Due to its advantages, such as biocompatibility and controllability, silk has been used in various biomedical applications. Nowadays, researchers have improved silk fibers with new functions to expand their applicability. Many studies have focused on improving leaves feeding for silkworms to produce fluorescence, and the study of organic afterglow silkworm cocoon silk (SCS) is an unprecedented innovative combination. Here, we use natural SCS to prepare room-temperature phosphorescent materials by doping with luminescent difluoroboron beta-diketonate (BF(2)bdk). SCS shells can provide a rigid environment for the BF(2)bdk triplet to suppress its nonradiative decay and oxygen quenching. In addition, room-temperature phosphorescent materials were prepared by improving leaves and processing raw silk as well as using natural products such as feathers and shells as matrices. There is a lot of potential application value of widely sourced, diverse in composition, environmentally friendly, and sustainable natural functionalized products.

The palladium -catalyzed allylic substitution (Tsuji -Trost) reaction is widely applied in organic synthesis, especially for the synthesis of stereochemically well-defined olefins. However, the synthesis of Z -olefins via the Tsuji -Trost reaction has been challenging due to the thermodynamic instability of the corresponding anti-TC-allyl- palladium intermediate. Here, we report a ligand-enabled palladium -catalyzed Z -retentive allylic substitution reaction that retains Z -olefin geometries. Palladium catalysts derived from sterically bulky phosphoramidite ligands well differentiate the reaction rates between the nucleophilic attack step and the TC-C5-TC isomerization process. The Z -retentive allylic substitution results from the nucleophilic attack occurring much faster than the isomerization process. The isomerization of anti-TC-allyl-palladium intermediate into its syn-counterpart has been observed at a low temperature. These results provide a prospective approach for the preparation of chiral Z -olefin compounds.

The reaction regioselectivity of gem-difluoroalkenes is dependent on the intrinsic polarity. Thus, the reversal of the regioselectivity of the addition reaction of gem-difluoroalkenes remains a formidable challenge. Herein, we described an unprecedented reversal of regioselectivity of hydrogen atom transfer (HAT) to gem-difluoroalkenes triggered by Fe-H species for the formation of difluoroalkyl radicals. Hydrogenation of the in situ generated radicals gave difluoromethylated products. Mechanism experiments and theoretical studies revealed that the kinetic effect of the irreversible HAT process resulted in the reversal of the regioselectivity of this scenario, leading to the formation of a less stable alpha-difluoroalkyl radical regioisomer. On basis of this new reaction of gem-difluoroalkene, the iron-promoted hydrohalogenation of gem-difluoroalkenes for the efficient synthesis of aliphatic chlorodifluoromethyl-, bromodifluoromethyl- and iododifluoromethyl-containing compounds was developed. Particularly, this novel hydrohalogenation of gem-difluoroalkenes provided an effect and large-scale access to various iododifluoromethylated compounds of high value for synthetic application.

Amino acid-derived quaternary ammonium salts were successfully applied in the asymmetric aza-Henry reaction of nitromethane to N-Boc trifluoromethyl ketimines. alpha-Trifluoromethyl beta-nitroamines were synthesized in good to excellent yields with moderate to good enantioselectivities. This reaction is distinguished by its mild conditions, low catalyst loading (1 mol%), and catalytic base. It also proceeded on a gram scale without loss of enantioselectivity. The products were transformed to a series of adamantane-type compounds containing chiral trifluoromethylamine fragments. The potent anticancer activities of these compounds against liver cancer HepG2 and melanoma B16F10 were evaluated. Six promising compounds with notable efficacy have potential for further development.

A novel Fe(III) complex, Fe-tBPCDTA, was synthesized and explored as a potential contrast agent for MRI. Compared to established agents like Fe-EDTA and Fe-tCDTA, Fe-tBPCDTA exhibited moderate relaxivity (r(1) = 1.17 s(-1)mmol(-1)) due to its enhanced second-sphere mechanism. It also displayed improved kinetic inertness, lower cytotoxicity, and enhanced redox stability. In vivo studies demonstrated its function as an extracellular fluid agent, providing tumor contrast comparable to that of Gd-DTPA at a higher dosage. Complete renal clearance occurred within 24 h. These findings suggest Fe-tBPCDTA as a promising candidate for further development as a safe and effective extracellular MRI contrast agent.

Low-valent transition-metal diazenido species are important intermediates in transition-metal-mediated dinitrogen reduction reactions. Isolable complexes of the type unanimously feature closed-shell diazenido ligands. Those bearing open-shell diazenido ligands have remained elusive. Herein, we report the synthesis, characterization, and reactivity of a d(7) iron(I) complex featuring an open-shell silyldiazenido ligand, [(ICy)Fe((NNSiPr3)-Pr-i)(eta(2):eta(2)-dvtms)] (1, ICy = 1,3-dicyclohexylimidazole-2-ylidene, dvtms = divinyltetramethyldisiloxane). Complex 1 is prepared in good yield by silylation of the iron(-I)-N-2 complex [K(18-crown-6)][(ICy)Fe(N-2)(eta(2):eta(2)-dvtms)] with (Pr3SiOTf)-Pr-i and has been fully characterized by various spectroscopic methods. Theoretical studies, in combination with characterization data, established an S = 1/2 ground spin-state for 1 that can best be described as a quartet iron(I) center featuring an antiferromagnetically coupled triplet silyldiazenido ligand. The diazenido and alkene ligands in 1 are labile, as indicated by the facile disproportionation reaction of 1 at ambient temperature to transform into the iron(II) bis(diazenido) species [(ICy)((NNSiPr3)-Pr-i)(2)Fe(dvtms)Fe((NNSiPr3)-Pr-i)(2)(ICy)] (2) and the iron(0) species [(ICy)Fe(eta(2):eta(2)-dvtms)] and also the alkene-exchange reaction of 1 with PhCH=CHBC8H14 to form [(ICy)Fe((NNSiPr3)-Pr-i)(eta(2)-trans-PhCH=CHBC8H14)] (3). Complex 1 is light-sensitive. Upon photolysis, it undergoes a (SiPr3)-Pr-i radical-transfer reaction to yield [(ICy)Fe(sigma:eta(2)-MeCHSiMe2OSiMe2CH=(CHSiPr3)-Pr-i)] (4) and N-2. The reactions of 1 with the trityl radical and organic bromides yield iron(II) complexes, which indicates its reducing nature. Moreover, 1 is a weak hydrogen-atom abstractor, as indicated by its inertness toward HSi(SiMe3)(3) and cyclohexa-1,4-diene and the low calculated N-H bond dissociation energy (48 kcal/mol) of its corresponding iron(II) iso-hydrazenido species.

A palladium-catalyzed ring-opening cyclization of (E) & (Z)-ene-vinylidenecyclopropanes has been developed via an intramolecular [3 + 2] cycloaddition process in the presence of a sterically bulky biaryl phosphine ligand, stereoselectively affording fused cis- & trans-bicyclo[4.3.0] skeletal products in good yields with a broad substrate scope and good functional tolerance. A plausible reaction mechanism was proposed on the basis of previous work and the DFT calculations.

Macrocyclization reactions that are capable of stereoselectively co-creating one or more stereogenic centers have become useful strategies for the effective syntheses of structurally and functionally diverse organic molecules. This JOCSynopsis summarizes the recent progress in the field of natural product and analogue syntheses, including both bioinspired and non-bioinspired macrocyclic disconnections. Selected examples are organized on the basis of the sources of the asymmetric inductions.

Reported herein is an unprecedented protocol for C(sp(3))-phosphinylation. With 1 mol% 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) as the catalyst, the visible light induced reaction of redox-active esters of aliphatic carboxylic acids with dimethyl arylphosphonites or diethyl alkylphosphonites at room temperature provides the corresponding decarboxylative phosphinylation products in satisfactory yields. The protocol exhibits broad substrate scope and wide functional-group compatibility, enabling the late-stage modification of complex molecules and rapid synthesis of bioactive phosphinic acids such as glutamine synthetase phosphinothricin and a kynureninase inhibitor. A radical-polar crossover mechanism involving the formation and subsequent oxidation of phosphoranyl radicals followed by nucleophilic demethylation (or deethylation) is proposed.

Herein, we establish a remote hydrosulfonamidation (HSA) of alkenes using palladium catalysis, where N-fluoro-N-(fluoro-sulfonyl)-carbamate with a sulfur(VI) fluoride moiety is demonstrated as a good amidation reagent. The anti-Markovnikov HSA reaction of terminal alkenes and the remote HSA of internal alkenes are achieved to efficiently yield primary N-alkyl-N-(fluorosulfonyl)-carbamates. In addition, this protocol enables the high-value utilization of alkane by combining the dehydrogenation process. The generated N-alkyl products exhibit a unique reactivity of sulfur(VI) fluorides, which can be directly transferred to N-alkyl sulfamides or amines via the sulfur(VI) fluoride exchange reaction, thereby streamlining their synthesis. Moreover, a (pyridyl) benzazole-type ligand proved to be vital for the excellent chemo- and regioselectivities.

Palladium-catalyzed selective cleavage of the distal C-C bond and proximal C-C bond of keto-vinylidenecyclopropanes by altering the sterically bulky phosphine ligands has been realized. The proximal C-C bond cleavage can be achieved by using dtbpf as a phosphine ligand, affording bicyclic products containing dihydrofuran skeletons in good yields along with broad substrate scope. In proximal C-C bond cleavage reactions, the eight-membered cyclic palladium intermediate plays a key role in the reaction. The [3 + 2] cycloaddition of keto-vinylidenecyclopropanes through the distal C-C bond cleavage can be effectively accomplished with tBuXPhos as a phosphine ligand and ZnCl2 as an additive, delivering bicyclic products containing tetrahydrofuran skeletons in good yields. The further transformation of these bicyclic products has been demonstrated, and the reaction mechanisms of two different C-C bond cleavage reactions have been investigated by control experiments and DFT calculations. A series of bicyclic products containing dihydrofuran and tetrahydrofuran skeletons were obtained by divergent palladium-catalyzed selective C-C bond cleavage of keto-VDCPs. The reaction mechanism was also investigated systematically.

The reason for the site selectivity previously reported for B(C6F5)(3)-catalyzed C(sp(3))-H alkylation of tertiary amines with electron-deficient olefins remains a mystery. The selectivity appears to be governed by the number of electron-withdrawing groups (EWGs) on the olefin: one EWG results in alpha-alkylation, whereas two EWGs (one on each end of the double bond) result in beta-alkylation. In this study, we solved the mystery and unlocked the pathway for beta-alkylation with olefins bearing only one EWG. Control experiments and density functional theory calculations provided a detailed picture of the reaction mechanism for both alpha- and beta-alkylation. Furthermore, we demonstrated the broad scope of the beta-alkylation reaction.

The thioether-connected bis-amino acid lanthionine (Lan) residues are class-defining residues of lanthipeptides. Typically, the cyclization step of lanthionine formation, which relies on the addition of a cysteine to an unsaturated dehydroamino acid, is directed either by a standalone cyclase LanC (class I) or by a cyclase domain (class II-IV). However, the pathways of characterized class V members often lack a known cyclase (domain), raising a question on the mechanism by which their multi-macrocycle systems are formed. Herein, we report a new RiPP gene cluster in Streptomyces TN 58, where it encodes the biosynthesis of 3 distinct class V lanthipeptides-termed triantimycins (TAMs). TAM A1 similar to A3 share an N-terminal ll-MeLan residue, and only TAM A1 contains an additional internal ll-Lan residue. TAM A1 also has a C-terminal (2S, 3R)-S-((Z)-2-aminovinyl)-3-methyl-d-cysteine (alloAviMeCys) residue, which is distinct from the previously reported (2S, 3S)-AviMeCys residue in other RiPPs. Gene deletion, heterologous coexpression, and structural elucidation demonstrated that the cyclization for an ll-MeLan formation occurs spontaneously and is independent of any known lanthionine cyclase. This study provides a new paradigm for lanthionine formation and facilitates genome mining and engineering efforts on RiPPs containing (Me)Lan and (allo)Avi(Me)Cys residues.

Protein turnover is an important mechanism to maintain proteostasis. Long-lived proteins (LLPs) are vulnerable to lose their function due to time -accumulated damages. In this study we employed in vivo stable isotope labeling in mice from birth to postnatal day 89. Quantitative proteomics analysis of ten tissues and plasma identified 2113 LLPs, including widespread and tissue -specific ones. Interestingly, a significant percentage of LLPs was detected in plasma, implying a potential link to age -related cardiovascular diseases. LLPs identified in brains were related to neurodegenerative diseases. In addition, the relative quantification of DNA -derived deoxynucleosides from the same tissues provided information about cellular DNA renewal and showed good correlation with LLPs in the brain. The combined data reveal tissue -specific maps of mouse LLPs that may be involved in pathology due to a low renewal rate and an increased risk of damage. Tissue -derived peripheral LLPs hold promise as biomarkers for aging and age -related diseases.

The catalytic access of silicon-stereogenic organosilanes remains a big challenge, and largely depends on the desymmetrization of the symmetric precursors with two identical substitutes attached to silicon atom. Here we report the construction of silicon-stereogenic organosilanes via catalytic kinetic resolution of racemic monohydrosilanes with good to excellent selectivity factors. Both Si-stereogenic dihydrobenzosiloles and Si-stereogenic monohydrosilanes could be efficiently accessed in one single operation via Rh-catalyzed enantioselective intramolecular hydrosilylation, employing (R,R)-Et-DuPhos as the optimal ligand. This catalytic protocol features mild conditions, a low catalyst loading (0.1 mol % [Rh(cod)Cl]2), high stereoinduction (S factor up to 152), and excellent scalability. Moreover, further derivatizations led to the efficient synthesis of uncommon middle-size (7- and 8-membered) Si-stereogenic silacycles. Preliminary mechanistic study indicates this reaction might undergo a modified Chalk-Harrod mechanism. Catalytic kinetic resolution strategy was developed for the access of chiral Si-stereogenic silanes. By employing Rh-catalyzed intramolecular hydrosilylation, both dihydrobenzosilole-based organosilanes and monohydrosilane containing ortho-vinyl group could be prepared with high efficiency and good to excellent selectivity factors in one single operation. image

Lysosomal transmembrane acetylation of heparan sulfates (HS) is catalyzed by HS acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT), whose dysfunction leads to lysosomal storage diseases. The mechanism by which HGSNAT, the sole non-hydrolase enzyme in HS degradation, brings cytosolic acetyl-coenzyme A (Ac-CoA) and lysosomal HS together for N-acyltransferase reactions remains unclear. Here, we present cryogenic-electron microscopy structures of HGSNAT alone, complexed with Ac-CoA and with acetylated products. These structures explain that Ac-CoA binding from the cytosolic side causes dimeric HGSNAT to form a transmembrane tunnel. Within this tunnel, catalytic histidine and asparagine approach the lumen and instigate the transfer of the acetyl group from Ac-CoA to the glucosamine group of HS. Our study unveils a transmembrane acetylation mechanism that may help advance therapeutic strategies targeting lysosomal storage diseases. This study reports the structure of lysosomal N-acetyltransferase HGSNAT providing insights into the mechanism of lysosomal transmembrane acetylation of heparan sulfate required for its catabolism.

Cyclin-dependent kinase 2 (CDK2) is a member of CDK family of kinases (CDKs) that regulate the cell cycle. Its inopportune or over -activation leads to uncontrolled cell cycle progression and drives numerous types of cancers, especially ovarian, uterine, gastric cancer, as well as those associated with amplified CCNE1 gene. However, developing selective lead compound as CDK2 inhibitors remains challenging owing to similarities in the ATP pockets among different CDKs. Herein, we described the optimization of compound 1 , a novel macrocyclic inhibitor targeting CDK2/5/7/9, aiming to discover more selective and metabolically stable lead compound as CDK2 inhibitor. Molecular dynamic (MD) simulations were performed for compound 1 and 9 to gain insights into the improved selectivity against CDK5. Further optimization efforts led to compound 22 , exhibiting excellent CDK2 inhibitory activity, good selectivity over other CDKs and potent cellular effects. Based on these characterizations, we propose that compound 22 holds great promise as a potential lead candidate for drug development.

Discoidin domain receptor 1 (DDR1) is a potential target for cancer drug discovery. Although several DDR1 kinase inhibitors have been developed, recent studies have revealed the critical roles of the noncatalytic functions of DDR1 in tumor progression, metastasis, and immune exclusion. Degradation of DDR1 presents an opportunity to block its noncatalytic functions. Here, we report the discovery of the DDR1 degrader LLC355 by employing autophagosome-tethering compound technology. Compound LLC355 efficiently degraded DDR1 protein with a DC50 value of 150.8 nM in non-small cell lung cancer NCI-H23 cells. Mechanistic studies revealed compound LLC355 to induce DDR1 degradation via lysosome-mediated autophagy. Importantly, compound LLC355 potently suppressed cancer cell tumorigenicity, migration, and invasion and significantly outperformed the corresponding inhibitor 1. These results underline the therapeutic advantage of targeting the noncatalytic function of DDR1 over inhibition of its kinase activity.

Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment. The precise role and therapeutic targeting potential of pericytes in tumor growth remains insufficiently explored. By selectively disrupting soluble guanylate cyclase (sGC) signaling in pericytes, this study reveals their impact on the vascular niche and tumor microenvironment.Pericyte-specific deletion of sGC results in detachment of pericytes from the endothelium within tumors. Pericyte sGC deletion induces transcriptome reprogramming in both pericytes and ECs. Pericytes and neighboring endothelial cells (ECs) within the vascular niche collectively regulate cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) within tumors. Inhibition of pericyte sGC enhances the susceptibility of tumor blood vessels to anti-angiogenic therapy. Pericyte-specific inhibition of nitric oxide receptor increases the vulnerability of angiogenic tumor vessels to anti-angiogenic therapy.

Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl mark on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader LLC0424 by leveraging the proteolysis-targeting chimera technology. LLC0424 potently degraded NSD2 protein with a DC50 value of 20 nM and a D max value of 96% in acute lymphoblastic leukemia (ALL) RPMI-8402 cells. Mechanistic studies revealed LLC0424 to selectively induce NSD2 degradation in a cereblon- and proteasome-dependent fashion. LLC0424 also caused continuous downregulation of H3K36me2 and growth inhibition of ALL cell lines with NSD2 mutation. Importantly, intravenous or intraperitoneal injection of LLC0424 showed potent NSD2 degradation in vivo.