Equipping Uridine with Three Dipeptide Motifs for the Inhibition of Radical-Induced DNA Oxidation.

We report the discovery and characterization of antioxidative effects of uridine linked with three dipeptide motifs against DNA oxidation induced by peroxyl radicals. First, the dipeptide motifs are constructed by using the Ugi four-component reaction (Ugi 4CR), in which caffeic, ferulic, sinapic, and syringic acids are used as the carboxylic acid resources, vanillin, benzaldehyde, and -hydroxybenzaldehyde are used as the aldehyde resources, tyramine- and dopamine-related isocyanides as well as ethyl isocyanoacetate are used as the isocyanide resources, and 2-(-aminophenyl)ethanol is used as the amine component. We found that the antioxidative effects of the Ugi 4CR products are 1.

Is it still worth renewing nucleoside anticancer drugs nowadays?

Nucleoside has situated the convergence point in the discovery of novel drugs for decades, and a large number of nucleoside derivatives have been constructed for screening novel pharmacological properties at various experimental platforms. Notably, nearly 20 nucleosides are approved to be used in the clinic treatment of various cancers. Nevertheless, the blossom of synthetic nucleoside analogs in comparison with the scarcity of nucleoside anticancer drugs leads to a question: Is it still worth insisting on the screening of novel anticancer drugs from nucleoside derivatives? Hence, this review attempts to emphasize the importance of nucleoside analogs in the discovery of novel anticancer drugs.

Potentiality of Nucleoside as Antioxidant by Analysis on Oxidative Susceptibility, Drug Discovery, and Synthesis.

Nucleosides are sensitive sites towards oxidations caused by endogenous and exogenous oxidative resources, and a large number of the produced DNA lesions behave as pathogenesis event1ually. We herein analyze oxidative modes of nucleosides and structure-activity relationships of some clinical nucleoside drugs. Together with our previous findings on the inhibitory effects of nucleoside derivatives against DNA oxidation, all these results imply a possibility for nucleoside to be a new member in the family of antioxidants.

What about the progress in the synthesis of flavonoid from 2020?

Flavonoids are a well-known family of natural polyphenols because of their prevalent properties in the physiological and medicinal field. In addition to a plethora of natural flavonoids, the construction of flavonoid skeletons still situates at the convergence point in the medicinal chemistry. Not surprisingly, amplification in the organic synthetic protocols showcases an expected avenue for accessing to abundant flavonoid scaffolds with special pharmacological activities.

Why natural antioxidants are readily recognized by biological systems? 3D architecture plays a role!

A great deal of investigations has convincingly outlined the correlation of pathogenesis of various fatal diseases with the damages caused by reactive oxygen species (ROS) in vivo. Not surprisingly, natural antioxidants play pivotal roles in the decreasing of these diseases by their hydrophilicity, permeability, multi-factored interactions with biological surroundings, while the antioxidative effects are dependent upon the bond energies, donors or acceptors of hydrogen bonds as well as other physical properties of the functional groups. However, in comparison with natural antioxidants the synthetic antioxidants sometimes exhibit potentially deleterious effects, viz.

Attaching a Dipeptide to Fullerene as an Antioxidant Hybrid against DNA Oxidation.

Emerging evidence has revealed that oxidative damages of DNA correlate with the pathogenesis of some diseases, and numerous investigations have also suggested that supplementation of antioxidants is beneficial for keeping health by rectifying redox status. Here, we construct antioxidative dipeptides with the Ugi four-component reaction (comprising -aminobenzyl alcohol, benzaldehyde, or vanillin, a series of antioxidative carboxylic acids and isocyanides as reagents) and then attempt to attach the dipeptides to [60]fullerene by the Bingel reaction. However, this endeavor does not lead to the amelioration of the radical-scavenging property because abilities of fullerenyl dipeptides to trap 2,2'-diphenyl-1-picrylhydrazyl and galvinoxyl radicals are still dependent upon the phenolic hydroxyl group in the dipeptide scaffold rather than upon the fullerenyl group.

Multicomponent Reactions for Integrating Multiple Functional Groups into an Antioxidant.

A large number of convincing evidences has revealed the correlation of the pathogeny of diseases with the oxidative damages of DNA, protein, biomembrane, and other biological species, while supplementation of antioxidants is demonstrated to be a promising way to avoid, at least, rectify the unbalance redox status in vivo. Although many endeavors have focused on synthesis of antioxidants, a main hurdle still hinders the wide usages of synthetic antioxidants because of low bioavailability and potential cytotoxicity. The search for antioxidants with multiple functional groups being recognized by different receptors becomes a much sought by researchers, and multicomponent reactions (MCRs) provide with powerful tools for the construction of multifunctional antioxidants.

Bridging free radical chemistry with drug discovery: A promising way for finding novel drugs efficiently.

Many diseases have been regarded to correlate with the in vivo oxidative damages, which are caused by overproduced free radicals from metabolic process or reactive oxygen species (ROS). This background motivates chemists to explore free radical reactions and to design a number of antioxidants, but whether free radical chemistry can be applied to accelerate the efficacy of the drug discovery is still underrepresented. Herein, in light of recent findings as well as kinetics on free radical reaction, the discipline of free radical chemistry is introduced to be a novel tool for finding potential drugs from antioxidant libraries accumulated during the study on free radical chemistry.

How to Start a Total Synthesis from the Wieland-Miescher Ketone?

Background: The Wieland-Miescher ketone consists of a couple of enantiomers of 9-methyl- Δ5(10)-octalin-1,6-dione, in which the configuration at 9-position is S- or R-type. The Robinson annulation of 2-methyl-1,3-cyclohexanedione with methyl vinyl ketone is able to afford the Wieland-Miescher ketone. As widely used in the total synthesis, the Wieland-Miescher ketone is treated at the beginning of total synthesis, and protocols for treating the Wieland-Miescher ketone are worthy to be addressed.

A Novel SNPs in Alpha-Lactalbumin Gene Effects on Lactation Traits in Chinese Holstein Dairy Cows.

Alpha-lactalbumin (α-LA) is a major whey protein in bovine and other mammalian milk, which regulates synthesis of lactose. Little is known about its genetic polymorphism and whether can be used as a potential marker for dairy ingredients, milk yield traits, and milk properties. To investigate its polymorphisms and their relationship with milk lactation traits in Chinese Holstein dairy cows, single-strand conformation polymorphism method (PCR-SSCP) and direct sequencing method were used to mark the α-LA gene SNPs.

Construction of 3D Antioxidants with Nucleosides as the Core: Inhibition of DNA Oxidation.

We herein attach ferulic and caffeic acids to -OH and -NH in cytidine, uridine, adenosine, or guanosine for achieving antioxidative hybrids with three-dimensional (3D) configuration. In the case of molecular docking computation, the nucleoside antioxidants with 3D configuration facilitate to bind with the groove of DNA and to cover the surface of a DNA helix. Experimentally, the antioxidative effects of nucleoside hybrids are measured in the inhibition of DNA oxidation caused by 2,2'-azobis(2-amidinopropane dihydrochloride) (AAPH), and the stoichiometric factor (, the number of free radical propagations terminated by one molecule of antioxidant) can be selected as a quantitative index for expressing antioxidative effects.

Anti-Oxidant in China: A Thirty-Year Journey.

Anti-oxidant refers to such a kind of endogenous or exogenous compound that is able to retard or even prohibit or oxidation with only small amount being used. The study of anti-oxidants starts nearly 30 years ago, and the research on this topic in China almost begins simultaneously with that in the world. Gratifyingly, contributions on anti-oxidants from China researchers have rapidly increased in the recent decade as anti-oxidants have become a hot topic in biochemistry, pharmacology, food science, chemistry as well as other related disciplines.

Enhancing Antioxidant Effect against Peroxyl Radical-Induced Oxidation of DNA: Linking with Ferrocene Moiety!

As a major member in the family of reactive oxygen species, peroxyl radical is able to abstract hydrogen atom from 4-position of ribose, leading to the collapse of DNA strand. Thus, inhibiting oxidative stress with exogenous antioxidants acts as a promising strategy to protect the integrity of DNA structure and is thereby suggested to be a pathway against developments of related diseases. Ferrocene as an organometallic scaffold is widely applied in the design of organometallic drugs, and redox of Fe(II)/Fe(III) in ferrocene offers advantage for providing electron to radicals.

5-Hydroxytryptamine and Dopamine Neurons in the Cerebellum of the New-Hatching Yangtze Alligator Alligator sinensis.

Nissl and immunohistochemical staining methods were used to morphologically characterize the cerebellum of the new-hatching Yangtze alligator, and the cerebellar histological structure and the distribution profiles of 5-hydroxytryptamine (5-HT) and dopamine (DA) neurons were investigated for the first time. The results of cerebellar histological structure showed that there was a ventriculus cerebelli in the cerebellum of the new-hatching Yangtze alligator, the surface of the cerebellar cortex was not very smooth, the cerebellar cortex could be divided into four layers, which include external granular layer, molecular layer, Purkinje cell layer and granular layer, Purkinje cell layer could be characterized specially by multilayer, two cerebellar nuclei termed as the nucleus cerebelli lateralis and the nucleus cerebelli medialis were found in the cerebellar medulla. 5-hydroxytryptamine-immunoreactive (5-HT-IR) and dopamine-immunoreactive (DA-IR) neurons and fibers distributed widely in the cerebellum.

Hybrid of Resveratrol and Glucosamine: An Approach To Enhance Antioxidant Effect against DNA Oxidation.

Resveratrol exhibits various pharmacological activities, which are dependent upon phenolic hydroxyl groups. In this work, glucosamine, lipoic acid, or adamantanamine moiety was applied for attaching to ortho-position of hydroxyl group in resorcinol moiety of resveratrol (known as position-2). Antioxidant effects of the obtained hybrids were characterized using DNA oxidative systems mediated by OH, Cu/glutathione (GSH), and 2,2'-azobis(2-amidinopropanehydrochloride) (AAPH), respectively.

Tetramer as efficient structural mode for organizing antioxidative carboxylic acids: The case in inhibiting DNA oxidation.

To overcome the problem on the relationship of antioxidative effect with the branch number in a tetramer, we herein designed a series of antioxidants with pentaerythritol, glycerol, and ethylene glycol as the cores, and gallic, ferulic, caffeic, and p-hydroxybenzoic acids as the antioxidative moieties. In the case of DNA oxidation mediated by 2,2'-azobis(2-amidinopropane hydrochloride, AAPH), it was found that the stoichiometric factor (n) of a carboxylic acid increased rapidly when the acid was esterified with ethylene glycol, glycerol, and pentaerythritol to form a dimer, trimer, and tetramer, respectively. Interestingly, the coefficient in the equation of n∼{branch} ({branch} referred to the number of branches) was higher than one, indicating that the antioxidative effect was enhanced more promptly than the increase of the number of branches.

2-Isocyano glucose used in Ugi four-component reaction: An approach to enhance inhibitory effect against DNA oxidation.

The Ugi four-component-reaction (Ugi 4CR) allowed synthesizing bisamide from carboxylic acid, aldehyde, amine, and isocyanide in one-pot operation. However, introducing 2-isocyano glucose into the Ugi 4CR and investigating the inhibitory effects of Ugi adducts against radical-induced oxidation of DNA remained technical challenges. We herein applied 2-isocyano glucose (acetylation of hydroxy groups) to perform a catalyst-free Ugi 4CR at room temperature.

Tetrahydropyrrolization of Resveratrol and Other Stilbenes Improves Inhibitory Effects on DNA Oxidation.

The inhibitory effect of resveratrol on DNA oxidation caused by 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH) was found to be enhanced if the C=C bond in resveratrol was converted into tetrahydropyrrole by reaction with azomethine ylide (CH2 =N(+) (CH3 )CH2 (-) ). This encouraged us to explore whether the inhibitory activities of other stilbenes could also be increased by the same method. We found that the inhibitory effects of the tetrahydropyrrole derivatives on AAPH-induced oxidation of DNA were higher than those of the corresponding stilbenes, because the tetrahydropyrrole motif can provide hydrogen atoms to be abstracted by radicals.

Development of amino- and dimethylcarbamate-substituted resorcinol as programmed cell death-1 (PD-1) inhibitor.

Blockading the interaction of programmed death-1 (PD-1) protein with its ligands (PD-Ls, such as PD-L1) was proved to be a pathway for suppressing the development of tumors and other degradations of biological species. Thus, finding PD-1 inhibitors situated at the convergence point of drug discovery. In addition to some monoclonal antibodies applied to treat cancers clinically, the screening of organic molecules for hindering the interaction of PD-1 with PD-L1 became an efficient strategy in the development of PD-1 inhibitors.

Coumarin sharing the benzene ring with quinoline for quenching radicals and inhibiting DNA oxidation.

Fifteen 8-substituted-phenyl-6-ferrocenyl-4-methyl-2H-pyrano[3,2-g]quinolin-2-ones were synthesized via Povarov three-component reaction, in which the substituted aromatic aldehydes reacted with ferrocenylacetylene and 7-amino-4-methylcoumarin in the presence of Ce(OTf)3 as the catalyst. The obtained coumarin-fused quinolines were applied to quench 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+)) and 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH) and to inhibit 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidation of DNA. It was found that the ferrocenyl group attaching to pyrano[3,2-g]quinolin-2-one scaffold can trap radicals and inhibit DNA oxidation even in the absence of phenolic hydroxyl group.

Coumarin-fused coumarin: antioxidant story from N,N-dimethylamino and hydroxyl groups.

Two coumarin skeletons can form chromeno[3,4-c]chromene-6,7-dione by sharing with the C ═ C in lactone. The aim of the present work was to explore the antioxidant effectiveness of the coumarin-fused coumarin via six synthetic compounds containing hydroxyl and N,N-dimethylamino as the functional groups. The abilities to quench 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+•)), 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), and galvinoxyl radical revealed that the rate constant for scavenging radicals was related to the amount of hydroxyl group in the scaffold of coumarin-fused coumarin.

Mutations in HSP70-2 gene change the susceptibility to clinical mastitis in Chinese Holstein.

To select the molecular markers susceptible to mastitis and reduce the loss induced by mastitis, the PCR-SSCP method was adopted to investigate the correlation between SNPs of the HSP70-2 gene and mastitis in 103 Chinese Holstein. 25 new polymorphisms were detected in this study: 9 SNPs (g.-115 G→A, g.

Ferrocenyl-appended aurone and flavone: which possesses higher inhibitory effects on DNA oxidation and radicals?

The aim of the present work was to compare the antioxidative effect of the ferrocenyl-appended aurone with that of ferrocenyl-appended flavone; therefore, nine aurones together with the flavone-type analogues were synthesized by using chalcone as the reactant. The radical-scavenging property was evaluated by reacting with the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+·)), 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), and galvinoxyl radical, respectively. The cytotoxicity was estimated by inhibiting 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidation of DNA.

Solvent-free Povarov reaction for synthesizing ferrocenyl quinolines: antioxidant abilities deriving from ferrocene moiety.

Twenty-two 2-phenyl-4-ferrocenylquinolines are synthesized by Povarov three-component-reaction (3CR) among the substituted anilines, benzaldehydes, and ferrocenylacetylene with Ce(OTf)3 being catalyst in the absence of solvents. The antioxidative effects of the obtained quinolines are estimated by quenching 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+·)), 2,2'-diphenyl-1-picrylhydrazyl (DPPH), and galvinoxyl radicals, and by inhibiting Cu(2+)/glutathione (GSH)-, hydroxyl radical (·OH)-, and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidations of DNA. It is found that the ferrocenyl group instead of hydroxyl group generates the antioxidative effect for quinoline to quench radicals and to protect DNA against radical-induced oxidations.