Skeleton Rearrangement Research Articles

Biosynthesis of Atypical Angucyclines Unveils New Ring Rearrangement Reactions Catalyzed by Flavoprotein Monooxygenases.

Six new angucycline structures, including spirocyclione A (1), which contains an unusual oxaspiro[5.5]undecane architecture, and its ring-A-cleaved product spirocyclione B (2), were discovered by heterologous expression of a type II polyketide biosynthetic gene cluster captured from a marine actinomycete strain Streptomyces sp. HDN155000. Three flavoprotein monooxygenases are confirmed to be responsible for the oxidative carbon skeleton rearrangements in the biosynthesis of compounds 1 and 2. The obtained compounds showed promising cytotoxicity against different types of cancer cells.

CXCR4 promotes migration, invasion, and epithelial-mesenchymal transition of papillary thyroid carcinoma by activating STAT3 signaling pathway.

Papillary thyroid cancer (PTC) is a serious threat to human health worldwide, while metastasis in the early phase limits therapeutic success and leads to poor survival outcomes. The CXC chemokine receptor type 4 (CXCR4) plays an important role in many cellular movements such as transcriptional modulation, cell skeleton rearrangement, and cell migration, and the change in CXCR4 levels are crucial in various diseases including cancer. In this study, we explored the role of CXCR4 in the migration and invasion of PTC and investigated the potential mechanisms underlying its effects. We analyzed the expression levels of CXCR4 in PTC tissues and cell lines. Would healing migration, Transwell invasion assay in vitro, and tail-vein lung metastasis assay In vivo were performed to evaluated the migration and invasion abilities of PTC cells with stable CXCR4 knockdown or overexpression. Signal transducers and activators of transcription (STAT3) signaling pathway-related protein expressions were examined by Western blotting assays. The results showed that CXCR4 was highly expressed in PTC cell lines and PTC tissues. CXCR4 knockdown in PTC cells dampened the migration, invasion, and epithelial-mesenchymal transition (EMT), whereas CXCR4 overexpression enhanced these properties. In vivo, we also found that CXCR4 promoted the metastasis of PTC. Mechanistic studies showed that CXCR4 played these vital roles through the STAT3 signaling pathway. Furthermore, PTC patients with high CXCR4 or p-STAT3 expression correlated with aggressive clinical characteristics such as extrathyroidal extension (ETE), and lymph node metastasis (LNM). We provided evidence that CXCR4 might activate the STAT3 signaling pathway and further promote PTC development. Thus, CXCR4 might be a novel therapeutic target for PTC.

Electrophilic aryl spiroannulation induced by diaryliodonium salts: efficient synthesis of [5,5]-spiro lactone-lactam scaffolds from α-cyanocarboxylates

Spirocyclic architectures represent one of the privileged three-dimensional scaffolds in pharmaceutical chemistry and drug discovery, while the new-skeletal synthesis of spiromolecules from simple starting materials remains a challenging task. Here, we report a first diaryliodonium salts mediated electrophilic aryl spiroannulation reaction from simple substrates α-cyanocarboxylate. With this strategy, a broad spectrum of new [5,5] spiro-fused skeletons could be efficiently constructed in one step via Cu-catalyzed cascaded N-arylation-acylation and etheral skeleton rearrangement reaction. The key point of this transformation was the intramolecular electrophilic cyclization due to the nucleophilicity of O-atom and electrophilicity of α-C induced by diaryliodonium salts. With this protocol, the more challenging activation of ether bonds was achieved via diaryliodonium salts-mediated. This method has the major advantages of a broad substrate scope and excellent functional group compatibility. Further synthesis elaboration was performed using substrate with steric hindrance to showcase the versatility of this methodology.

Novel Types of Phyllobilins in a Fern - Molecular Reporters of the Evolution of Chlorophyll Breakdown in the Paleozoic Era.

Breakdown of chlorophyll (Chl), as studied in angiosperms, follows the pheophorbide a oxygenase/phyllobilin (PaO/PB) pathway, furnishing linear tetrapyrroles, named phyllobilins (PBs). In an investigation with fern leaves we have discovered iso-phyllobilanones (iPBs) with an intriguingly rearranged and oxidized carbon skeleton. We report here a key second group of iPBs from the fern and on their structure analysis. Previously, these additional Chl-catabolites escaped their characterization, since they exist in aqueous media as mixtures of equilibrating isomers. However, their chemical dehydration furnished stable iPB-derivatives that allowed the delineation of the enigmatic structures and chemistry of the original natural catabolites. The structures of all fern-iPBs reflect the early core steps of a PaO/PB-type pathway and the PB-to-iPB carbon skeleton rearrangement. A striking further degradative chemical ring-cleavage was observed, proposed to consume singlet molecular oxygen (1O2). Hence, Chl-catabolites may play a novel active role in detoxifying cellular 1O2. The critical deviations from the PaO/PB pathway, found in the fern, reflect evolutionary developments of Chl-breakdown in the green plants in the Paleozoic era.

Rhodium(III)-Catalyzed Oxidative 1,3-Aryl Migration of α-Aryl Allylic Alcohols.

A Rh(III)-catalyzed oxidative 1,3-aryl migration of α-arylallylic alcohols via Csp2-Csp3 σ bond activation has been developed. This method provides an efficient strategy to allow for allylic alcohol-based skeleton rearrangement, in which various secondary and tertiary α-arylallylic alcohols are rapidly converted to β-aryl-α, β-unsaturated ketones and aldehydes.

Cytochrome P450-Mediated Skeleton Rearrangement of Taxadiene in an Engineered Escherichia coli System.

In this study, we constructed a taxadiene overproduction platform and identified a cytochrome P450, CYP701A8, that activates the inert C-H bonds in taxadiene to produce three oxidized products (1-3). Compound 1 possesses a newly identified 1 (15→11) abeotaxane skeleton, while 3 features a distinctive 6/10-fused carbocyclic core with an α,β-unsaturated ketone moiety. Our quantum computations suggested a carbocation-driven rearrangement in the formation of 1. These results support CYP701A8 as a promising biocatalyst for the generation of novel taxane diterpenoids.

Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade.

Skeleton rearrangement could rapidly transfer simple molecules to complex structures and has significant potential in the total synthesis of natural products. We developed a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization that was successfully applied for the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of (±)-7(R)-geissoschizol oxindole/(±)-7(S)-geissoschizol oxindole. In addition, the geissoschizol oxindoles were revised to their C3 epimers, and the mechanism for the reversed stereochemistry through the retro-Mannich/Mannich cascade was proposed and supported by density functional theory calculations.

Thymosin β4 Regulates the Differentiation of Thymocytes by Controlling the Cytoskeletal Rearrangement and Mitochondrial Transfer of Thymus Epithelial Cells.

The thymus is one of the most crucial immunological organs, undergoing visible age-related shrinkage. Thymic epithelial cells (TECs) play a vital role in maintaining the normal function of the thymus, and their degeneration is the primary cause of age-induced thymic devolution. Thymosin β4 (Tβ4) serves as a significant important G-actin sequestering peptide. The objective of this study was to explore whether Tβ4 influences thymocyte differentiation by regulating the cytoskeletal rearrangement and mitochondrial transfer of TECs. A combination of H&E staining, immunofluorescence, transmission electron microscopy, RT-qPCR, flow cytometry, cytoskeletal immunolabeling, and mitochondrial immunolabeling were employed to observe the effects of Tβ4 on TECs' skeleton rearrangement, mitochondrial transfer, and thymocyte differentiation. The study revealed that the Tβ4 primarily regulates the formation of microfilaments and the mitochondrial transfer of TECs, along with the formation and maturation of double-negative cells (CD4-CD8-) and CD4 single-positive cells (CD3+TCRβ+CD4+CD8-) thymocytes. This study suggests that Tβ4 plays a crucial role in thymocyte differentiation by influencing the cytoskeletal rearrangement and mitochondrial transfer of TECs. These effects may be associated with Tβ4's impact on the aggregation of F-actin. This finding opens up new avenues for research in the field of immune aging.

On‐Surface Interchain Coupling and Skeletal Rearrangement of Indenofluorene Polymers

AbstractOn‐surface synthesis serves as a powerful approach to construct π‐conjugated carbon nanostructures that are not accessible by conventional wet chemistry. Nevertheless, this method has been limited by the types and numbers of available on‐surface transformations. While the majority of successful cases exploit thermally triggered dehalogenative carbon–carbon coupling and cyclodehydrogenation, rearrangement of appropriate functional moieties has received limited research attention. Here, the unprecedented interchain coupling and thermally induced skeleton rearrangement are described of (dihydro)indeno[2,1‐b]fluorene (IF) polymers on an Au(111) surface under ultrahigh vacuum conditions, leading to different ladder polymers as well as fully fused graphene nanoribbon segments containing pentagonal and heptagonal rings. Au‐coordinated nanoribbons are also observed. All structures are unambiguously characterized by high‐resolution scanning probe microscopy. The current results provide an avenue to fabricating a wider variety of π‐conjugated polymers and carbon nanostructures comprising nonhexagonal rings as well as rarely explored organometallic nanoribbons.

Shedding light on the poly(5‐ethylidene‐2‐norbornene) microstructural differences: Skeleton rearrangements during polymerization

AbstractHere, an attempt is made to study one of the less noticed aspects of the polymerization of 5‐ethylidene‐2‐norbornene (ENB) by nickel α‐diimine catalysts. Therefore, several (co)polymerization runs using MMAO‐activated binuclear catalyst (BNC) and mononuclear catalyst (MNC) were undertaken. Catalyst activities as high as 561.1 and 925.0 (kgpol mol−1Ni h−1) were observed for ENB polymerization by MNC and BNC, respectively. However, the utilization of comonomer (norbornene [NB]) led to a dramatic decline in the catalyst activities, reaching low levels of 69.4 and 144.4 (kgpol mol−1Ni h−1), respectively. Structural characterization (NMR and FTIR) corroborated the occurrence of ring opening via β‐C elimination and the subsequent β‐H elimination. Additionally, tandem transannular polymerization and ring‐opening metathesis polymerization of ENB were evidenced. The findings demonstrated that the transannular polymerization prevailed during the polymerization, albeit the MNC catalyst showed a higher contribution of ring opening via β‐C elimination. Importantly, comonomer (NB) was displayed to alter the governing polymerization mechanism. According to DMTA analysis, the structures of the monomer and catalyst were found to significantly influence the polymer damping behavior and microstructure heterogeneity. That is, the NB‐ENB copolymer obtained by MNC exhibited the lowest Tg value and highest tan δ along with the diminished microstructure heterogeneity.

Mn(I)-catalyzed sigmatropic rearrangement of β, γ-unsaturated alcohols

Sigmatropic rearrangement provides a versatile strategy to site-selectively reorganize carbon-skeleton with high atom- and step-economy. Herein, we disclose a Mn(I)-catalyzed sigmatropic rearrangement of β, γ-unsaturated alcohols via C-C σ bond activation. A variety of α-aryl-allylic alcohols and α-aryl-propargyl alcohols could undergo in-situ 1,2- or 1,3- sigmatropic rearrangements to allow for converting to complex structural arylethyl- and arylvinyl- carbonyl compounds under a simple catalytic system. More importantly, this catalysis model can be further applied to assemble macrocyclic ketones through bimolecular [2n + 4] coupling-cyclization and monomolecular [n + 1] ring-extension. The presented skeleton rearrangement would be a useful tool complementary to the traditional molecular rearrangement.

Selective Construction of Spiro or Fused Heterocyclic Scaffolds via One-pot Cascade Reactions of 1-Arylpyrazolidinones with Maleimides.

Presented herein is a controllable selective construction of spiro or fused heterocyclic scaffolds through the one-pot cascade reactions of 1-phenylpyrazolidinones with maleimides. To be specific, succinimide spiro pyrazolo[1,2-a]pyrazolones were effectively formed via [4 + 1] spiroannulation of 1-phenylpyrazolidinones with maleimides through simultaneous C(sp2)-H bond activation/functionalization and intramolecular cyclization along with the traceless fusion of the pyrazolidinonyl unit into the final product. In this reaction, air acts as a cost-effective and environmentally sustainable oxidant to assist the regeneration of the Rh(III) catalyst. Alternatively, succinimide-fused pyrazolidinonylcinnolines were formed from the same starting materials through an initial [4 + 1] spiroannulation followed by base-promoted skeleton rearrangement of the in situ formed spiro product without isolation. Notable features of these protocols include easily tunable selectivity, broad substrate scope, cost-effective and sustainable oxidant, excellent atom economy, and facile scalability.

Lewis Acid-Catalyzed Chemodivergent and Regiospecific Reaction of Phenols with Quaternary Peroxyoxindoles.

The indium-catalyzed regiospecific coupling of substituted phenol derivatives and quaternary peroxyoxindoles for the synthesis of C2 or C4 benzoxazin-3-one-substituted phenols via skeletal rearrangement is described. This reaction is demonstrated with 17 examples with good yields and diverse aryl substituents. In contrast to the indium-catalyzed reaction, the Cu(OTf)2-catalyzed reaction of the phenol with quaternary peroxyoxindoles afforded C2 or C4 2-oxindole-substituted phenol derivatives. This diverse catalytic reaction generated various biologically important phenol-substituted 2-oxindole derivatives directly without any skeleton rearrangement and was demonstrated with 19 examples in high yield. The regiospecificity and the reaction pathways were explained with the support of density functional theory (DFT).

Smart Covalent Organic Framework with Proton-Initiated Switchable Photocatalytic Aerobic Oxidation

To conveniently regulate photocatalytic reactions, the design and development of smart photocatalysts, which can realize a series of controllable regulation of their structure, physicochemical properties, photocatalytic activity, and selectivity by simple external stimuli, such as chemical substances, pH, light, electric field, and heat, has aroused keen interest. However, the relevant research is still in its infancy. Herein, a smart imine covalent-organic-framework (COF) photocatalyst HP-n (n represents the pH of COF pretreatment, n = 1∼7) with proton-initiated switchable photocatalytic aerobic oxidation has been prepared. In the structure, the imine units can be reversibly protonated, which leads to the COF skeleton rearrangement from the phenolic to its quinone structure. The corresponding absorption band edge is expanded from 463 nm (HP-7) to 630 nm (HP-1). Meanwhile, the excitation energy transfer, oxygen adsorption, and activation change significantly, endowing HP-n with smartly switchable 1O2 production and interesting proton-initiated efficiency photocatalytic sulfide oxidation with both conversion and sulfoxide selectivity >99%. This work demonstrates a smart imine-COF photocatalyst, which paves the way for the development of smart photocatalysts and reveals the critical roles of protons in the structure–property–activity relationship of COF photocatalysts.

Iron-Catalyzed Benzene Ring Expansion of α-Azido-N-phenylamides

AbstractNitrenoid-mediated C–H insertion and cycloaddition reactions are gaining increasing importance in modern organic synthesis. However, the nitrene-mediated benzene ring expansion, which constitutes a potent tool for breaking the benzene ring, has sparely been explored for synthetic purposes. Herein we report that nitrene cycloaddition to the benzene ring can be enabled intramolecularly by iron catalysis. By using FeCl2 and N-heterocyclic carbene SIPr·HCl as the catalyst, α-azido-N-phenylamides can be converted into 1,3-dihydro-2H-azepin-2-ones in good yields through a novel skeleton rearrangement. The rearrangement features a cascade of nitrene cycloaddition, C–N cleavage, water addition, and electrocyclic ring-opening. In the case that the N-phenyl ring is substituted with a methoxy group at the meta or para position, azepin-2-one-fused imidazolinones can also be obtained. The present reactions provide an effective method for benzene ring expansion as well as for the preparation of azepin-2-one compounds.

A gene cluster in Ginkgo biloba encodes unique multifunctional cytochrome P450s that initiate ginkgolide biosynthesis

The ginkgo tree (Ginkgo biloba) is considered a living fossil due to its 200 million year’s history under morphological stasis. Its resilience is partly attributed to its unique set of specialized metabolites, in particular, ginkgolides and bilobalide, which are chemically complex terpene trilactones. Here, we use a gene cluster-guided mining approach in combination with co-expression analysis to reveal the primary steps in ginkgolide biosynthesis. We show that five multifunctional cytochrome P450s with atypical catalytic activities generate the tert-butyl group and one of the lactone rings, characteristic of all G. biloba trilactone terpenoids. The reactions include scarless C–C bond cleavage as well as carbon skeleton rearrangement (NIH shift) occurring on a previously unsuspected intermediate. The cytochrome P450s belong to CYP families that diversifies in pre-seed plants and gymnosperms, but are not preserved in angiosperms. Our work uncovers the early ginkgolide pathway and offers a glance into the biosynthesis of terpenoids of the Mesozoic Era.

ERK-Smurf1-RhoA signaling is critical for TGFβ-drived EMT and tumor metastasis.

Epithelial-mesenchymal transition (EMT) has fundamental roles in various biological processes. However, there are still questions pending in this fast-moving field. Here we report that in TGFβ-induced EMT, ERK-mediated Smurf1 phosphorylation is a prerequisite step for RhoA degradation and the consequent mesenchymal state achievement. Upon TGFβ treatment, activated ERK phosphorylates Thr223 of Smurf1, a member of HECT family E3 ligase, to promote Smurf1-mediated polyubiquitination and degradation of RhoA, thereby leading to cell skeleton rearrangement and EMT. Blockade of phosphorylation of Smurf1 inhibits TGFβ-induced EMT, and accordingly, dramatically blocks lung metastasis of murine breast cancer in mice. Hence, our study reveals an unknown role of ERK in TGFβ-induced EMT and points out a potential strategy in therapeutic intervention.

Genes and enzymes involved in the biodegradation of the quaternary carbon compound pivalate in the denitrifying Thauera humireducens strain PIV‐1

Quaternary carbon-containing compounds exist in natural and fossil oil-derived products and are used in chemical and pharmaceutical applications up to industrial scale. Due to the inaccessibility of the quaternary carbon atom for a direct oxidative or reductive attack, they are considered as persistent in the environment. Here, we investigated the unknown degradation of the quaternary carbon-containing model compound pivalate (2,2-dimethyl-propionate) in the denitrifying bacterium Thauera humireducens strain PIV-1 (formerly Thauera pivalivorans). We provide multiple evidence for a pathway comprising the activation to pivalyl-CoA and the carbon skeleton rearrangement to isovaleryl-CoA. Subsequent reactions proceed similar to the catabolic leucine degradation pathway such as the carboxylation to 3-methylglutaconyl-CoA and the cleavage of 3-methyl-3-hydroxyglutaryl-CoA to acetyl-CoA and acetoacetate. The completed genome of Thauera humireducens strain PIV-1 together with proteomic data was used to identify pivalate-upregulated gene clusters including genes putatively encoding pivalate CoA ligase and adenosylcobalamin-dependent pivalyl-CoA mutase. A pivalate-induced gene encoding a putative carboxylic acid CoA ligase was heterologously expressed, and its highly enriched product exhibited pivalate CoA ligase activity. The results provide the first experimental insights into the biodegradation pathway of a quaternary carbon-containing model compound that serves as a blueprint for the degradation of related quaternary carbon-containing compounds.

Glutamate mutase and 2-methyleneglutarate mutase.

Glutamate mutase converts ( S )-glutamate to ( S , S )-3-methylaspartate, whereas 2-methyleneglutarate mutase isomerizes 2-methyleneglutarate to ( R )-3-methylitaconate. Both enzymes occur in amino acid fermenting clostridia, require coenzyme B 12 (adenosylcobalamin) and catalyze a reversible, radical carbon skeleton rearrangement. The enzymes are assayed using the consecutive enzymes in their fermentation pathways: methylaspartase and methylitaconate isomerase, which produce the higher absorbing mesaconate and 2,3-dimethylmaleate, respectively. Although the quaternary structures of glutamate mutase and 2-methyleneglutarate mutase are different, the binding mode of coenzyme B 12 and their catalytic mechanism appear to be very similar. The crystal structure of glutamate mutase and EPR spectroscopy of both enzymes during catalysis revealed a distance of 6.6 Å between the C-H bond of the substrate to be cleaved and the Co-atom of cob(II)alamin. Methods are described for facile production of both enzymes in Escherichia coli and purification.

A method for the production, purification and liposome reconstitution of cobamide synthase.

Cobamides are essential for the performance of a variety of reactions such methyl transfers, carbon skeleton rearrangements, and eliminations in both prokaryotes and eukaryotes. However, cobamide biosynthesis is limited to a subset of bacteria and archaea. The biosynthesis pathway culminates with the activation and attachment of a lower ligand to the corrin ring; this branch of the pathway is known as nucleotide loop assembly (NLA) pathway. The cobamide synthase (CobS) enzyme is the penultimate step in NLA pathway, and catalyzes the attachment of an α-ribotide to the activated corrin ring. While other NLA enzymes have been well-studied, studies of CobS have proven difficult to date. CobS is an integral membrane protein, and limitations have been largely due to difficulties in protein purification. Here we provide a method to purify CobS, reconstitute protein in proteoliposomes, and assay for its activity.