Triple-negative breast cancer (TNBC) represents a highly malignant subtype of breast cancer with limited therapeutic options. In this study, we designed and synthesized a series of 1,4-DHP derivatives by structure-based strategy, 43 was documented to be a potent SIRT3 activator and exhibited profound anti-proliferative activity in BT-549 and MDA-MB-231 cells with low toxicity over normal cells. Additionally, 43 displayed the ability of direct binding to SIRT3 with a K value of 51.
View Article and Find Full Text PDFTriple-negative breast cancer has become a major problem in clinical treatment due to its high heterogeneity, and Plant-derived drug discovery has been the focus of attention for novel anti-tumor therapeutics. In this study, Miliusol, a natural product isolated from the rarely reported plant Miliusa tenuistipitata, was identified as the lead compound, and 25 miliusol derivatives were designed and synthesized under antiproliferative activity guidance. The results revealed that ZMF-24 was demonstrated to have potent anti-TNBC proliferation with IC values of 0.
View Article and Find Full Text PDFAn ideal tumor treatment strategy involves therapeutic approaches that can enhance the immunogenicity of the tumor microenvironment while simultaneously eliminating the primary tumor. A cholic acid-modified iridium(III) (Ir3) photosensitizer, targeted to the endoplasmic reticulum (ER), has been reported to exhibit potent type I and type II photodynamic therapeutic effects against triple-negative breast cancer (MDA-MB-231). This photosensitizer induces pyroptotic cell death mediated by gasdermin E (GSDME) through photodynamic means and enhances tumor immunotherapy.
View Article and Find Full Text PDFAcute myeloid leukemia (AML) represents a highly malignant subtype of leukemia with limited therapeutic options. In this study, we propose a novel therapeutic strategy for treating AML by inhibiting SIRT3 to regulate mitochondrial metabolism network involved in energy metabolism and epigenetic modifications essential for AML survival. A series of thieno [3,2-d]pyrimidine-6-carboxamide derivatives were designed and synthesized by structure-based strategy, 17f was documented to be a potent and acceptable selective SIRT3 inhibitor with IC value of 0.
View Article and Find Full Text PDFCancer reprogramming is an important facilitator of cancer development and survival, with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation, even under sufficient oxygen supply condition. This metabolic alteration, known as the Warburg effect, serves as a significant indicator of malignant tumor transformation. The Warburg effect primarily impacts cancer occurrence by influencing the aerobic glycolysis pathway in cancer cells.
View Article and Find Full Text PDFDrug nephrotoxicity has high fatality rates and complications. To study this conditional, traditionally, Gentamicin (GM) is used to induce acute injury and establish a nephrotic syndrome model. Baicalin, a flavonoid derived from baicalin with potent anti-inflammatory and antioxidant activity, has been used to treat various inflammatory diseases.
View Article and Find Full Text PDFToxicol Appl Pharmacol
February 2024
With the increasing incidence of chronic kidney disease (CKD), the development of safe and effective anti-renal fibrosis drugs is particularly urgent. Recently, Baicalin has been considered to have a renal protective effect, but its bioavailability is too low. Therefore, we synthesized baicalin-2-ethoxyethyl ester (BAE) by esterification of baicalin.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
January 2024
Azomethine imines, as a prominent class of 1,3-dipolar species, hold great significance and potential in organic and medicinal chemistry. However, the reported synthesis of centrally chiral azomethine imines relies on kinetic resolution, and the construction of axially chiral azomethine imines remains unexplored. Herein, we present the synthesis of axially chiral azomethine imines through copper- or chiral phosphoric acid catalyzed ring-closure reactions of N'-(2-alkynylbenzylidene)hydrazides, showcasing high efficiency, mild conditions, broad substrate scope, and excellent enantioselectivity.
View Article and Find Full Text PDFTriple-negative breast cancer (TNBC) is the most poorly treated subtype of breast cancer, and targeting the heterogeneity of TNBC has emerged as a fascinating therapeutic strategy. In this study, we propose for the first time that dual-targeting PAK1 and HDAC6 is a promising novel strategy for TNBC treatment due to their essential roles in the regulation of energy metabolism and epigenetic modification. We discovered a novel dual-targeting PAK1/HDAC6 inhibitor, 6 - (2-(cyclopropylamino) - 6 - (2,4-dichlorophenyl) - 7 - oxopyrido [2,3-d] pyrimidin - 8 (7H) -yl) - N-hydroxyhexanamide (ZMF-23), which presented profound inhibitory activity against PAK1 and HDAC6 and robust antiproliferative potency in MDA-MB-231 cells.
View Article and Find Full Text PDFATPase family AAA domain-containing protein 2 (ATAD2) has been emerging as a hot anti-cancer drugable target due to its oncogenic epigenetic modification closely associated with cancer cells proliferation, apoptosis, migration and drug resistance. In this study, we design a series of theophylline derivatives as novel ATAD2 inhibitors through fragment-based screening and scaffold growth strategy. A novel potent ATAD2 inhibitor (compound is discovered with an IC value of 0.
View Article and Find Full Text PDFCoactivator-associated arginine methyltransferase 1 (CARM1), a type I protein arginine methyltransferase (PRMT), has been widely reported to catalyze arginine methylation of histone and non-histone substrates, which is closely associated with the occurrence and progression of cancer. Recently, accumulating studies have demonstrated the oncogenic role of CARM1 in many types of human cancers. More importantly, CARM1 has been emerging as an attractive therapeutic target for discovery of new candidate anti-tumor drugs.
View Article and Find Full Text PDFDrug Discov Today
July 2023
Poly (ADP-ribose) polymerase 1 (PARP1), a key enzyme in DNA repair, has emerged as a promising anticancer druggable target. An increasing number of PARP1 inhibitors have been discovered to treat cancer, most notably those characterized by BRCA1/2 mutations. Although PARP1 inhibitors have achieved great clinical success, their cytotoxicity, development of drug resistance, and restriction of indication have weakened their clinical therapeutic effects.
View Article and Find Full Text PDFACS Chem Neurosci
February 2023
Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects more than ten million people worldwide. However, the current PD treatments are still limited and alternative treatment strategies are urgently required. Leucine-rich repeat kinase 2 (LRRK2) has been recognized as a promising target for PD treatment.
View Article and Find Full Text PDFATPase family AAA domain-containing protein 2 (ATAD2) has been widely reported to be a new emerging oncogene that is closely associated with epigenetic modifications in human cancers. As a coactivator of transcription factors, ATAD2 can participate in epigenetic modifications and regulate the expression of downstream oncogenes or tumor suppressors, which may be supported by the enhancer of zeste homologue 2. Moreover, the dominant structure (AAA + ATPase and bromine domains) can make ATAD2 a potential therapeutic target in cancer, and some relevant small-molecule inhibitors, such as GSK8814 and AZ13824374, have also been discovered.
View Article and Find Full Text PDFMitochondria-targeted photodynamic therapy (PDT) has recently been recognized as a promising strategy for effective cancer treatment. In this work, a mitochondria-targeted near-infrared (NIR) aggregation-induced emission (AIE)-active phosphorescent Ir(III) complex (Ir1) is reported with highly favourable mitochondria-targeted bioimaging and cancer PDT properties. Complex Ir1 has strong absorption in the visible light region (∼500 nm) and can effectively produce singlet oxygen (O) under green light (525 nm) irradiation.
View Article and Find Full Text PDFAcute lung injury (ALI) is a common respiratory disease in clinics, which is characterized by alveolar-capillary membrane loss, plasma protein leakage, pulmonary edema, massive neutrophil infiltration, and the release of proinflammatory cytokines and mediators. Rhodiola rosea L. an adaptogenic plant rich in phenylethanoloids, phenylpropanoids, monoterpenes, has anti-inflammatory and antioxidant effects.
View Article and Find Full Text PDFA primary strategy employed in cancer therapy is the inhibition of topoisomerase II (Topo II), implicated in cell survival. However, side effects and adverse reactions restrict the utilization of Topo II inhibitors. Thus, investigations focus on the discovery of novel compounds that are capable of inhibiting the Topo II enzyme and feature safer toxicological profiles.
View Article and Find Full Text PDFThe clinical application of gentamicin may lead to acute kidney injury (AKI), and the nephrotoxicity of gentamicin is related to the pathological mechanism of several oxidative and inflammatory cytokines. Plant-derived essential oils have good anti-inflammatory and antioxidant properties. This study aimed to clarify the protective effect of essential oils (AOs) on gentamicin-induced AKI in rats and its possible mechanism.
View Article and Find Full Text PDFCurrently, the development of selective fluorescent probes toward targeted enzymes is still a great challenge, due to the existence of numerous isoenzymes that share similar catalytic capacity. Herein, a double-filtering strategy was established to effectively develop isoenzyme-specific fluorescent probe(s) for cytochrome P450 (CYP) which are key enzymes involving in metabolism of endogenous substances and drugs. In the first-stage of our filtering approach, near-infrared (NIR) fluorophores with alkoxyl group were prepared for the screening of CYP-activated fluorescent substrates using a CYPs-dependent incubation system.
View Article and Find Full Text PDFPhytochemical investigation on the concentrate of Huangjing wine, resulted in the isolation of three new tyrosol derivatives 4-hydroxyphenethyl 2-(R)-hydroxy-3-phenylpropionate (), 4-hydroxyphenethyl(4-hydroxy-3-methoxyphenyl)propionate () and 4-hydroxyphenethyl ethyl succinate (), together with 5 known compounds, ferulic acid (), L-phenyllactic acid (), hydroxytyrosol (), dihydroferulic acid (), cyclo(L-Pro-D-Tyr) (). Their structures were elucidated using spectroscopic analysis and by comparison with the literature data. All compounds displayed antioxidant effect in the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical.
View Article and Find Full Text PDFThe prevalence of hyperuricemia is considered high worldwide. Hyperuricemia occurs due to decreased excretion of uric acid, increased synthesis of uric acid, or a combination of both mechanisms. There is growing evidence that hyperuricemia is associated with a decline of renal function.
View Article and Find Full Text PDFAtorvastatin ester (Ate) is a structural trim of atorvastatin that can regulate hyperlipidemia. The purpose of this study was to evaluate the lipid-lowering effect of Ate. Male Sprague Dawley (SD) rats were fed a high-fat diet for seven months and used as a hyperlipidemia model.
View Article and Find Full Text PDFFatty acid amide hydrolase (FAAH) is primarily responsible for the inactivation of fatty acid ethanolamide (FAE) and is involved in a variety of biological functions related to diseases of the nervous system. Herein, we developed a highly selective and sensitive FAAH-activated near-infrared fluorescent probe named DAND and achieved the real-time detection and imaging of FAAH activity in complex biosystems. Moreover, a visual high-throughput screening method was established using DAND, piperine was identified as a novel inhibitor of FAAH.
View Article and Find Full Text PDFBioorg Med Chem Lett
September 2021
The excessive activation of histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) signaling promotes tumor growth and progression. We proposed that dual targeting mTOR and HDAC inhibitors is a promising strategy for triple negative breast cancer (TNBC) treatment. In this study, a series of dual mTOR/HDAC6 inhibitors were designed and synthesized by structure-based strategy.
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