Total Synthesis of Quebrachamine and Kopsiyunnanine D.

The total syntheses of (±)-quebrachamine and (±)-kopsiyunnanine D are reported. Key transformations include an intermolecular Horner-Wadsworth-Emmons olefination to merge the two fragments convergently and an intramolecular Mitsunobu reaction to introduce the synthetically challenging nine-membered azonane ring efficiently.

In vitro and in vivo anticancer activity of novel Rh(III) and Pd(II) complexes with pyrazolopyrimidine derivatives.

Six pyrazolopyrimidine rhodium(III) or palladium(II) complexes, [Rh(L1)(H2O)Cl3] (1), [Rh(L2)(CH3OH)Cl3] (2), [Rh(L3)(H2O)Cl3] (3), [Rh2(L4)Cl6]·CH3OH (4), [Rh(L5)(CH3CN)Cl3]·0.5CH3CN (5), and [Pd(L5)Cl2] (6), were synthesized and characterized. These complexes showed high cytotoxicity against six tested cancer cell lines. Most of the complexes showed higher cytotoxicity to T-24 cells in vitro than cisplatin. Mechanism studies indicated that complexes 5 and 6 induced G2/M phase cell cycle arrest through DNA damage, and induced apoptosis via endoplasmic reticulum stress response. In addition, complex 5 also induced cell apoptosis via mitochondrial dysfunction. Complexes 5 and 6 showed low in vivo toxicity and high tumor growth inhibitory activity in mouse tumor models. The inhibitory effect of rhodium complex 5 on tumor growth in vivo was more pronounced than that of palladium complex 6.

Arene-Ruthenium(II)/Osmium(II) Complexes Potentiate the Anticancer Efficacy of Metformin via Glucose Metabolism Reprogramming.

Targeting metabolic reprogramming to treat cancer could increase overall survival and reduce side effects. Here, we put forward a strategy using arene-ruthenium(II)/osmium(II) complexes to potentiate the anticancer effect of metformin (Met.) via glucose metabolism reprogramming. Complexes 1-6 with oxoglaucine derivatives as ligands were synthesized and their anti-tumor activities were tested under hypoglycemia. Results indicated that 2 and 5 potentiated the anticancer effects of Met. under hypoglycemia, exhibiting lower toxicity, slower blood glucose decline and inhibition of early tumor liver metastasis. Combination of 5 with Met. could be used as a new strategy to treat cancer under hypoglycemia through glucose metabolism reprogramming.

Isolation, Absolute Configuration, and Biological Activities of Chebulic Acid and Brevifolincarboxylic Acid Derivatives from Euphorbia hirta.

Twenty new chebulic acid and brevifolincarboxylic acid derivatives, including eight optically pure or achiral compounds (1-7 and 14) and six pairs of enantiomers (8a/8b-13a/13b), along with nine known analogues (15-23), were isolated from an EtOH extract of the aerial parts of Euphorbia hirta. The absolute configurations of the new compounds were assigned based on single-crystal X-ray diffraction analysis and comparison of the experimental and calculated ECD data. Racemic or scalemic mixtures of 8-13 were isolated, and their enantiomers were analyzed by chiral-phase HPLC-ECD measurements. Compound 12 possesses an unprecedented 2H-cyclopenta[de]chromene-2,5(4H)-dione scaffold. Compounds 12, 20, and 23 displayed moderate inhibitory effects against lipopolysaccharide-induced nitric oxide production in BV-2 microglial cells, while all the isolates exhibited significant DPPH radical scavenging activities with EC50 values of 2.2-15.8 µM.

Syntheses, Crystal Structures, and Antitumor Activities of Copper(II) and Nickel(II) Complexes with 2-((2-(Pyridin-2-yl)hydrazono)methyl)quinolin-8-ol.

Two transition metal complexes with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (L), [Cu(L)Cl2]2 (1) and [Ni(L)Cl2]·CH2Cl2 (2), were synthesized and fully characterized. Complex 1 exhibited high in vitro antitumor activity against SK-OV-3, MGC80-3 and HeLa cells with IC50 values of 3.69 ± 0.16, 2.60 ± 0.17, and 3.62 ± 0.12 µM, respectively. In addition, complex 1 caused cell arrest in the S phase, which led to the down-regulation of Cdc25 A, Cyclin B, Cyclin A, and CDK2, and the up-regulation of p27, p21, and p53 proteins in MGC80-3 cells. Complex 1 induced MGC80-3 cell apoptosis via a mitochondrial dysfunction pathway, as shown by the significantly decreased level of bcl-2 protein and the loss of Δψ, as well as increased levels of reactive oxygen species (ROS), intracellular Ca2+, cytochrome C, apaf-1, caspase-3, and caspase-9 proteins in MGC80-3 cells.

Synthesis, Structure Characterization and Antitumor Activity Study of a New Iron(III) Complex of 5-Nitro-8-hydroxylquinoline (HNOQ).

A new iron(III) complex (1) of 5-nitro-8-hydroxylquinoline (HNOQ) was synthesized and structurally characterized in its solid state and solution state by IR, UV-Vis, electrospray ionization (ESI)-MS, elemental analysis, conductivity and X-ray single crystal diffraction analysis. The DNA binding study suggested that complex 1 interacted with calf thymus (ct)-DNA mainly via an intercalative binding mode. By 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the in vitro cytotoxicity of complex 1, comparing with HNOQ and cisplatin, was screened towards a series of tumor cell lines as well as the normal liver cell line HL-7702. Complex 1 showed higher cytotoxicity towards the tested tumor cell lines but lower cytotoxicity towards HL-7702 than HNOQ, in which the T-24 was the most sensitive cell line for 1. Complex 1 caused G2 phase cell cycle arrest and induced cell apoptosis in T-24 cells in a dose-dependent mode, evidenced by changes in cell morphology. Targeting the mitochondrial pathway due to the redox potential of Fe(III)/Fe(II), the apoptotic mechanism in T-24 cells treated by 1 was investigated by reactive oxygen species (ROS) detection, intracellular [Ca(2+)] measurement and caspase-9 and caspase-3 activity assay. It suggested that complex 1 induced cell apoptosis by triggering the caspase-9 and caspase-3 activation via a mitochondrion-mediated pathway.

Oxoisoaporphine as Potent Telomerase Inhibitor.

Two compounds previously isolated from traditional Chinese medicine, Menispermum dauricum (DC), 6-hydroxyl-oxoisoaporphine (H-La), and 4,6-di(2-pyridinyl)benzo[h]isoindolo[4,5,6-de]quinolin-8(5H)-one (H-Lb), were known to have in vitro antitumor activity and to selectively bind human telomeric, c-myc, and bcl-2 G-quadruplexes (G4s). In this study, the binding properties of these two compounds to telomerase were investigated through molecular docking and telomeric repeat amplication protocol and silver staining assay (TRAP-silver staining assay). The binding energies bound to human telomerase RNA were calculated by molecular docking to be -6.43 and -9.76 kcal/mol for H-La and H-Lb, respectively. Compared with H-La, the ligand H-Lb more strongly inhibited telomerase activity in the SK-OV-3 cells model.

Attomolar detection of proteins via cascade strand-displacement amplification and polystyrene nanoparticle enhancement in fluorescence polarization aptasensors.

Extremely sensitive and accurate measurements of protein markers for early detection and monitoring of diseases pose a formidable challenge. Herein, we develop a new type of amplified fluorescence polarization (FP) aptasensor based on allostery-triggered cascade strand-displacement amplification (CSDA) and polystyrene nanoparticle (PS NP) enhancement for ultrasensitive detection of proteins. The assay system consists of a fluorescent dye-labeled aptamer hairpin probe and a PS NP-modified DNA duplex (assistant DNA/trigger DNA duplex) probe with a single-stranded part and DNA polymerase. Two probes coexist stably in the absence of target, and the dye exhibits relatively low FP background. Upon recognition and binding with a target protein, the stem of the aptamer hairpin probe is opened, after which the opened hairpin probe hybridizes with the single-stranded part in the PS NP-modified DNA duplex probe and triggers the CSDA reaction through the polymerase-catalyzed recycling of both target protein and trigger DNA. Throughout this CSDA process, numerous massive dyes are assembled onto PS NPs, which results in a substantial FP increase that provides a readout signal for the amplified sensing process. Our newly proposed amplified FP aptasensor enables the quantitative measurement of proteins with the detection limit in attomolar range, which is about 6 orders of magnitude lower than that of traditional homogeneous aptasensors. Moreover, this sensing method also exhibits high specificity for target proteins and can be performed in homogeneous solutions. In addition, the suitability of this method for the quantification of target protein in biological samples has also been shown. Considering these distinct advantages, the proposed sensing method can be expected to provide an ultrasensitive platform for the analysis of various types of target molecules.

Regioselective palladium-catalyzed decarboxylative cross-coupling reaction of alkenyl acids with coumarins: synthesis of 3-styrylcoumarin compounds.

A novel and efficient protocol for the regioselective synthesis of 3-styrylcoumarins from readily available cinnamic acids and coumarins is presented. The reaction proceeds via a decarboxylative cross-coupling mediated by a catalytic amount of Pd(OAc)2, with Ag2CO3 as an oxidant, and with 1,10-phenanthroline as a ligand. A plausible reaction mechanism for this process is depicted, and the resulting 3-styrylcoumarins show excellent fluorescence quantum yields.

Synthesis and Biological Evaluation of Novel Dehydroabietic Acid Derivatives Conjugated with Acyl-Thiourea Peptide Moiety as Antitumor Agents.

A series of dehydroabietic acid (DHAA) acyl-thiourea derivatives were designed and synthesized as potent antitumor agents. The in vitro pharmacological screening results revealed that the target compounds exhibited potent cytotoxicity against HeLa, SK-OV-3 and MGC-803 tumor cell lines, while they showed lower cytotoxicity against HL-7702 normal human river cells. Compound 9n (IC50 = 6.58 ± 1.11 µM) exhibited the best antitumor activity against the HeLa cell line and even displayed more potent inhibitory activity than commercial antitumor drug 5-FU (IC50 = 36.58 ± 1.55 µM). The mechanism of representative compound 9n was then studied by acridine orange/ethidium bromide staining, Hoechst 33,258 staining, JC-1 mitochondrial membrane potential staining, TUNEL assay and flow cytometry, which illustrated that this compound could induce apoptosis in HeLa cells. Cell cycle analysis indicated that compound 9n mainly arrested HeLa cells in the S phase stage. Further investigation demonstrated that compound 9n induced apoptosis of HeLa cells through a mitochondrial pathway.

Synthesis and antitumor activities of novel dipeptide derivatives derived from dehydroabietic acid.

A series of dipeptide derivatives from dehydroabietic acid were designed and synthesized as novel antitumor agents. The antitumor activities screening indicated that many compounds showed moderate to high levels of inhibition activities against NCI-H460, HepG2, SK-OV-3, BEL-7404, HeLa and HCT-116 cancer cell lines and that some displayed more potent inhibitory activities than commercial anticancer drug 5-fluorouracil. The mechanism of representative compound 7b was studied by AO/EB staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining, TUNEL assay, DNA ladder assay and flow cytometry, which exhibited that the compound could induce apoptosis in HeLa cells. Further investigation showed that compound 7b induced apoptosis of HeLa cells through a mitochondrial pathway.

A planar Schiff base platinum(II) complex: crystal structure, cytotoxicity and interaction with DNA.

A new platinum(II) complex of salphen derivative, namely Schiff base ligand that derived from o-phenylenediamine and 5-chlorosalicylaldehyde was synthesized. The complex possessed a planar mononuclear structure. The in vitro cytotoxicities of the complex were evaluated by microculture tetrozolium (MTT) assay against seven human tumor cell lines with the IC50 values of ca. 11.61 µM. Cell cycle analysis indicated that the complex induced apoptosis and G1-phase arrest in A549 cells. The results of colony formation assay showed that the complex could suppress the proliferation and viability of A549 cells. The binding of the complex to potential target DNA were investigated by fluorescence spectroscopy, viscosity measurements, fluorescence polarization and agarose gel electrophoresis. The results suggest that the most probable binding mode of the complex is intercalation.

Copper(II) complexes with plumbagin and bipyridines target mitochondria for enhanced chemodynamic cancer therapy.

The combination of mitochondrial targeting and chemodynamic therapy is a promising anti-cancer strategy. Three mitochondria targeting copper(II) complexes (Cu1-Cu3) with plumbagin and bipyridine ligands for enhanced chemodynamic therapy were synthesized and characterized. Their anti-proliferative activity to HeLa cells was higher than that of cisplatin, and their toxicity to normal cells was low. Cellular uptake and distribution studies indicated that Cu1 and Cu3 were mainly accumulated in mitochondria. The mechanism studies showed that Cu1 and Cu3 converted intracellular H2O2 into toxic hydroxyl radicals by consuming glutathione, leading to mitochondrial dysfunction. Treatment with the copper complex caused ER stress and cell arrest in the S phase which resulted in apoptosis. In vivo, Cu1 and Cu3 effectively inhibited the growth of HeLa xenograft tumors without obvious toxic and side effects.

The comparative analysis of Lonicerae Japonicae Flos and Lonicerae Flos: A systematical review.

ETHNOPHARMACOLOGICAL RELEVANCE: Lonicerae Japonicae Flos (LJF) and Lonicerae Flos (LF) were once used as the same herb in China, but they were distinguished by Chinese Pharmacopoeia in 2005 in terms of their medicinal history, plant morphology, medicinal properties and chemical constituents. However, their functions, flavor, and meridian tropism are the same according to the Chinese pharmacopoeia 2020 edition, making researchers and customers confused. AIM OF THE REVIEW: This review aimed to provide a comparative analysis of LJF and LF in order to provide a rational application in future research. MATERIALS AND METHODS: The information was gathered from China National Knowledge Infrastructure (CNKI), SciFinder, Google Scholar, PubMed, Web of Science, and Chinese Masters and Doctoral Dissertations (all chosen articles were reviewed attentively from 1980.1 to 2023.8). RESULTS: Till now, 507 chemical compounds have been isolated and identified in LJF, while 223 ones (79 overlapped compounds) are found in LF, including organic acids and derivatives, flavonoids, triterpenoids, iridoids, and essential oil components, etc. In addition, the pharmacological activities of LJF and LF, especially for their anti-influenza efficacy and mechanism, and their difference in terms of pharmacokinetic parameters, toxicology, and clinical applications were also summarized. CONCLUSION: The current work offers comparative information between LJF and LF in terms of botany, traditional uses, phytochemistry, ethnopharmacology, pharmacokinetics, toxicology, and pharmacology, especially their anti-influenza activities. Despite the same clinical applications and similar chemical components in LJF and LF, differentiated components were still existed, resulting in differentiated pharmacological activities and pharmacokinetics parameters. Moreover, the research about anti-influenza mechanism and functional substances of LJF and LF is dramatically limited, restricting their clinical applications. In addition, few studies have investigated the metabolism feature of LF in vivo, which is one of the important bases for revealing the pharmacological mechanism of LF. At the same time, the toxicity of LJF and LF is not fully studied, and the toxic compounds of LJF and LF need to be screened out in order to standardize the drug use and improve their rational applications.

Discovery of mitochondrion-targeting copper(II)-plumbagin and -bipyridine complexes as chemodynamic therapy agents with enhanced antitumor activity.

Four copper(II)-plumbagin and -bipyridine complexes (Cu1-Cu4) were synthesized as chemodynamic therapy agents with enhanced antitumor activity. As lipophilic and positively charged compounds, Cu1-Cu4 were preferentially accumulated in mitochondria and activated the mitochondrial apoptosis pathway. Mechanistic studies showed that Cu1-Cu4 reacted with GSH to reduce Cu2+ ions to Cu+ ions, catalyzed the formation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (H2O2) through a Fenton-like reaction, induced mitochondrial dysfunction, and activated caspase-9/3, which eventually led to apoptosis. Cu1-Cu4 arrested HeLa cells in the S phase and eventually killed cancer cells. Cu2 showed a favorable pharmacokinetic profile in mice. Moreover, Cu2 effectively inhibited the growth of HeLa xenografts in nude mice and showed low toxicity in vivo.

Label-free colorimetric aptasensor based on nicking enzyme assisted signal amplification and DNAzyme amplification for highly sensitive detection of protein.

Highly sensitive detection of proteins is essential to biomedical research as well as clinical diagnosis. Here, we develped a novel label-free colorimetric aptasensor based on nicking enzyme assisted signal amplification and DNAzyme amplification for highly sensitive detection of protein. The system consists of a hairpin DNA probe carrying an aptamer sequence for target, a G-riched DNA probe containing two G-riched DNAzyme segments and the recognition sequence as well as cleavage site for nicking enzyme, a blocker DNA, and the nicking enzyme. The hybridization of the G-riched DNA with the blocker DNA prohibits the formation of the activated DNAzymes in the absence of target. Upon addition of target to the system, the hairpin probe is opened by the specific recognition of the target to its aptamer. The open hairpin probe hybridizes with a G-riched DNA and forms a DNA duplex, which triggers the selective cleavage of the G-riched DNA probe by nicking enzyme, leading to the release of the aptamer-target complex and the G-riched DNAzyme segments. The released open hairpin probe then hybridizes with another G-riched DNA probe, and the cycle starts anew, resulting in the continuous cleavage of the G-riched DNA probes, generating a much of G-riched DNAzyme segments. The G-riched DNAzyme segments interact with hemin and generates the activated DNAzyme that can catalyze the H2O2-mediated oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(2-)) to the colored ABTS(•-), thus providing the amplified colorimetric detection of target. With the use of thrombin (Tb) as a proof-of-principle analyte, this sensing platform can detect Tb specifically with a detection limit as low as 1.5 pM, which is at least 4 orders of magnitude lower over the unamplified colorimetric assay. Moreover, the assay does not involve any chemical modification of DNA, which is simple and low-cost. This sensing platform provides a promising approach for the amplified analysis of target molecules.

Hyperoncotic albumin attenuates lung and intestine injuries caused by peritonitis-induced sepsis in rats.

BACKGROUND: Hyperoncotic albumin may be a therapeutic option to improve tissue perfusion and organ injury in sepsis. To clarify the hypothesis and its mechanism, hyperoncotic albumin was administered to the rats in a polymicrobial sepsis-peritonitis model. MATERIALS AND METHODS: Peritonitis was induced by a surgery of cecal ligation and puncture (CLP) in 27 male Wistar rats. For control purposes, sham operations without ligating and puncturing the cecum were performed in 20 rats. Three hours later, rats were randomized to receive intravenously 3 mL/kg of 5% albumin, 25% albumin, or normal saline. All the hemodynamic and biochemical parameters were measured during the 18-h observation. RESULTS: In septic rats, 25% albumin attenuated hypotension, vascular hyporeactivity to norepinephrine, and the elevated serum levels of lactate dehydrogenase and blood urea nitrogen. However, these improvements were not noted in CLP rats after 5% albumin treatment. In addition, 25% albumin decreased metabolic acidosis and improved the CLP-induced hypoperfusion in the intestine and kidney. Superoxide levels in the aorta and lung and the protein expression of inducible nitric oxide synthase in the lung were also attenuated by 25% albumin in CLP rats. Microscopic findings confirmed that 25% albumin attenuated the substantial swelling and cell infiltration in the intestine and lung caused by CLP. CONCLUSIONS: In this sepsis rat model, 25% albumin reduced macro- and microhemodynamic changes and attenuated intestine and lung injuries in peritonitis-induced sepsis.

Antitumor activity of synthetic three copper(II) complexes with terpyridine ligands.

Three new synthetic terpyridine copper(II) complexes were characterized. The copper(II) complexes induced apoptosis of three cancer cell lines and arrested T-24 cell cycle in G1 phase. The complexes were accumulated in mitochondria of T-24 cells and caused significant reduction of the mitochondrial membrane potential. The complexes increased both intracellular ROS and Ca2+ levels and activated the caspase-3/9 expression. The apoptosis was further confirmed by Western Blotting analysis. Bcl-2 was down-regulated and Bax was upregulated after treatment with complexes 1-3. The in vivo studies showed that complexes 1-3 obviously inhibited the growth of tumor without significant toxicity to other organs.

In vitro and in vivo antitumor activities of Ru and Cu complexes with terpyridine derivatives as ligands.

Six terpyridine ligands(L1-L6) with chlorophenol or bromophenol moiety were obtained to prepare metal terpyridine derivatives complexes: [Ru(L1)(DMSO)Cl2] (1), [Ru(L2)(DMSO)Cl2] (2), [Ru(L3)(DMSO)Cl2] (3), [Cu(L4)Br2]·DMSO (4), Cu(L5)Br2 (5), and [Cu(L6)Br2]⋅CH3OH (6). The complexes were fully characterized. Ru complexes 1-3 showed low cytotoxicity against the tested cell lines. Cu complexes 4-6 exhibited higher cytotoxicity against several tested cancer cell lines compared to their ligands and cisplatin, and lower toxicity towards normal human cells. Copper(II) complexes 4-6 arrested T-24 cell cycle in G1 phase. The mechanism studies indicated that complexes 4-6 accumulated in mitochondria of T-24 cells and caused significant reduction of the mitochondrial membrane potential, increase of the intracellular ROS levels and the release of Ca2+, and the activation of the Caspase cascade, finally inducing apoptosis. Animal studies showed that complex 6 obviously inhibited the tumor growth in a mouse xenograft model bearing T-24 tumor cells without significant toxicity.

Platinum-Based Mcl-1 Inhibitor Targeting Mitochondria Achieves Enhanced Antitumor Activity as a Single Agent or in Combination with ABT-199.

Discovery of small molecule inhibitors targeting Mcl-1 (Myeloid cell leukemia 1) confronts many challenges. Based on the fact that Mcl-1 is mainly localized in mitochondria, we propose a new strategy of targeting mitochondria to improve the binding efficiency of Mcl-1 inhibitors. We report the discovery of complex 9, the first mitochondrial targeting platinum-based inhibitor of Mcl-1, which selectively binds to Mcl-1 with high binding affinity. Complex 9 was mainly concentrated in the mitochondria of tumor cells which led to an enhanced antitumor efficacy. Complex 9 induced Bax/Bak-dependent apoptosis in LP-1 cells and synergized with ABT-199 to kill ABT-199 resistant cells in multiple cancer models. Complex 9 was effective and tolerable as a single agent or in combination with ABT-199 in mouse models. This research work demonstrated that developing mitochondria-targeting Mcl-1 inhibitors is a new potentially efficient strategy for tumor therapy.