Ligand-Enabled C6-Selective C-H Arylation of Pyrrolo[2,3-d] Pyrimidine Derivatives with Pd Catalysts: An Approach to the Synthesis of EGFR Inhibitor AEE-788.

Herein, we report the Pd(II)-catalyzed direct C-H arylation of pyrrolo[2,3-d]pyrimidine derivatives with aryl iodides, which is enabled by bidentate pyridine-pyridine ligands. A range of aryl iodides proved to be suitable coupling partners affording the desired products in good yields with high levels of C6 selectivity. This protocol features good tolerance of reactive functional groups, mild reaction conditions, and a simple reaction system, which provides an expeditious route to an essential class of 6-arylpyrrolo[2,3-d]pyrimidines frequently found in bioactive compounds, and provides a step-economical access to the second-generation EGFR inhibitor AEE-788.

Iron-catalyzed benzylic C-H thiolation via photoinduced ligand-to-metal charge-transfer.

Here, we describe an iron-catalyzed benzylic C-H thiolation of alkylarenes via photoinduced ligand-to-metal charge-transfer. The protocol features operational simplicity, mild reaction conditions, and the use of FeCl3 as catalyst and thiols/disulfides as sulfur sources, which enables the transformation of diverse benzylic C-H bonds into C-S bonds with a high efficiency.

Visible-Light-Induced Highly Site-Selective Direct C-H Phosphorylation of Pyrrolo[2,3-d]pyrimidine Derivatives with H-Phosphine Oxides.

An efficient and highly regioselective C6-phosphorylation protocol for pyrrolo[2,3-d]pyrimidine (7-DAP) derivatives with various H-phosphine oxides induced by visible light at room temperature is described for the first time. This protocol has been successfully achieved by the combination of Na2-eosin Y as a photocatalyst and LPO as an oxidant under transition metal- and additive-free conditions. The broad substrate scope, good functional group tolerance, excellent regioselectivity, and air tolerant conditions make this process favorable for the functional modification of pyrrolo[2,3-d]pyrimidine scaffold and enrich the phosphorylated 7-DAP compounds for further biological evaluation.

Ruthenium-catalysed direct C-H amidation of 4-aryl-pyrrolo[2,3-d]pyrimidines with acyl/phosphoryl azides.

A ruthenium-catalysed arene ortho C-H amidation of 4-aryl-pyrrolo[2,3-d]pyrimidine derivatives with acyl azides or phosphoryl azides as the nitrogen sources toward C-N bond formation was developed. This protocol could offer a novel and direct approach to access a series of amidated and phosphoramidated pyrrolo[2,3-d]pyrimidine derivatives in moderate to good yields, thereby evading the general Curtius rearrangement. The protocol features significant functional group tolerance and a single-step process, with the release of only innocuous molecular nitrogen as the byproduct.

LiBF4-Promoted Aromatic Fluorodetriazenation under Mild Conditions.

An efficient and mild fluorination method through LiBF4-promoted aromatic fluorodetriazenation of 3,3-dimethyl-1-aryltriazenes is developed. The reaction proceeds smoothly and tends to complete within 2 h in the absence of a protic acid or strong Lewis acid. This method tolerates a wide range of functional groups and affords the aryl fluoride products in moderate to excellent yields.

Palladium-Catalyzed Highly Regioselective C6 Arylation of Pyrrolo[2,3-d]pyrimidine Derivatives with Arylboronic Acids.

A mild and selective C6 arylation strategy for pyrrolo[2,3-d]pyrimidine derivatives with arylboronic acids at room temperature is described. This unified protocol has been achieved by the synergistic combination of Pd(II)/TEMPO catalysis and CF3CO2H promotion under silver-, base-, and additive-free conditions. The broad substrate scope, good functional group tolerance, excellent regioselectivity, and air and moisture tolerant conditions make this process attractive for the effective synthesis and modification of targeted small molecule drugs.

Palladium-catalysed site-selective arene ortho C-H fluoroalkoxylation of 4-aryl-pyrrolo[2,3-d]pyrimidines.

A palladium-catalysed direct arene C-H fluoroalkoxylation of 4-aryl-pyrrolo[2,3-d]pyrimidine derivatives with fluorinated alcohols is described. Highly site-selective mono- or bis-fluoroalkoxylation can be achieved by tuning the reaction conditions, affording various fluoroalkoxylated pyrrolo[2,3-d]pyrimidine derivatives in moderate to good yields, which offer rational tailoring of their biological activity for their application in the field of pharmaceutical chemistry.

Design, synthesis, and biological evaluation of C-8 modified curcumol derivatives against colorectal cancer cell lines.

A series of structurally modified curcumol derivatives at C-8 position were designed and synthesized, whose structures were confirmed by 1H NMR,13C NMR, and HRMS analysis. The tested compounds were evaluated for in vitro antitumor activity against colorectal cancer cell lines SW620, HCT116, and CaCo2. Many of the tested candidates exhibited higher inhibition efficiency than curcumol. Among them, compound 3 l shows the best inhibitory effect on the viability of SW620 with IC50 value of 19.90 ± 0.64 µM. The structure-activity relationships of these derivatives were discussed, which showed that the introduction of amino or aryl groups tended to increase the anti-cancer activity. In addition, compound 3 l may inhibit cancer cell proliferation through triggering cell apoptosis.

TIGAR alleviates oxidative stress in brain with extended ischemia via a pentose phosphate pathway-independent manner.

TP53-induced glycolysis and apoptosis regulator (TIGAR) alleviates oxidative stress and protects against ischemic neuronal injury by shifting glucose metabolism into the pentose phosphate pathway (PPP). However, the brain alters glucose metabolism from PPP to glycolysis during prolonged ischemia. It is still unknown whether and how TIGAR exerts the antioxidant activity and neuroprotection in prolonged ischemic brains. Here, we determined the significant upregulation of TIGAR that was proportional to the duration of ischemia. However, TIGAR failed to upregulate the NADPH level but still alleviated oxidative stress in neuronal cells with prolonged oxygen glucose-deprivation (OGD). Furthermore, inhibiting PPP activity, either by the expression of mutant TIGAR (which lacks enzymatic activity) or by silencing Glucose 6-phosphate dehydrogenase, still retained antioxidant effects and neuroprotection of TIGAR with prolonged OGD. Intriguingly, TIGAR-induced autophagy alleviated oxidative stress, contributing to neuron survival. Further experiments indicated that TIGAR-induced autophagy neutralized oxidative stress by activating Nrf2, which was cancelled by ML385 or Nrf2 knockdown. Remarkably, either Atg7 deletion or Nrf2 silencing abolished the neuroprotection of TIGAR in mice with prolonged ischemia. Taken together, we found a PPP-independent pathway in which TIGAR alleviates oxidative stress. TIGAR induces autophagy and, thus, activates Nrf2, offering sustainable antioxidant defense in brains with extended ischemia. This previously unexplored mechanism of TIGAR may serve as a critical compensation for antioxidant activity caused by the lack of glucose in ischemic stroke.

Design, synthesis, and anticancer activity evaluation of curcumol derivatives.

A new series of C-14 curcumol derivatives as potent anticancer agents were designed and synthesized by click reaction, whose structures were confirmed by 1H NMR,13C NMR, and HRMS analysis. All the synthesized compounds were evaluated for in vitro antitumor activity against colorectal cancer cell lines SW620 and HCT116. Most of them exhibited higher inhibitory activity than curcumol. Especially, compound 3j shows good inhibitory activity against SW620 with IC50 value of 8.10 ± 0.13 µM. The structure-activity relationships (SARs) of these derivatives were discussed. In addition, flow cytometry revealed that compound 3j induced SW620 cells apoptosis by facilitating apoptosis-related proteins expressions. Our findings suggested that fluorine functional group on phenyl ring tended to increase the anticancer activity.

BNIP3L/NIX-mediated mitophagy: molecular mechanisms and implications for human disease.

Mitophagy is a highly conserved cellular process that maintains the mitochondrial quantity by eliminating dysfunctional or superfluous mitochondria through autophagy machinery. The mitochondrial outer membrane protein BNIP3L/Nix serves as a mitophagy receptor by recognizing autophagosomes. BNIP3L is initially known to clear the mitochondria during the development of reticulocytes. Recent studies indicated it also engages in a variety of physiological and pathological processes. In this review, we provide an overview of how BNIP3L induces mitophagy and discuss the biological functions of BNIP3L and its regulation at the molecular level. We further discuss current evidence indicating the involvement of BNIP3L-mediated mitophagy in human disease, particularly in cancer and neurological disorders.

Pd-Catalyzed solvent-controlled site-selective arene C-H monoacyloxylation of pyrrolo[2,3-d]pyrimidine derivatives.

An efficient and highly regioselective Pd-catalyzed direct arene C(sp2)-H acyloxylation of pyrrolo[2,3-d]pyrimidine derivatives is reported. The key strategy involves the utilization of the unique reactivity of pyrrolo[2,3-d]pyrimidine and the employment of pyrrolo[2,3-d]pyrimidine as the directing group. A variety of monoacyloxylated pyrrolo[2,3-d]pyrimidine derivatives can be achieved by switching the solvents under mild conditions, and they can be further modified and exhibit various biological activities.

Design, synthesis and structure-activity relationship studies of 4-indole-2-arylaminopyrimidine derivatives as anti-inflammatory agents for acute lung injury.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), a clinically high mortality disease, has not been effectively treated till now, and the development of anti-acute lung injury drugs is imminent. Acute lung injury was efficiently treated by inhibiting the cascade of inflammation, and reducing the inflammatory response in the lung. A series of novel compounds with highly efficient inhibiting the expression of inflammatory factors were designed by using 4-indolyl-2-aminopyrimidine as the core skeleton. Totally eleven 4-indolyl-2-arylaminopyrimidine derivatives were designed and synthesized. As well, the related anti-ALI activity of these compounds was evaluated. Compounds 6c and 6h showed a superior activity among these compounds, and the inhibition rate of IL-6 and IL-8 release ranged from 62% to 77%, and from 65% to 72%, respectively. Furthermore, most of compounds had no significant cytotoxicity in vitro. The infiltration of inflammatory cells into lung tissue significantly reduced by using compound 6h (20 mg/kg) in the ALI mice model, which achieved the effect of protecting lung tissue and improving ALI. In addition, the inflammatory response was inhibited by using compound 6h through inhibiting phosphorylation of p-38 and ERK in MAPK signaling pathway, and resulted in protective effect on ALI. These data indicated that compound 6h showed good anti-inflammatory activity in vitro and in vivo, which was expected to become a leading compound for the treatment of ALI.

Natural compounds modulate the autophagy with potential implication of stroke.

Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes. Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents. Increasing evidence support that autophagy protects neuronal cells from ischemic injury. However, under certain circumstances, autophagy activation induces cell death and aggravates ischemic brain injury. Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke. In the present work, we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment.

Recent developments of small molecules with anti-inflammatory activities for the treatment of acute lung injury.

Acute Lung Injury (ALI) can be caused by various diseases or conditions such as sepsis, pneumonia, trauma, shock, and inhalation of toxic gases. Many efforts have been made to identify new agents capable of treating ALI, and many compounds have shown interesting activities in the treatment of ALI. However, most of these compounds have only been tested for their clinical significance using in vitro and in vivo animal models. In this review, the developments in the design and structural modification of effective active agents for the treatment of ALI is summarized. Firstly, the application of α, ß-unsaturated carbonyl moieties as an importantly superior framework in the development of natural product-derived anti-ALI agents is described. As well, the biological activities of the hybrid derivatives from natural products are discussed. Secondly, the potential of synthetic small molecule active compounds in the treatment of ALI is demonstrated. In addition, the structure activity relationship (SAR) and possible mechanisms of action in new chemical molecular entities were investigated. This present mini-review will be useful to scientists in research fields of medicinal chemistry, organic synthesis, and also various biological applications particularly for the development of novel anti-ALI agents.

Discovery and biological evaluation of proteolysis targeting chimeras (PROTACs) as an EGFR degraders based on osimertinib and lenalidomide.

Epidermal growth factor receptor (EGFR) is one of the important and valuable drug targets. Overexpression of EGFR is associated with the development of many types of cancer. In this study, three PROTACs small molecules (16a-16c) were designed, synthesized and evaluated for their cytotoxicity against the growth in different NSCLC cell line and the degradation effect. The bioassay results indicated that 16c has a good inhibition in PC9 cells and H1975 cells, and the corresponding IC50 value was 0.413 µM and 0.657 µM, respectively. Western blotting results demonstrated that compound 16c could serve as an effective EGFRdel19-targeting degrader in PC9 cells.

Identification of constituents in Gui-Zhi-Jia-Ge-Gen-Tang by LC-IT-MS combined with LC-Q-TOF-MS and elucidation of their metabolic networks in rat plasma after oral administration.

Gui-Zhi-Jia-Ge-Gen-Tang (GZJGGT) is a traditional Chinese medicine (TCM) prescription commonly used to treat cervical spondylopathy, scapulohumeral periarthritis, etc. Though it is widely applied in clinical practice, the effective constituents of GZJGGT remain unclear. This was the first report on the identification of the chemical constituents from GZJGGT in vitro and in vivo using LC-IT-MS combined with LC-Q-TOF-MS. A total of 141 constituents were detected in GZJGGT, and 77 were identified. These compounds mainly included flavonoid glycosides, triterpene saponins, monoterpene glycosides, puerosides, and organic acids. Among them, 12 compounds were unequivocally identified in comparison with reference substances. Additionally, a diagnostic base peak ion filtering strategy for rapid classification of flavonoid O-glycosides and C-glycosides was proposed. After gastrointestinal administration of GZJGGT to rats, 45 prototypes and 48 metabolites in rat plasma were speculated. In addition, the metabolic profile of GZJGGT was portrayed to understand interrelationship between metabolites.

Liposomal doxorubicin loaded PLGA-PEG-PLGA based thermogel for sustained local drug delivery for the treatment of breast cancer.

The aim of this research is to utilize a hybrid system of liposomal doxorubicin (DOX-Lip) loaded thermogel (DOX-Lip-Gel) to realize the steady sustained delivery of doxorubicin (DOX), a small hydrophilic drug, for the treatment of breast cancer locally. Herein, liposomal doxorubicin was prepared via the traditional film dispersion method with the particle size of 75 nm and drug entrapment efficiency of 86%. And, the triblock copolymer of poly (D, L-lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly (D, L-lactide -co-glycolide) (PLGA-PEG-PLGA) was synthesized via ring-opening polymerization to prepare the thermosensitive hydrogel through dissolving the polymers in DOX-Lip solution. The liposome loaded hydrogel was in a sol state at room temperature and converted into the gel state at body temperature and would degrade gradually during the time in vivo. The drug release of DOX out of DOX-Lip-Gel could be in a steady sustained manner up to 11 days without significant burst release as compared to that of DOX-loaded hydrogel (DOX-Gel). An orthotopic breast cancer model was adopted to evaluate the in vivo antitumor efficacy. And, the results revealed DOX-Lip-Gel had better antitumor efficiency as well as lower side effects.

Characterization of the chemical constituents in Hongjingtian injection by liquid chromatography quadrupole time-of-flight mass spectrometry.

Hongjingtian injection is made from Rhodiola wallichiana and used in the treatment of stable angina pectoris associated with coronary heart disease. In this study, the chemical constituents in Hongjingtian injection were comprehensively studied using liquid chromatography quadrupole time-of-flight mass spectrometry. A total of 49 compounds were identified or assumed, including 10 organic acids, nine phenylethanoids, 10 phenylpropanoids, two flavonoid glycosides, seven monoterpene glycosides, seven octylglycosides and four other types of compounds. The structures of seven compounds were confirmed by comparing their retention times, MS and UV spectra with the corresponding authentic standards. Amongst the 49 compounds, 35 were firstly found in R. wallichiana, while they have been reported in other species of the genus Rhodiola, including Rhodiola crenulata, Rhodiola sacra, Rhodiola rosea and Rhodiola kirilowii. The possible fragmentation pathways in the mass spectrometry of the major types of compounds are proposed and summarized. Our study demonstrates a rapid method for characterizing the chemical constituents present in the Hongjingtian injection, which could also be applied to the identification of chemical constituents in other TCM formulae containing R. wallichiana.

Site-selective synthesis of functionalized dibenzo[f,h]quinolines and their derivatives involving cyclic diaryliodonium salts via a decarboxylative annulation strategy.

Here we report a site-selective synthesis of functionalized dibenzo[f,h]quinolines and their derivatives, which could be used as OLED materials. The key step is the double cross coupling reaction between the 2-chloropyridinyl acids and the cyclic diaryliodonium salts, where the carboxylic acid was unprecedentedly employed as both a traceless directing group and a functional handle in a one-pot atom- and step-economical process.