized a fluorescent quinolinium derivative, QUCO-1 , which actively lit up with mtRNA in both normal and cancer cells in vitro. Additionally, we evaluated the function of QUCO-1 as an mtRNA ligand and found that it effectively induced severe mitochondrial dysfunction and OXPHOS inhibition in RKO colorectal cancer cells. Treatment with QUCO-1 resulted in apoptosis, cell cycle blockage at the G2/M phase, and the effective inhibition of cell proliferation. Our findings suggest that QUCO-1 has great potential as a promising probe and therapeutic agent for mtRNA, with the potential for treating colorectal cancer.

Inter-organelle interactions play a vital role in diverse biological processes. Thus, chemical tools are highly desirable for understanding the spatiotemporal dynamic interplay among organelles in live cells and in vivo . However, designing such tools is still a great challenge due to the lack of universal design strategies. To break this bottleneck, herein, a novel unimolecular platform integrating the twisted intramolecular charge transfer (TICT) and aggregation-induced emission (AIE) dual mechanisms was proposed. As a proof of concept, two organelles, lipid droplets (LDs) and mitochondria, were selected as models. Also, the first TICT-AIE integration molecule, BETA-1 , was designed for simultaneous and dual-color imaging of LDs and mitochondria. BETA-1 can simultaneously target LDs and mitochondria due to its lipophilicity and cationic structure and emit cyan fluorescence in LDs and red fluorescence in mitochondria. Using BETA-1 , for the first time, we obtained long-term tracking of dynamic LD-mitochondrion interactions and identified several impressive types of dynamic interactions between these two organelles. More importantly, the increase in LD-mitochondrion interactions during ferroptosis was revealed with BETA-1 , suggesting that intervening in the LD-mitochondrion interactions may modulate this cell death. BETA-1 was also successfully applied for in vivo imaging of LD-mitochondrion interactions in C. elegans . This study not only provides an effective tool for uncovering LD-mitochondrion interactions and deciphering related biological processes but also sheds light on the design of new probes with an integrated TICT-AIE mechanism for imaging of inter-organelle interactions.

The homologous recombination repair (HRR) pathway is critical for repairing double-strand breaks (DSB). Inhibition of the HRR pathway is usually considered a promising strategy for anticancer therapy. The Bloom's Syndrome Protein (BLM), a DNA helicase, is essential for promoting the HRR pathway. Previously, we discovered quinazolinone derivative 9h as a potential BLM inhibitor, which suppressed the proliferation of colorectal cancer (CRC) cell HCT116. Herein, a new series of quinazolinone derivatives with N3-substitution was designed and synthesized to improve the anticancer activity and explore the structure-activity relationship (SAR). After evaluating their BLM inhibitory activity, the SAR was discussed, leading to identifying compound 21 as a promising BLM inhibitor. 21 exhibited the potent BLM-dependent cytotoxicity against the CRC cells but weak against normal cells. Further evaluation revealed that 21 could disrupt the HRR level while inhibiting BLM located on the DSB site and trigger DNA damage in the CRC cells. This compound effectively suppressed the proliferation and invasion of CRC cells, along with cell cycle arrest and apoptosis. Consequently, 21 might be a promising candidate for treating CRC, and the BLM might be a new potential therapeutic target for CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Euphylonoids A ( 1 ) and B ( 2 ), two highly modified jatrophane diterpenoids, were isolated from Euphorbia hylonoma . 1 represents a new 9(10→18)- abeo -8,12-cyclojatrophane skeleton containing a cage-like 3,8-dioxatricyclo[5.1.2.0 4,9 ]decane core, while 2 is a 14(13→20)- abeo -8,12-cyclojatrophane featuring an unusual 17-oxatetracyclo[12.2.1.0 1,5 .0 9,13 ]heptadecane framework. Their structural elucidation was completed by spectroscopic, chemical, computational, and single-crystal X-ray diffraction means. 2 significantly inhibited early adipogenesis in 3T3-L1 adipocytes via activating AMP-activated protein kinase signaling.

RNA imaging is of great importance for understanding its complex spatiotemporal dynamics and cellular functions. Considerable effort has been devoted to the development of small-molecule fluorescent probes for RNA imaging. However, most of the reported studies have mainly focused on improving the photostability, permeability, long emission wavelength, and compatibility with live-cell imaging of RNA probes. Less attention has been paid to the selectivity and detection limit of this class of probes. Highly selective and sensitive RNA probes are still rarely available. In this study, a new set of styryl probes were designed and synthesized, with the aim of upgrading the detection limit and maintaining the selectivity of a lead probe QUID-1 for RNA. Among these newly synthesized compounds, QUID-2 was the most promising candidate. The limit of detection (LOD) value of QUID-2 for the RNA was up to 1.8 ng/mL in solution. This property was significantly improved in comparison with that of QUID-1 . Further spectroscopy and cell imaging studies demonstrated the advantages of QUID-2 over a commercially available RNA staining probe, SYTO RNASelect, for highly selective and sensitive RNA imaging. In addition, QUID-2 exhibited excellent photostability and low cytotoxicity. Using QUID-2 , the global dynamics of RNA were revealed in live cells. More importantly, QUID-2 was found to be potentially applicable for detecting RNA granules in live cells. Collectively, our work provides an ideal probe for RNA imaging. We anticipate that this powerful tool may create new opportunities to investigate the underlying roles of RNA and RNA granules in live cells.

c-MYC is a key driver of tumorigenesis. Repressing the transcription of c-MYC by stabilizing the G-quadruplex (G4) structure with small molecules is a potential strategy for cancer therapy. Herein, we designed and synthesized 49 new derivatives by introducing carbohydrates to our previously developed c-MYC G4 ligand 1 . Among these compounds, 19a coupled with a d-glucose 1,2-orthoester displayed better c-MYC G4 binding, stabilization, and protein binding disruption abilities than 1 . Our further evaluation indicated that 19a blocked c-MYC transcription by targeting the promoter G4, leading to c-MYC -dependent cancer cell death in triple-negative breast cancer cell MDA-MB-231. Also, 19a significantly inhibited tumor growth in the MDA-MB-231 mouse xenograft model accompanied by c-MYC downregulation. Notably, the safety of 19a was dramatically improved compared to 1 . Our findings indicated that 19a could become a promising anticancer candidate, which suggested that introducing carbohydrates to improve the G4-targeting and antitumor activity is a feasible option.

The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold ( 1 ). Among the new compounds, a6 with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and 1 in TNBC cells. Remarkably, a6 caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, a6 significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.

Topo II and Hsp90 are promising targets. In this study, we first verified the structural similarities between Topo IIα ATPase and Hsp90α N-ATPase. Subsequently, 720 compounds from the Food and Drug Administration (FDA) drug library and kinase library were screened using the malachite green phosphate combination with the Topo II-mediated DNA relaxation and MTT assays. Subsequently, the antimalarial drug quinacrine was found to be a potential dual-target inhibitor of Topo II and Hsp90. Mechanistic studies showed that quinacrine could specifically bind to the Topo IIα ATPase domain and inhibit the activity of Topo IIα ATPase without impacting DNA cleavage. Furthermore, our study revealed that quinacrine could bind Hsp90 N-ATPase and inhibit Hsp90 activity. Significantly, quinacrine has broad antiproliferation activity and remains sensitive to the multidrug-resistant cell line MCF-7/ADR and the atypical drug-resistant tumor cell line HL-60/MX2. Our study identified quinacrine as a potential dual-target inhibitor of Topo II and Hsp90, depending on the ATP-binding domain, positioning it as a hit compound for further structural modification.

Benzothiazolium and benzoxazolium are common groups for the construction of hemicyanine dyes; however, their isosteric analogue benzoselenazolium have rarely been studied. Here, we report the development of the first benzoselenazolium-based hemicyanine dye for the selective detection of G-quadruplexes. This molecule, SEMA-1, was validated as a red-emitting and activatable fluorescent probe whose fluorescence would only be activated in the presence of G-quadruplexes in buffer solution. Consistent with this, SEMA-1 was found to accumulate in nucleoli and could be used to detect the high abundance of nucleolar rDNA and rRNA G-quadruplexes in fixed HeLa cells. On the other hand, due to the retained mitochondrial membrane potential in live HeLa cells, SEMA-1 was captured by mitochondria and had the potential to detect the mitochondrial G-quadruplexes. Collectively, this work demonstrates the value of developing G-quadruplex-specific fluorescent probes from novel benzoselenazolium-based hemicyanine scaffold., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Reported herein is an in situ-generated hypervalent iodine-incorporating fluoroarylation of benzylidenecyclopropanes using commercially available HF·Py and aryl iodides as fluorine and aryl sources, respectively. The reaction proceeds via regioselective 1,2-fluoroiodination of a double bond followed by an iodonio-[3,3]-rearrangement of the formed cyclopropyl-I (III) species. The protocol offers facile access to valuable monofluorinated 1,1-bis-benzyl-alkenes with mild reaction conditions and moderate to good yields. The synthetic utility of the products was demonstrated by further transformations. Preliminary mechanistic studies were conducted.

Ligand-Induced duplex-quadruplex transition within the c-MYC promoter region is one of the most studied and advanced ideas for c-MYC regulation. Despite its importance, there is a lack of methods for monitoring such process in cells, hindering a better understanding of the essence of c-MYC G-quadruplex as a drug target. Here we developed a new fluorescent probe ISCH-MYC for specific c-MYC G-quadruplex recognition based on GTFH (G-quadruplex-Triggered Fluorogenic Hybridization) strategy. We validated that ISCH-MYC displayed distinct fluorescence enhancement upon binding to c-MYC G-quadruplex, which allowed the duplex-quadruplex transition detection of c-MYC G-rich DNA in cells. Using ISCH-MYC, we successfully characterized the induction of duplex to G-quadruplex transition in the presence of G-quadruplex stabilizing ligand PDS and further monitored and evaluated the altered interactions of relevant transcription factors Sp1 and CNBP with c-MYC G-rich DNA. Thus, our study provides a visualization strategy to explore the mechanism of G-quadruplex stabilizing ligand action on c-MYC G-rich DNA and relevant proteins, thereby empowering future drug discovery efforts targeting G-quadruplexes., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background and Purpose: Non-alcoholic steatohepatitis (NASH) is the more severe form of metabolic associated fatty liver disease (MAFLD) and no pharmacological treatment as yet been approved. Identification of novel therapeutic targets and their agents is critical to overcome the current inadequacy of drug treatment for NASH., Experimental Approach: The correlation between heat shock factor 1 (HSF1) levels and the development of NASH and the target genes of HSF1 in hepatocyte were investigated by chromatin-immunoprecipitation sequencing. The effects and mechanisms of SYSU-3d in alleviating NASH were examined in relevant cell models and mouse models (the Ob/Ob mice, high-fat and high-cholesterol diet and the methionine-choline deficient diet-fed mice). The actions of SYSU-3d in vivo were evaluated., Key Results: HSF1 is progressively reduced with mitochondrial dysfunction in NASH pathogenesis and activation of this transcription factor by its newly identified activator SYSU-3d effectively inhibited all manifestations of NASH in mice. When activated, the phosphorylated HSF1 (Ser326) translocated to nucleus and bound to the promoter of PPARγ coactivator-1α (PGC-1α) to induce mitochondrial biogenesis. Thus, increasing mitochondrial adaptive oxidation and inhibiting oxidative stress. The deletion of HSF1 and PGC-1α or recovery of HSF1 in HSF1-deficiency cells showed the HSF1/PGC-1α pathway was mainly responsible for the anti-NASH effects of SYSU-3d independent of AMP-activated protein kinase (AMPK)., Conclusion and Implications: Activation of HSF1 is a practical therapeutic approach for NASH treatment via the HSF1/PGC-1α/mitochondrial pathway and SYSU-3d can be considered as a potential candidate for the treatment of NASH., (© 2021 The British Pharmacological Society.)

I-motifs play key regulatory roles in biological processes, holding great potential as attractive therapeutic targets. In the present study, we developed a novel fluorescent probe G59 with strong and selective binding to the c-myc gene promoter i-motif. G59 had an i-motif-binding carbazole moiety conjugated with naphthalimide fluorescent groups. G59 could differentiate the c-myc i-motif from other DNA structures through selective activation of its fluorescence, with its apparent visualization in solution. The smart probe G59 showed excellent sensitivity, with a low fluorescent detection limit of 154 nM and effective stabilization to the c-myc i-motif. G59 could serve as a rapid and sensitive probe for label-free screening of selective c-myc i-motif binding ligands under neutral crowding conditions. To the best of our knowledge, G59 is the first fluorescent probe with high sensitivity for recognizing the i-motif structure and screening for selective binding ligands.

Promoting energy expenditure is known to curb obesity and can be exploited for its treatment. Our previous study has demonstrated that activation of HSF1/PGC-1α axis efficiently induced mitochondrial biogenesis and adaptive oxidation and thus ameliorating lipid accumulation, however, whether it can be a therapeutic approach for metabolic disorders treatment needs explored. Here, a high-efficient and specific HSF1/PGC-1α activator screening system was established and the natural clinical liver-protecting agent matrine was identified as a robust HSF1/PGC-1α activator. Matrine treatment efficiently induced mitogenesis and thermogenic program in primary mouse adipose stem cell derived adipocytes by enriching HSF1 to the promoter of Pgc-1α. Deficiency of PGC-1α in adipocytes diminished the browning induction ability of matrine. Oral administration of matrine to the obese mice induced by high fat and high cholesterol diet increased energy expenditure and corrected the degeneration of thermogenesis in brown adipose tissue (BAT). Also, matrine treatment markedly induced the transformation of brown-like adipocytes in subcutaneous white adipose tissue (sWAT) via a mechanism of HSF1/PGC-1α, thereby attenuating obesity and myriads of metabolic disorders. This led to an improvement in adaptive thermogenesis to cold stimuli. These findings are of great significance in understanding the regulation mechanisms of the HSF1/PGC-1α axis in thermogenesis and providing a novel therapeutic approach for obesity treatment. Matrine may have potential therapeutic implications for the treatment of obesity in clinics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The indolyl-4(3 H )-quinazolinone core is an important structural motif in functional molecules. However, few methods exist for its direct modification, which limits its potential application. Reported herein is a palladium-mediated amination of halogen-containing indolyl-4(3 H )-quinazolinones with a variety of primary and secondary amines via the corresponding palladium oxidative addition complexes. The protocol allows the facile synthesis of indolyl-4(3 H )-quinazolinone derivatives with amino groups at all the positions of the benzene ring in moderate to good yields with mild reaction conditions and good functional group tolerance. Furthermore, the antitumor activity of these products was evaluated.

The mitochondrial DNA G-quadruplex (mtDNA G4) is a potential regulatory element for the regulation of mitochondrial functions; however, its relevance and specific roles in diseases remain largely unknown. Here, we engineered a set of chemical probes, including MitoISCH , an mtDNA G4-specific fluorescent probe, together with MitoPDS , a mitochondria-targeted G4-stabilizing agent, to thoroughly investigate mtDNA G4s. Using MitoISCH to monitor previously intractable dynamics of mtDNA G4s, we surprisingly found that their formation was prevalent only in endothelial and cancer cells that rely on glycolysis for energy production. Consistent with this, promotion of mtDNA G4 folding by MitoPDS in turn caused glycolysis-related gene activation and glycolysis enhancement. Remarkably, this close relationship among mtDNA G4s, glycolysis, and cancer cells further allowed MitoISCH to accumulate in tumors and label them in vivo. Our work reveals an unprecedented link between mtDNA G4s and cell glycolysis, suggesting that mtDNA G4s may be a novel cancer biomarker and therapeutic target deserving further exploration.

Because of the lack of facile and accurate methods to track stress granule (SG) dynamics in live cells and in vivo , in-depth studies of the biological roles of this attractive membraneless organelle have been limited. Herein, we report the first small-molecule probe, TASG , for the selective, convenient and real-time monitoring of SGs. This novel molecule can simultaneously bind to SG RNAs, the core SG protein G3BP1, and their complexes, triggering a significant enhancement in fluorescence intensity, making TASG broadly applicable to SG imaging under various stress conditions in fixed and live cells, ex vivo and in vivo . Using TASG , the complicated endogenous SG dynamics were revealed in both live cells and C. elegans . Collectively, our work provides an ideal probe that has thus far been absent in the field of SG investigations. We anticipate that this powerful tool may create exciting opportunities to investigate the underlying roles of SGs in different organisms.

Telomere is a specialized DNA-protein complex that plays an important role in maintaining chromosomal integrity. Shelterin is a protein complex formed by six different proteins, with telomeric repeat factors 1 (TRF1) and 2 (TRF2) binding to double-strand telomeric DNA. Telomeric DNA consists of complementary G-rich and C-rich repeats, which could form G-quadruplex and intercalated motif (i-motif), respectively, during cell cycle. Its G-rich transcription product, telomeric repeat-containing RNA (TERRA), is essential for telomere stability and heterochromatin formation. After extensive screening, we found that acridine derivative 2c and acridine dimer DI26 could selectively interact with TRF1 and telomeric i-motif, respectively. Compound 2c blocked the binding of TRF1 with telomeric duplex DNA, resulting in up-regulation of TERRA. Accumulated TERRA could bind with TRF1 at its allosteric site and further destabilize its binding with telomeric DNA. In contrast, DI26 could destabilize telomeric i-motif, resulting in down-regulation of TERRA. Both compounds exhibited anti-tumour activity for A549 cells, but induced different DNA damage pathways. Compound 2c significantly suppressed tumour growth in A549 xenograft mouse model. The function of telomeric i-motif structure was first studied with a selective binding ligand, which could play an important role in regulating TERRA transcription. Our results showed that appropriate level of TERRA transcript could be important for stability of telomere, and acridine derivatives could be further developed as anti-cancer agents targeting telomere. This research increased understanding for biological roles of telomeric i-motif, TRF1 and TERRA, as potential anti-cancer drug targets.

Novel mansonone F derivative MSN54 (9-bromo-2,3-diethylbenzo[de]chromene-7,8-dione) exhibited significant cytotoxicity against twelve human tumor cell lines in vitro, with particularly strong potency against HL-60/MX2 cell line resistant to Topo II poisons. MSN54 was found to have IC 50 of 0.69 and 1.43 µM against HL-60 and HL-60/MX2 cells, respectively. The resistance index is 10 times lower than that of the positive control VP-16 (etoposide). Various biological assays confirmed that MSN54 acted as a Topo IIα specific non-intercalative catalytic inhibitor. Furthermore, MSN54 exhibited good antitumor efficacy and low toxicity at a dose of 5 mg/kg in A549 tumor xenograft models. Thus, compound MSN54 is a promising candidate for the development of novel antitumor agents., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A hypervalent iodine(III)-mediated ring-contractive fluorination reaction of 2-alkylidenecyclobutanol derivatives is presented. The protocol allows the facile synthesis of β-monofluorinated cyclopropanecarbaldehydes via a fluorination/semipinacol rearrangement cascade using nucleophilic Py·HF as the fluorine source. For challenging electron-rich arene substrates, the installation of a protecting group on the free alcohol is pivotal for maintaining the reaction efficiency. The synthetic utility was demonstrated by the scalability of this reaction and further transformations of the products.

The geminal difluorocyclobutane core is a valuable structural element in medicinal chemistry. Strategies for gem -difluorocyclobutanes, especially the 2-substituted cases, are limiting and often suffer from harsh reaction conditions. Reported herein is a migratory gem -difluorination of aryl-substituted methylenecycloproanes (MCPs) for the synthesis of 2-arylsubstituted gem -difluorocyclobutanes. Commercially available Selectfluor (F-TEDA-BF 4 ) and Py·HF were used as the fluorine sources. The protocol proceeds via a Wagner-Meerwein rearrangement with mild reaction conditions, good functional group tolerance, and moderate to good yields. The product could be readily transformed to gem -difluorocyclobutane-containing carboxylic acid, amine, and alcohol, all of which are useful building blocks for biologically active molecule synthesis.

Upregulation of platelet-derived growth factor receptor β (PDGFR-β) has been found to be associated with development of various types of cancers, which has become an attractive target for anti-tumor treatment. Previously, we have synthesized and studied an acridone derivative B19, which can selectively bind to and stabilize oncogene c-myc promoter i-motif, resulting in down-regulation of c-myc transcription and translation, however its effect on tumor cells apoptosis requires improvement. In the present study, we synthesized a variety of B19 derivatives containing a known anti-cancer fluorescent chromophore naphthalimide for the purpose of enhancing anti-cancer activity. After screening, we found that acridone-naphthalimide derivative WZZ02 could selectively stabilize PDGFR-β promoter G-quadruplex and destabilize its corresponding i-motif structure, without significant interaction to other oncogenes promoter G-quadruplex and i-motif. WZZ02 down-regulated PDGFR-β gene transcription and translation in a dose-dependent manner, possibly due to above interactions. WZZ02 could significantly inhibit cancer cell proliferation, and induce cell apoptosis and cycle arrest. WZZ02 exhibited tumor growth inhibition activity in MCF-7 xenograft tumor model, which could be due to its binding interactions with PDGFR-β promoter G-quadruplex and i-motif. Our results suggested that WZZ02 as a dual G-quadruplex/i-motif binder could be effective on both oncogene replication and transcription, which could become a promising lead compound for further development with improved potency and selectivity. The wide properties for the derivatives of 1,8-naphthalimide could facilitate further in-depth mechanistic studies of WZZ02 through various fluorescent physical and chemical methods, which could help to further understand the function of PDGFR-β gene promoter G-quadruplex and i-motif., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Borylated aza-arenes are of great importance in the area of organic synthesis. A radical borylative cyclization of isocyanoarenes with N-heterocyclic carbene borane (NHC-BH 3 ) under metal-free conditions was developed. The reaction allows the efficient assembly of several types of borylated aza-arenes (phenanthridines, benzothiazoles, etc.), which are difficult to access using alternative methods. Mild reaction conditions, a good functional-group tolerance, and generally good efficiencies were observed. The utility of these products is demonstrated, and the mechanism is discussed.

α-Haloboronates are useful organic synthons that can be converted to a diverse array of α-substituted alkyl borons. Methods to α-haloboronates are limiting and often suffer from harsh reaction conditions. Reported herein is a photochemical radical C-H halogenation of benzyl N-methyliminodiacetyl (MIDA) boronates. Fluorination, chlorination, and bromination reactions were effective by using this protocol. Upon reaction with different nucleophiles, the C-Br bond in the brominated product could be readily transformed to a series of C-C, C-O, C-N, C-S, C-P, and C-I bonds, some of which are difficult to forge with α-halo sp 2 -B boronate esters. An activation effect of B(MIDA) moiety was found., (© 2020 Wiley-VCH GmbH.)