Anticancer efficacy triggered by synergistically modulating the homeostasis of anions and iron: Design, synthesis and biological evaluation of dual-functional squaramide-hydroxamic acid conjugates.

Targeting the homeostasis of anions and iron has emerged as a promising therapeutic approach for the treatment of cancers. However, single-targeted agents often fall short of achieving optimal treatment efficacy. Herein we designed and synthesized a series of novel dual-functional squaramide-hydroxamic acid conjugates that are capable of synergistically modulating the homeostasis of anions and iron. Among them, compound 16 exhibited the most potent antiproliferative activity against a panel of selected cancer cell lines, and strong in vivo anti-tumor efficacy. This compound effectively elevated lysosomal pH through anion transport, and reduced the levels of intracellular iron. Compound 16 could disturb autophagy in A549 cells and trigger robust apoptosis. This compound caused cell cycle arrest at the G1/S phase, altered the mitochondrial function and elevated ROS levels. The present findings clearly demonstrated that synergistic modulation of anion and iron homeostasis has high potentials in the development of promising chemotherapeutic agents with dual action against cancers.

Bicyclic Amidine-Triggered Cyclization of o-Alkynylisocyanobenzenes: Synthesis of Lactam-Derived Quinolines.

Efficient access to the synthesis of lactam-derived quinoline through a bicyclic amidine-triggered cyclization reaction from readily prepared o-alkynylisocyanobenzenes has been developed. The reaction was initiated by nucleophilic attack of the bicyclic amidines to o-alkynylisocyanobenzenes, subsequently with intramolecular cyclization to produce a DBU-quinoline-based amidinium salt, followed by hydrolysis to afford the lactam-derived quinoline in moderate to good yields.

Divergent synthesis of difluoromethylated indole-3-carbinols, bisindolylmethanes and indole-3-methanamines.

Indole-3-carbinol, bisindolylmethanes (BIMs) and indole-3-methanamines exhibit diverse therapeutic activities. Fluorinated molecules are widely used in pharmaceuticals. Herein we report a facile and straightforward method for the successful synthesis of difluoromethylated indole-3-carbinols, bisindolylmethanes and indole-3-methanamines by a Friedel-Crafts reaction. The reaction involves the in situ generation of difluoroacetaldehyde from difluoroacetaldehyde ethyl hemiacetal in the presence of a base or an acid. This protocol is distinguished by its good to excellent yields, broad substrate compatibility, good functional group tolerance and scalability.

Design, synthesis, and evaluation of 2,2'-bipyridyl derivatives as bifunctional agents against Alzheimer's disease.

Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease. Metal ion dyshomeostasis and Aß aggregation have been proposed to contribute to AD progression. Metal ions can bind to Aß and promote Aß aggregation, and ultimately lead to neuronal death. Bifunctional (metal chelation and Aß interaction) compounds are showing promise against AD. In this work, eleven new 3,3'-diamino-2,2'-bipyridine derivatives 4a-4k were synthesized, and evaluated as bifunctional agents for AD treatment. In vitro Aß aggregation inhibition assay confirmed that most of the synthesized compounds exhibited significant self-induced Aß1-42 aggregation inhibition. Among them, compound 4d displayed the best inhibitory potency of self-induced Aß1-42 aggregation with IC50 value of 9.4 µM, and it could selectively chelate with Cu2+ and exhibited 66.2% inhibition of Cu2+-induced Aß1-42 aggregation. Meanwhile, compound 4d showed strong neuroprotective activity against Aß1-42 and Cu2+-treated Aß1-42 induced cell damage. Moreover, compound 4d in high dose significantly reversed Aß-induced memory impairment in mice.

The Clinical Efficacy of Autologous Platelet-Rich Plasma Interventional Circulatory Perfusion Combined with Radiofrequency Ablation and Thermocoagulation in the Treatment of Discogenic Low Back Pain.

Objective: In this study, we aimed to explore the efficacy of the autologous platelet-rich plasma (PRP) interventional circulatory perfusion combined with radiofrequency ablation and thermocoagulation (RFAT) in the treatment of discogenic low back pain (DLBP). Methods: From January 2020 to November 2022, 158 patients of the Second Affiliated Hospital of Nanchang University were selected as the study subjects, and 24 patients met the exclusion criteria. The 134 patients who met the inclusion criteria were divided into 65 patients in the control group (3 patients lost to follow-up) and 69 patients in the observation group (5 patients lost to follow-up), so 126 patients were actually completed the study, including 62 patients in the control group and 64 patients in the observation group. The control group responsible disc received RFAT, and an interventional circulatory perfusion was performed; the observation group received RFAT, and an interventional circulatory perfusion was performed, and then autologous PRP 2 ml was injected. Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) were performed before and 4 and 8 weeks after treatment, and the efficacy was evaluated at 4 and 8 weeks after treatment. The changes of lumbar disc MRI before and after treatment were observed. Results: The differences in the Visual Analog Scale (VAS) scores and the Oswestry Disability Index (ODI) between the observation group and the control group before the treatment were not statistically significant (P > 0.05 in both). However, four weeks and eight weeks after the treatment, the VAS scores and the ODIs were significantly lower in both groups than those before the treatment (P < 0.05 in both). In terms of the therapeutic efficacy, eight weeks after the treatment, the total effective rates in the control group and the observation group were 67.7% and 87.5%, respectively, with the observation group being superior to the control group (P < 0.05). Conclusion: After RFAT, interventional circulatory perfusion combined with autologous PRP intramedullary injection in the lumbar disc is a safe and effective treatment for DLBP, and it had superior long-term effects in improving the clinical symptoms and patient dysfunction than the RFAT and interventional circulatory perfusion.

Design, Synthesis and Antitumor Activity of Novel Selenium-Containing Tepotinib Derivatives as Dual Inhibitors of c-Met and TrxR.

Cellular mesenchymal-epithelial transition factor (c-Met), an oncogenic transmembrane receptor tyrosine kinase (RTK), plays an essential role in cell proliferation during embryo development and liver regeneration. Thioredoxin reductase (TrxR) is overexpressed and constitutively active in most tumors closely related to cancer recurrence. Multi-target-directed ligands (MTDLs) strategy provides a logical approach to drug combinations and would adequately address the pathological complexity of cancer. In this work, we designed and synthesized a series of selenium-containing tepotinib derivatives by means of selenium-based bioisosteric modifications and evaluated their antiproliferative activity. Most of these selenium-containing hybrids exhibited potent dual inhibitory activity toward c-Met and TrxR. Among them, compound 8b was the most active, with an IC50 value of 10 nM against MHCC97H cells. Studies on the mechanism of action revealed that compound 8b triggered cell cycle arrest at the G1 phase and caused ROS accumulations by targeting TrxR, and these effects eventually led to cell apoptosis. These findings strongly suggest that compound 8b serves as a dual inhibitor of c-Met and TrxR, warranting further exploitation for cancer therapy.

Design, Synthesis, and Evaluation of Chalcone Derivatives as Multifunctional Agents against Alzheimer's Disease.

Fifteen chalcone derivatives 3a-3o were synthesized, and evaluated as multifunctional agents against Alzheimer's disease. In vitro studies revealed that these compounds inhibited self-induced Aß1-42 aggregation effectively ranged from 45.9-94.5 % at 20 µM, and acted as potential antioxidants. Their structure-activity relationships were summarized. In particular, (2E)-3-[4-(dimethylamino)phenyl]-1-(pyridin-2-yl)prop-2-en-1-one (3g) exhibited an excellent inhibitory activity of 94.5 % at 20 µM, and it could disassemble the self-induced Aß1-42 aggregation fibrils with ratio of 57.1 % at 20 µM concentration. In addition, compound 3g displayed good chelating ability for Cu2+ , and could effectively inhibit and disaggregate Cu2+ -induced Aß aggregation. Moreover, compound 3g exerted low cytotoxicity, significantly reversed Aß1-42 -induced SH-SY5Y cell damage. More importantly, compound 3g remarkably ameliorated scopolamine-induced memory impairment in mice. In summary, all the results revealed compound 3g was a potential multifunctional agent for AD therapy.

Photochemical Radical C-H Halogenation of Benzyl N-Methyliminodiacetyl (MIDA) Boronates: Synthesis of α-Functionalized Alkyl Boronates.

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 sp2 -B boronate esters. An activation effect of B(MIDA) moiety was found.

Vaccine resistant pseudorabies virus causes mink infection in China.

BACKGROUND: Pseudorabies, a highly contagious infectious disease of swine is caused by pseudorabies virus (PRV). PRV can cause fatal infection in other animal species. RESULTS: We report a deadly outbreak of pseudorabies that killed 87.2% (3522/4028) minks in a farm in 2014 in Shandong Province, China. PRV was isolated by using Vero cell culture and detected in mink samples by PCR from minks died during the outbreak. Epidemiological analysis indicated that 5.8% of minks (33/566) were PCR positive to PRV in Shandong Province. Phylogenetic analysis indicated that the PRV strains isolated from minks in this study were in the same clade with the Chinese porcine PRV isolates, which are resistant to the PRV vaccine. CONCLUSIONS: We demonstrated that pseudorabies virus caused an outbreak of minks in a farm in Shandong Province of China and the virus has a very high infection rate in minks in Shandong Province, which is a challenge for the fur industry in China.

Experimental and Theoretical Studies on Rhodium-Catalyzed Coupling of Benzamides with 2,2-Difluorovinyl Tosylate: Diverse Synthesis of Fluorinated Heterocycles.

Fluorinated heterocycles play an important role in pharmaceutical and agrochemical industries. Herein, we report on the synthesis of four types of fluorinated heterocycles via rhodium(III)-catalyzed C-H activation of arenes/alkenes and versatile coupling with 2,2-difluorovinyl tosylate. With N-OMe benzamide being a directing group (DG), the reaction delivered a monofluorinated alkene with the retention of the tosylate functionality. Subsequent one-pot acid treatment allowed the efficient synthesis of 4-fluoroisoquinolin-1(2H)-ones and 5-fluoropyridin-2(1H)-ones. When N-OPiv benzamides were used, however, [4 + 2] cyclization occurred to provide gem-difluorinated dihydroisoquinolin-1(2H)-ones. Synthetic applications have been demonstrated and the ready availability of both the arene and the coupling partner highlighted the synthetic potentials of these protocols. Mechanistically, these two processes share a common process involving N-H deprotonation, C-H activation, and olefin insertion to form a 7-membered rhodacycle. Thereafter, different reaction pathways featuring ß-F elimination and C-N bond formation are followed on the basis of density functional theory (DFT) studies. These two pathways are DG-dependent and led to the open chain and cyclization products, respectively. The mechanistic rationale was supported by detailed DFT studies. In particular, the origins of the intriguing selectivity in the competing ß-F elimination versus C-N bond formation were elucidated. It was found that ß-F elimination is a facile event and proceeds via a syn-coplanar transition state with a low energy barrier. The C-N bond formation proceeds via a facile migratory insertion of the Rh-C(alkyl) into the Rh(V) amido species. In both reactions, the migratory insertion of the alkene is turnover-limiting, which stays in good agreement with the experimental studies.

Manganese(I)-Catalyzed Regio- and Stereoselective 1,2-Diheteroarylation of Allenes: Combination of C-H Activation and Smiles Rearrangement.

Heteroarenes are important structural motif in functional molecules. A MnI -catalyzed 1,2-diheteroarylation of allenes via a C-H activation/Smiles rearrangement cascade is presented. The reaction occurred under additive-free or even solvent-free conditions, which allowed the creation of two C-C and one C-N bonds in a single operation. A series of structurally diverse bicyclic or tricyclic compounds bearing an exocyclic double bond were constructed in good to excellent efficiency. The decarboxylative ring-opening of the products led to the facile synthesis of vicinal biheteroaryls. Synthetic applications were demonstrated and preliminary mechanistic studies were conducted.

Syndecan-4, a PRRSV attachment factor, mediates PRRSV entry through its interaction with EGFR.

The causative agent of porcine reproductive and respiratory syndrome is the PRRS virus (PRRSV), an enveloped, single-stranded and positive-sense RNA virus. The host factors and mechanisms that are involved in PRRSV entry are still largely unknown. In our present studies, we found that syndecan-4, one of the heparan sulfate proteoglycans, plays a critical role in PRRSV entry, especially in PRRSV attachment. Moreover, EGFR interacts with syndecan-4 in MACR-145 cells and disruption of their interaction impaired PRRSV entry. Furthermore, EGFR inhibitor AG1478 or syndecan-4 derived peptide SSTN87-131 inhibited syndecan-4 endocytosis induced by PRRSV entry. Altogether, syndecan-4, a PRRSV attachment factor, mediated PRRSV entry by interacting with EGFR.

Advances in the development of phosphodiesterase-4 inhibitors.

Phosphodiesterase 4 (PDE4) hydrolyzes cyclic adenosine monophosphate (cAMP) and plays a vital roles in many biological processes. PDE4 inhibitors have been widely studied as therapeutics for the treatment of various diseases, including asthma, chronic obstructive pulmonary disease (COPD) and psoriasis. Many PDE4 inhibitors have progressed to clinical trials and some have been approved as therapeutic drugs. Although many PDE4 inhibitors have been approved to enter clinical trials, however, the development of PDE4 inhibitors for the treatment of COPD or psoriasis has been hampered by their side effects of emesis. Herein, this review summarizes advances in the development of PDE4 inhibitors over the last ten years, focusing on PDE4 sub-family selectivity, dual target drugs, and therapeutic potential. Hopefully, this review will contribute to the development of novel PDE4 inhibitors as potential drugs.

Synthesis of α-Boryl Ketones via Hydration or Oxidation of B(MIDA)-Decorated Alkynes.

α-Boryl ketones are traditionally challenging targets in organic synthesis. Reported herein is a mild and metal-free synthesis of α-boryl ketones via the hydration or oxidation of N-methyliminodiacetyl boronate (B(MIDA))-decorated alkynes. A new hydration system comprised of AcCl and H2O in HFIP allows the hydration of arylethynyl B(MIDA)s at room temperature with decent functional group tolerance. An oxidative carbon deletion process of propargylic B(MIDA)s is also developed for the synthesis of aliphatic α-boryl ketones. An intriguing ß-boron effect was observed to account for the unique site- and chemoselectivities. The application of the products in the synthesis of borylated heterocycles was demonstrated.

Rh(III)-catalyzed redox-neutral C-H alkenylation of benzamides with gem-difluorohomoallylic silyl ethers via ß-H elimination.

Fluorinated molecules are widely used in pharmaceutical and agrochemical industries. Herein we report the synthesis of 2-(3,3-difluoro-4-(silyloxy)but-1-en-1-yl)benzamides from the unprecedented rhodium(III)-catalyzed alkenylation of various benzamides with difluorohomoallylic silyl ethers. The practicability of this protocol is demonstrated by its broad substrate compatibility, good functional group tolerance, ready scalability and high regioselectivity. The oxygen in difluorohomoallylic silyl ethers makes ß-H elimination feasible, which suppresses both the ß-F elimination and dialkenylation of benzamides. This redox-neutral reaction proceeds efficiently via N-O bond cleavage without external oxidants and thus provides new opportunities for the synthesis of elaborate difluorinated compounds from readily available fluorinated synthons.

Design, Synthesis, and Antitumor Efficacy of Substituted 2-Amino[1,2,4]triazolopyrimidines and Related Heterocycles as Dual Inhibitors for Microtubule Polymerization and Janus Kinase 2.

Preclinical and clinical studies have demonstrated the synergistic effect of microtubule-targeting agents in combination with Janus kinase 2 (JAK2) inhibitors, prompting the development of single agents with enhanced therapeutic efficacy by dually inhibiting tubulin polymerization and JAK2. Herein, we designed and synthesized a series of substituted 2-amino[1,2,4]triazolopyrimidines and related heterocycles as dual inhibitors for tubulin polymerization and JAK2. Most of these compounds exhibited potent antiproliferative activity against the selected cancer cells, with compound 7g being the most active. This compound effectively inhibits both tubulin assembly and JAK2 activity. Furthermore, phosphorylated compound 7g (i.e., compound 7g-P) could efficiently convert to compound 7g in vivo. Compound 7g, whether it was administered directly or in the form of a phosphorylated prodrug (i.e., compound 7g-P), significantly inhibited the growth of A549 xenografts in nude mice. The present findings strongly suggest that compound 7g represents a promising chemotherapeutic agent with high antitumor efficacy.

Facile access to 2-hydroxy-2-substituted indole-3-ones via a copper-catalyzed oxidative cyclization of 2-arylethynylanilines.

This paper reports a practical and versatile oxidative cyclization of 2-arylethynylanilines towards 2-hydroxy-2-substituted indol-3-ones via a copper-catalyzed radical approach in the presence of O2. The transformation of 2-hydroxy-2-arylindol-3-ones to 3-hydroxy-3-arylindol-2-ones proceeds well with good yields and highlights the practicability and utility of this catalytic system. Mechanistic investigations showed that the acetyl substituent on 2-arylaethynylanilines played an important role in the formation of the cyclic products and the reaction proceeded via an N-center radical-based 5-endo-dig aza-cyclization pathway.

Design, synthesis and anti-inflammatory activity study of lansiumamide analogues for treatment of acute lung injury.

Acute lung injury (ALI) is an inflammation-mediated respiratory disease with a high mortality rate. Medications with anti-inflammatory small molecules have been demonstrated in phase I and II clinical trials to considerably reduce the ALI mortality. In this study, two series of lansiumamide analogues were designed, synthesized, and evaluated for anti-inflammatory activity for ALI treatment. We found that compound 8n exhibited the best anti-inflammatory activity through inhibiting LPS-induced expression of the proinflammatory cytokines interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in Raw264.7 cells and activating the Nrf2/HO-1 pathway. Furthermore, we discovered in a LPS-induced ALI mice model that compound 8n significantly reduced the infiltration of inflammatory cells into lung tissue to achieve the effect of protecting lung tissues and improving ALI. Additionally, our mice model study revealed that compound 8n had a good expectorant effect. These results consistently support that lansiumamide analogue 8n represents a new class of anti-inflammatory agents with potential as a lead compound for further development into a therapeutic drug for ALI treatment.

Design, synthesis, and biological evaluation of diaryl heterocyclic derivatives targeting tubulin polymerization with potent anticancer activities.

A series of diaryl heterocyclic analogues were designed and synthesized as tubulin polymerization inhibitors. Among them, compound 6y showed the highest antiproliferative activity against HCT-116 colon cancer cell line with an IC50 values of 2.65 µM. Compound 6y also effectively inhibited tubulin polymerization in vitro (IC50 of 10.9 µM), and induced HCT-116 cell cycle arrest in G2/M phase. In addition, compound 6y exhibited high metabolic stability on human liver microsomes (T1/2 = 106.2 min). Finally, 6y was also effective in suppressing tumor growth in a HCT-116 mouse colon model without apparent toxicity. Collectively, these results suggest that 6y represents a new class of tubulin inhibitors deserving further investigation.

Synthesis and evaluation of cytotoxic effects of novel α-methylenelactone tetracyclic diterpenoids.

A series of tetracyclic diterpenoids bearing the α-methylenelactone group have been synthesized and screened for their in vitro anti-tumor activities against six human cancer cell lines. The results showed that compounds 1c, 2a and 2b exhibited significant cytotoxicity superior to the positive control doxorubicin hydrochloride against MDA-MB-231, K562 and HepG2 cell lines. In particular, compound 2b was identified as the most promising anticancer agent against HepG2 cells with IC(50) value of 0.09µM.