Integrated Anchored Stapling and Hierarchical Dynamics: MSICDA-Driven CREBBP Bromodomain Inhibition.

Despite recent success in the computational approaches of cyclic peptide design, current studies face challenges in modeling noncanonical amino acids and nonstandard cyclizations due to limited data. To address this challenge, we developed an integrated framework for the tailored design of stapled peptides (SPs) targeting the bromodomain of CREBBP (CREBBP-BrD). We introduce a powerful combination of anchored stapling and hierarchical molecular dynamics to design and optimize SPs by employing the MultiScale integrative conformational dynamics assessment (MSICDA) strategy, which involves an initial virtual screening of over 1.5 million SPs, followed by comprehensive simulations amounting to 154.54 µs across 5418 of instances. The MSICDA method provides a detailed and holistic stability view of peptide-protein interactions, systematically isolated optimized peptides and identified two leading candidates, DA#430 and DA#99409, characterized by their enhanced stability, optimized binding, and high affinity toward the CREBBP-BrD. In cell-free assays, DA#430 and DA#99409 exhibited 2- to 12-fold greater potency than inhibitor SGC-CBP30. Cell studies revealed higher peptide selectivity for cancerous versus normal cells over small molecules. DA#430 combined with (+)-JQ-1 showed promising synergistic effects. Our approach enables the identification of peptides with optimized binding, high affinity, and enhanced stability, leading to more precise and effective cyclic peptide design, thereby establishing MSICDA as a generalizable and transformative tool for uncovering novel targeted drug development in various therapeutic areas.

Molecular Dynamics and In Vitro Studies Elucidating the Tunable Features of Reconfigurable Nanodiscs for Guiding the Optimal Design of Curcumin Formulation.

In this study, we advance our exploration of Apolipoprotein A-I (apoA-I) peptide analogs (APAs) for their application in nanodisc (ND) assembly, focusing on the dynamic conformational characteristics and the potential for drug delivery. We explore APA-ND interactions with an emphasis on curcumin encapsulation, utilizing molecular dynamic simulations and in vitro assessments to evaluate the efficacy of various APA-ND formulations as drug carriers. The methodological approach involved the generation of three unique apoA-I α-11/3 helical mimics, resulting in fifteen distinct APAs. Their structural integrity was rigorously assessed using ColabFold-AF2, with particular attention to pLDDT and pTM scores. Extensive molecular dynamics simulations, covering 1.7 µs across 17 ND systems, were conducted to investigate the influence of APA sequence variations on ND stability and interactions. This study reveals that the composition of APAs, notably the presence of Proline, Serine, and Tryptophan, significantly impacts ND stability and morphology. Oligomeric APAs, in particular, demonstrated superior stability and distinct interaction patterns compared to their monomeric counterparts. Additionally, hydrodynamic diameter measurements over eight weeks indicated sequence-dependent stability, highlighting the potential of specific APA configurations for sustained colloidal stability. In vitro study successfully encapsulated curcumin in [AA]3/DMPC ND formulations, revealing concentration-dependent stability and interaction dynamics. The findings underscore the remarkable capability of APA-NDs to maintain structural integrity and efficient drug encapsulation, positioning them as a promising platform for drug delivery. The study concludes by emphasizing the tunability and versatility of APA-NDs in drug formulation, potentially revolutionizing nanomedicine by enabling customized APA sequences and ND properties for targeted drug delivery.

Novel berberine derivatives as p300 histone acetyltransferase inhibitors in combination treatment for breast cancer.

Adenoviral E1A binding protein p300 (EP300 or p300) and its similar paralog, cyclic-AMP response element binding protein (CBP), are important histone acetyltransferases (HAT) and transcriptional co-activators in epigenetics, participating in numerous cellular pathways including proliferation, differentiation and apoptosis. The overexpression or dysregulation of p300/CBP is closely related to oncology-relevant disease. The inhibition of p300 HAT has been found to be a potential drug target. Berberine has been reported to show anticancer activity and synergistic effect in combination with some of the clinical anticancer drugs via modulation of various pathways. Here, the present study sought to discover more chemotypes of berberine derivatives as p300 HAT inhibitors and to examine the combination of these novel analogues with doxorubicin for the treatment of breast cancer. A series of novel berberine derivatives with modifications of A/B/D rings of berberine have been designed, synthesized and screened. Compound 7b was found to exhibit inhibitory potency against p300 HAT with IC50 values of 1.51 µM. Western blotting proved that 7b decreased H3K27Ac and interfered with the expression of oncology-relevant protein in MCF-7 cells. Further bioactive evaluation showed that combination of compound 7b with doxorubicin could significantly inhibit tumor growth and invasion in vitro and in vivo.

Translational Challenges and Prospective Solutions in the Implementation of Biomimetic Delivery Systems.

Biomimetic delivery systems (BDSs), inspired by the intricate designs of biological systems, have emerged as a groundbreaking paradigm in nanomedicine, offering unparalleled advantages in therapeutic delivery. These systems, encompassing platforms such as liposomes, protein-based nanoparticles, extracellular vesicles, and polysaccharides, are lauded for their targeted delivery, minimized side effects, and enhanced therapeutic outcomes. However, the translation of BDSs from research settings to clinical applications is fraught with challenges, including reproducibility concerns, physiological stability, and rigorous efficacy and safety evaluations. Furthermore, the innovative nature of BDSs demands the reevaluation and evolution of existing regulatory and ethical frameworks. This review provides an overview of BDSs and delves into the multifaceted translational challenges and present emerging solutions, underscored by real-world case studies. Emphasizing the potential of BDSs to redefine healthcare, we advocate for sustained interdisciplinary collaboration and research. As our understanding of biological systems deepens, the future of BDSs in clinical translation appears promising, with a focus on personalized medicine and refined patient-specific delivery systems.

Pathway to Construct α-Acyloxy Esters by B(C6F5)3-Catalyzed O-H Insertion of Carboxylic Acids with Sulfoxonium Ylides.

We report the first example of B(C6F5)3-catalyzed O-H insertion reaction of sulfoxonium ylides and carboxylic acids, achieving efficient construction of diester moieties under metal-free condition. This protocol is characterized by broad substrate tolerance, particularly for various phenylacetic acids, and good compatibility with water/air condition, which is superior to most other methods.

Synthesis of Oxo-Bridged Dibenzoazocines through Ruthenium-Catalyzed [4 + 3]-Cycloannulation of Aza-ortho-quinone Methides with Carbonyl Ylides.

Oxo-bridged dibenzoazocines are furnished within a single synthetic step at room temperature via ruthenium-catalyzed [4 + 3]-cycloannulation of aza-ortho-quinone methides with carbonyl ylides. Exclusive diastereoselectivity, excellent yield, mild reaction conditions, and broad substrate scope are distinguishing features of this protocol. The product could be prepared on a gram scale and could be further functionalized into diverse substituted dihydroisobenzofuran derivatives and a dibenzoazocine scaffold.

The Pyridotriazole Works as a Traceless Directing Group: A C-H Activation/Annulation Cascade Reaction with Iodonium Ylides.

A novel Rh-catalyzed cascade reaction of pyridotriazoles with iodonium ylides is reported. This one-pot procedure involves a triazole-directed ortho-position C-H carbene insertion, followed by intramolecular denitrogenation annulation. It was noteworthy that this reaction provided straightforward access to 1H-isochromene frameworks with excellent yields (up to 94% yield).

Rh(III)-Catalyzed C-H Olefination Cascades to Divergently Construct Diverse Polyheterocycles by Tuning Manipulations of Directing Groups.

Inspired by the diversity created by nature, organic chemists have been using a divergent strategy to improve the synthetic efficiency of diverse molecules. Transition-metal-catalyzed C-H functionalization has become one of the most straightforward, powerful, and atom-economical methods to construct complex scaffolds. However, C-H activation initiated divergent transformation to prepare diverse molecules is still limited. To address this challenge, we herein developed Rh(III)-catalyzed C-H olefination/annulation reaction cascades to divergently construct diverse polyheterocycles by tuning manipulations of directing groups (DGs). Up to 9 distinct scaffolds were creatively synthesized under simple conditions with good functional group tolerance, chemo-, and regioselectivity. Such a versatile strategy and its extension may encourage researchers to discover more promising manipulations of DGs for transition-metal-catalyzed C-H bond activation, making diverse available targets and materials that would have been previously out of range.

Palladium-catalyzed cross-coupling reaction of sulfoxonium ylides and benzyl bromides by carbene migratory insertion.

A palladium-catalyzed cross-coupling reaction of sulfoxonium ylides and benzyl bromides has been developed, which has potential safety advantages over previous carbene coupling reactions using either diazo compounds or their in situ precursors. This reaction affords polysubstituted olefins, and features good substrate tolerance and is suitable for late-stage modification of biologically active molecules. Pd-carbene migratory insertion is supposed to be involved in this coupling reaction.

Blue Light-promoted Carbene Transfer Reactions of Tosylhydrazones.

Metal-free photochemical carbene-transfer reactions of tosylhydrazones were developed under blue light irradiation at room temperature. This reaction constructs C-X (X=C, N, O, S) bonds and cyclopropanes from readily available and stable starting materials.

Decreased IL-37 expression in hepatocellular carcinoma tissues and liver cancer cell lines.

The role of IL-37 in cancer is currently largely unknown. The present study aimed to investigate IL-37 expression in hepatocellular carcinoma (HCC), paracancerous tissues (PT) and liver cancer cell lines, and their associations between IL-37 and NF-κB. A total of 65 HCC and 65 PT tissues were collected. The expression of IL-37 and NF-κB in tissues was detected by immunohistochemistry (IHC) and the data was analyzed using SPSS software. In the in vitro studies, IL-37 gene was transfected into HepG2 and MHCC97H cell lines with Lipofectamine 3000, and the protein regulation of NF-κB by IL-37 was verified by immunofluorescence (IF) and western blotting. In HCC, the positive expression rates of IL-37 and NF-kB were 21.5 and 95.4%, respectively. In PT, strong positive staining of IL-37and weak positive staining of NF-κB were observed. The normal expression levels of IL-37 and NF-κB, the increased IL-37 and decreased NF-κB induced by IL-37 gene transfection were observed through IF in cell lines. In terms of clinical significance, the difference in IL-37 expression between HCC and PT was statistically significant (χ2=55.05; P<0.001). IL-37 expression in HCC but not PT was negatively associated with serum AFP (χ2=6.522; P=0.039). IL-37 expression in PT was associated with sex (χ2=13.12; P=0.003) and tumor size (χ2=7.996; P=0.045). NF-κB expression in PT was associated with age, sex and BCLC stage. Notably, there was a negative correlation between IL-37 and NF-κB in HCC (r=-0.277; P=0.029) but not in PT (P>0.05). IL-37 overexpression downregulated the NF-κB protein by 56.50% in HepG2 cells (P<0.05) and 30.52% in MHCC97H cells (P<0.05). In conclusion, the expression of IL-37 in HCC and PT was specifically associated with serum AFP and tumor size, respectively. IL-37 expression was negatively correlated with NF-κB protein expression in HCC tissues and liver cancer cell lines.

Low expression of IL-37 protein is correlated with high Oct4 protein expression in hepatocellular carcinoma.

OBJECTIVE: The function of IL-37 in cancer remains largely unclear. The present research was to probe the protein expression of IL-37 and Oct4 in hepatocellular carcinoma (HCC), para-cancerous tissues (PT) and cancer cell lines, and discuss their relationship. METHODS: Forty-nine HCC specimens and forty-nine PT samples were collected for immunohistochemical staining of IL-37 and Oct4 protein. Then, the correlations among IL-37, Oct4 and the clinical indicators were analyzed. In further in vitro studies, IL-37 was over expressed in HepG2 and MHCC97H cancer cell lines by gene transfection using a lipo3000 kit. Finally, the protein expression of IL-37 and Oct4 was detected by immunofluorescence and western blot to verify the in vivo correlation between IL and 37 and Oct4. RESULTS: In HCC, IL-37 protein expression was weakly positive with a positive rate of 12.2% while Oct4 expression was strongly positive with a positive rate of 91.8%. In PT, strong positive IL-37 (83.7%) and weakly positive Oct4 (91.8%) were shown. The increased IL-37 and decreased Oct4 induced by IL-37 gene transfection were observed through IF in cells. In terms of clinical significance, the difference of IL-37 expression between HCC and PT was statistically significant (χ2 = 51.815, P = 3.2796 × 10-11). IL-37 in tumor tissues was associated with serum AFP (χ2 = 5.515, P = 0.048) and cirrhosis (χ2 = 7.451, P = 0.014). IL-37 expression of PT was link to gender (χ2 = 10.376, P = 0.013) and tumor size (χ2 = 8.118, P = 0.04). The expression of Oct4 in HCC was related to the patient's gender and cirrhosis. Importantly, there was a negative correlation between IL and 37 and Oct4 in tumor tissues (r = -0.299, P = 0.047) but not in PT (P > 0.05). Oct4 protein expression was down-regulated by IL-37 by 63.35% in HepG2 cells (P < 0.05) and 95.20% in MHCC97H cells (P < 0.05). CONCLUSION: IL-37 expression in tumor tissues and PT was related to serum AFP and liver cirrhosis, tumor size, respectively. IL-37 protein expression was correlated with Oct4 in cancer cell lines and tumor tissues but not PT. The present study indicated that IL-37 might play a role in the development of HCC.

Water-mediated C-H activation of arenes with secure carbene precursors: the reaction and its application.

A water-mediated C-H activation using sulfoxonium ylides is reported, providing a general, green and step-economic approach to construct a C-C bond and varieties of useful N-heterocycle scaffolds. Notably, the "water-mediated" activation, in contrast to that in organic solvents, shows great potential in pharmaceutical, biochemistry and chemical industries.

Correction: Synthesis of indoles and quinazolines via additive-controlled selective C-H activation/annulation of N-arylamidines and sulfoxonium ylides.

Correction for 'Synthesis of indoles and quinazolines via additive-controlled selective C-H activation/annulation of N-arylamidines and sulfoxonium ylides' by Ruizhi Lai et al., Chem. Commun., 2019, 55, 4039-4042.

Synthesis of indoles and quinazolines via additive-controlled selective C-H activation/annulation of N-arylamidines and sulfoxonium ylides.

Selective synthesis of indole and quinazoline products was achieved through a precise control of the C-H activation/annulation by changing the additives from NaOAc to CuF2/CsOAc. This strategy constructs indole and quinazoline scaffolds efficiently, and hence is of great interest in pharmaceutical, agricultural and chemical industries.

[Cp*RhIII ]/Ionic Liquid as a Highly Efficient and Recyclable Catalytic Medium for C-H Amidation.

A [Cp*RhIII ]-catalyzed direct C-H amidation is carried out in ionic liquid. Both C(sp2 )-H bonds of (hetero)arenes and alkenes and unactivated C(sp3 )-H bonds can be easily amidated with high functional-group tolerance and excellent yields under these conditions. Notably, using [Cp*RhIII ]/[BMIM]BF4 (BMIM=1-butyl-3-methylimidazolium) as the green and recyclable medium is environmentally benign, in light of characteristics such as the reusability of the expensive rhodium catalyst, avoidance of highly toxic organic solvents, and mild reaction conditions, as well as a short reaction time.