Exploring the In Vivo Existence Forms (23 Original Constituents and 147 Metabolites) of Astragali Radix Total Flavonoids and Their Distributions in Rats Using HPLC-DAD-ESI-IT-TOF-MSn

Astragali Radix total flavonoids (ARTF) is one of the main bioactive components of Astragali Radix (AR), and has many pharmacological effects. However, its metabolism and effective forms remains unclear. The HPLC-DAD-ESI-IT-TOF-MSⁿ technique was used to screen and tentatively identify the in vivo original constituents and metabolites of ARTF and to clarify their distribution in rats after oral administration. In addition, modern chromatographic methods were used to isolate the main metabolites from rat urine and NMR spectroscopy was used to elucidate their structures. As a result, 170 compounds (23 original constituents and 147 metabolites) were tentatively identified as forms existing in vivo, 13 of which have the same pharmacological effect with ARTF. Among 170 compounds, three were newly detected original constituents in vivo and 89 were new metabolites of ARTF, from which 12 metabolites were regarded as new compounds. Nineteen original constituents and 65 metabolites were detected in 10 organs. Four metabolites were isolated and identified from rat urine, including a new compound (calycoisn-3’-O-glucuronide methyl ester), a firstly-isolated metabolite (astraisoflavan-7-O-glucoside-2’-O-glucuronide), and two known metabolites (daidzein-7-O-sulfate and calycosin-3’-O-glucuronide). The original constituents and metabolites existing in vivo may be material basis for ARTF efficacy, and these findings are helpful for further clarifying the effective forms of ARTF.     

In Vitro Liver Metabolism of Six Flavonoid C-Glycosides

Several medical plants belonging to the genera Passiflora, Viola, and Crataegus accumulate flavonoid C-glycosides, which likely contribute to their efficacy. Information regarding their phase I and II metabolism in the liver are lacking. Thus, in vitro liver metabolism of orientin, isoorientin, schaftoside, isoschaftoside, vitexin, and isovitexin, all of which accumulated in Passiflora incarnata L., was investigated by incubation in subcellular systems with human liver microsomes and human liver S9 fraction. All metabolite profiles were comprehensively characterized using HPLC-DAD and UHPLC–MS/MS analysis. Mono-glycosylic flavones of the luteolin-type orientin and isoorientin showed a broad range of mono-glucuronidated and mono-sulfated metabolites, whereas for mono-glycosylic flavones of the apigenin-type vitexin and isovitexin, only mono-glucuronidates could be detected. For di-glycosylic flavones of the apigenin-type schaftosid and isoschaftosid, no phase I or II metabolites were identified. The main metabolite of isoorientin was isolated using solid-phase extraction and prep. HPLC-DAD and identified as isoorientin-3′-O-α-glucuronide by NMR analysis. A second isolated glucuronide was assigned as isoorientin 4′-O-α-glucuronide. These findings indicate that vitexin and isovitexin are metabolized preferentially by uridine 5′-diphospho glucuronosyltransferases (UGTs) in the liver. As only orientin and isoorientin showed mono-sulfated and mono-glucuronidated metabolites, the dihydroxy group in 3′,4′-position may be essential for additional sulfation by sulfotransferases (SULTs) in the liver. The diglycosylic flavones schaftoside and isoschaftoside are likely not accepted as substrates of the used liver enzymes under the chosen conditions.     

Convenient syntheses of metabolically important quercetin glucuronides and sulfates

Synthetic approaches to the major human plasma metabolites of quercetin, quercetin 3′-sulfate and the β-d-glucopyranosiduronic acid derivatives 3′-methylquercetin 3-glucuronide (isorhamnetin 3-glucuronide), quercetin 3-glucuronide and quercetin 3′-glucuronide are described. This is the first report of the chemical synthesis of quercetin 3′-glucuronide. All procedures start from the same precursor, 4′,7-di-O-benzylquercetin, and all are more convenient than existing methods.     

Phytochemistry and Biological Activities of Iris Species Growing in Iraqi Kurdistan and Phenolic Constituents of the Traditional Plant Iris postii

A dozen Iris species (Iridaceae) are considered traditional remedies in Kurdistan, especially for treating inflammations. Phytochemical studies are still scarce. The information reported in the literature about Iris species growing in Kurdistan has been summarized in the first part of this paper, although, except for Iris persica, investigations have been performed on vegetal samples collected in countries different from Kurdistan. In the second part of the work, we have investigated, for the first time, the contents of the methanolic extracts of Iris postii aerial parts and rhizomes that were collected in Kurdistan. Both extracts exhibited a significant dose-dependent free radical scavenging and total antioxidant activities, comparable to those of ascorbic acid. Medium-pressure liquid chromatographic separations of the two extracts afforded l-tryptophan, androsin, isovitexin, swertisin, and 2″-O-α-l-rhamnopyranosyl swertisin from the aerial parts, whereas ε-viniferin, trans-resveratrol 3,4′-O-di-β-d-glucopyranoside, and isotectorigenin were isolated from the rhizomes. This is the first finding of the last three metabolites from an Iris species. The various remarkable biological activities of isolated compounds scientifically sustain the traditional use of I. postii as a medicinal plant.     

Prunetin 4′-O-Phosphate,a Novel Compound,in RAW 264.7 Macrophages Exerts Anti-Inflammatory Activity via Suppression of MAP Kinases and the NFκB Pathway

Biorenovation, a microbial enzyme-assisted degradation process of precursor compounds, is an effective approach to unraveling the potential bioactive properties of the derived compounds. In this study, we obtained a new compound, prunetin 4′-O-phosphate (P4P), through the biorenovation of prunetin (PRN), and investigated its anti-inflammatory effects in lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells. The anti-inflammatory effect of P4P was evaluated by measuring the production of prostaglandin-E₂ (PGE₂), nitric oxide (NO), which is an inflammation-inducing factor, and related cytokines such as tumor necrosis factor-α (TNFα), interleukin-1β (IL1β), and interleukin-6 (IL6). The findings demonstrated that P4P was non-toxic to cells, and its inhibition of the secretion of NO—as well as pro-inflammatory cytokines—was concentration-dependent. A simultaneous reduction in the protein expression level of pro-inflammatory proteins such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was observed. Moreover, the phosphorylation of mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase (JNK), p38 MAPK (p38), and nuclear factor kappa B (NFκB) was downregulated. To conclude, we report that biorenovation-based phosphorylation of PRN improved its anti-inflammatory activity. Cell-based in vitro assays further confirmed that P4P could be applied in the development of anti-inflammatory therapeutics.     

Synthesis,Neuroprotection, and Antioxidant Activity of 1,1′-Biphenylnitrones as α-Phenyl-N-tert-butylnitrone Analogues in In Vitro Ischemia Models

Herein, we report the neuroprotective and antioxidant activity of 1,1′-biphenyl nitrones (BPNs) 1–5 as α-phenyl-N-tert-butylnitrone analogues prepared from commercially available [1,1′-biphenyl]-4-carbaldehyde and [1,1′-biphenyl]-4,4′-dicarbaldehyde. The neuroprotection of BPNs 1-5 has been measured against oligomycin A/rotenone and in an oxygen–glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that BPNs 1–5 have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN), and they are quite similar to N-acetyl-L-cysteine (NAC), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone BPHBN5, bearing two N-tert-Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC₅₀ = 13.16 ± 1.65 and 25.5 ± 3.93 μM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen–glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC₅₀ = 11.2 ± 3.94 μM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone BPMN3, with one N-Bn radical, and BPMN2, with only one N-tert-Bu substituent. The antioxidant activity of BPNs 1-5 has also been analyzed for their capacity to scavenge hydroxyl free radicals (82% at 100 μM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68% at 100 μM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these BPNs, the final effect is also dependent on the substitutent that is being incorporated. Thus, BPNs bearing N-tert-Bu and N-Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo-bis-nitrone BPHBN5 as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity.     

A Versatile Solid-Phase Approach to the Synthesis of Oligonucleotide Conjugates with Biodegradable Hydrazone Linker

One of the ways to efficiently deliver various drugs, including therapeutic nucleic acids, into the cells is conjugating them with different transport ligands via labile or stable bonds. A convenient solid-phase approach for the synthesis of 5′-conjugates of oligonucleotides with biodegradable pH-sensitive hydrazone covalent bonds is proposed in this article. The approach relies on introducing a hydrazide of the ligand under aqueous/organic media to a fully protected support-bound oligonucleotide containing aldehyde function at the 5′-end. We demonstrated the proof-of-principle of this approach by synthesizing 5′-lipophilic (e.g., cholesterol and α-tocopherol) conjugates of modified siRNA and non-coding RNAs imported into mitochondria (antireplicative RNAs and guide RNAs for Mito-CRISPR/system). The developed method has the potential to be extended for the synthesis of pH-sensitive conjugates of oligonucleotides of different types (ribo-, deoxyribo-, 2′-O-methylribo-, and others) with ligands of different nature.     

Luteolin-3′-O-Phosphate Inhibits Lipopolysaccharide-Induced Inflammatory Responses by Regulating NF-κB/MAPK Cascade Signaling in RAW 264.7 Cells

Luteolin (LT), present in most plants, has potent anti-inflammatory properties both in vitro and in vivo. Furthermore, some of its derivatives, such as luteolin-7-O-glucoside, also exhibit anti-inflammatory activity. However, the molecular mechanisms underlying luteolin-3′-O-phosphate (LTP)-mediated immune regulation are not fully understood. In this paper, we compared the anti-inflammatory properties of LT and LTP and analyzed their molecular mechanisms of action; we obtained LTP via the biorenovation of LT. We investigated the anti-inflammatory activities of LT and LTP in macrophage RAW 264.7 cells. We confirmed from previously reported literature that LT inhibits the production of nitric oxide and prostaglandin E₂, as well as the expression of inducible NO synthetase and cyclooxygenase-2. In addition, expressions of inflammatory genes and mediators, such as tumor necrosis factor-α, interleukin-6, and interleukin-1β, were suppressed. LTP showed anti-inflammatory activity similar to LT, but better anti-inflammatory activity in all the experiments, while also inhibiting mitogen-activated protein kinase and nuclear factor-kappa B more effectively than LT. At a concentration of 10 μM, LTP showed differences of 2.1 to 44.5% in the activity compared to LT; it also showed higher anti-inflammatory activity. Our findings suggest that LTP has stronger anti-inflammatory activity than LT.     

Substrate Specificity of Chimeric Enzymes Formed by Interchange of the Catalytic and Specificity Domains of the 5′-Nucleotidase UshA and the 3′-Nucleotidase CpdB

The 5′-nucleotidase UshA and the 3′-nucleotidase CpdB from Escherichia coli are broad-specificity phosphohydrolases with similar two-domain structures. Their N-terminal domains (UshA_Ndom and CpdB_Ndom) contain the catalytic site, and their C-terminal domains (UshA_Cdom and CpdB_Cdom) contain a substrate-binding site responsible for specificity. Both enzymes show only partial overlap in their substrate specificities. So, it was decided to investigate the catalytic behavior of chimeras bearing the UshA catalytic domain and the CpdB specificity domain, or vice versa. UshA_Ndom–CpdB_Cdom and CpdB_Ndom–UshA_Cdom were constructed and tested on substrates specific to UshA (5′-AMP, CDP-choline, UDP-glucose) or to CpdB (3′-AMP), as well as on 2′,3′-cAMP and on the common phosphodiester substrate bis-4-NPP (bis-4-nitrophenylphosphate). The chimeras did show neither 5′-nucleotidase nor 3′-nucleotidase activity. When compared to UshA, UshA_Ndom–CpdB_Cdom conserved high activity on bis-4-NPP, some on CDP-choline and UDP-glucose, and displayed activity on 2′,3′-cAMP. When compared to CpdB, CpdB_Ndom–UshA_Cdom conserved phosphodiesterase activities on 2′,3′-cAMP and bis-4-NPP, and gained activity on the phosphoanhydride CDP-choline. Therefore, the non-nucleotidase activities of UshA and CpdB are not fully dependent on the interplay between domains. The specificity domains may confer the chimeras some of the phosphodiester or phosphoanhydride selectivity displayed when associated with their native partners. Contrarily, the nucleotidase activity of UshA and CpdB depends strictly on the interplay between their native catalytic and specificity domains.     

When UDG and hAPE1 Meet Cyclopurines. How (5′R) and (5′S) 5′,8-Cyclo-2′-deoxyadenosine and 5′,8-Cyclo-2′-deoxyguanosine Affect UDG and hAPE1 Activity?

Ionizing radiation is a factor that seriously damages cellular mechanisms/macromolecules, e.g., by inducing damage in the human genome, such as 5′,8-cyclo-2′-deoxypurines (cdPus). CdPus may become a component of clustered DNA lesions (CDL), which are notably unfavorable for the base excision repair system (BER). In this study, the influence of 5′S and 5′R diastereomers of 5′,8-cyclo-2′-deoxyadenosine (cdA) and 5′,8-cyclo-2′-deoxyguanosine (cdG) on the uracil-DNA glycosylase (UDG) and human AP site endonuclease 1 (hAPE1) activity has been taken under consideration. Synthetic oligonucleotides containing 2′-deoxyuridine (dU) and cdPu were used as a model of single-stranded CDL. The activity of the UDG and hAPE1 enzymes decreased in the presence of RcdG compared to ScdG. Contrary to the above, ScdA reduced enzyme activity more than RcdA. The presented results show the influence of cdPus lesions located within CDL on the activity of the initial stages of BER dependently on their position toward dU. Numerous studies have shown the biological importance of cdPus (e.g., as a risk of carcinogenesis). Due to that, it is important to understand how to recognize and eliminate this type of DNA damage from the genome.     

3D Metal–Organic Frameworks Based on Co(II) and Bithiophendicarboxylate: Synthesis,Crystal Structures,Gas Adsorption,and Magnetic Properties

Three new 3D metal-organic porous frameworks based on Co(II) and 2,2′-bithiophen-5,5′-dicarboxylate (btdc²⁻) [Co₃(btdc)₃(bpy)₂]·4DMF, 1; [Co₃(btdc)₃(pz)(dmf)₂]·4DMF·1.5H₂O, 2; [Co₃(btdc)₃(dmf)₄]∙2DMF∙2H₂O, 3 (bpy = 2,2′-bipyridyl, pz = pyrazine, dmf = N,N-dimethylformamide) were synthesized and structurally characterized. All compounds share the same trinuclear carboxylate building units {Co₃(RCOO)₆}, connected either by btdc^2– ligands (1, 3) or by both btdc^2– and pz bridging ligands (2). The permanent porosity of 1 was confirmed by N₂, O₂, CO, CO₂, CH₄ adsorption measurements at various temperatures (77 K, 273 K, 298 K), resulted in BET surface area 667 m²⋅g⁻¹ and promising gas separation performance with selectivity factors up to 35.7 for CO₂/N₂, 45.4 for CO₂/O₂, 20.8 for CO₂/CO, and 4.8 for CO₂/CH₄. The molar magnetic susceptibilities χ_p(T) were measured for 1 and 2 in the temperature range 1.77–330 K at magnetic fields up to 10 kOe. The room-temperature values of the effective magnetic moments for compounds 1 and 2 are μ_eff (300 K) ≈ 4.93 μ_B. The obtained results confirm the mainly paramagnetic nature of both compounds with some antiferromagnetic interactions at low-temperatures T < 20 K in 2 between the Co(II) cations separated by short pz linkers. Similar conclusions were also derived from the field-depending magnetization data of 1 and 2.     

Isomers of Terpyridine as Ligands in Coordination Polymers and Networks Containing Zinc(II) and Cadmium(II)

The use of divergent 4,2′:6′,4″- and 3,2′:6′,3″-terpyridine ligands as linkers and/or nodes in extended coordination assemblies has gained in popularity over the last decade. However, there is also a range of coordination polymers which feature 2,2′:6′,2″-terpyridine metal-binding domains. Of the remaining 45 isomers of terpyridine, few have been utilized in extended coordination arrays. Here, we provide an overview of coordination polymers and networks containing isomers of terpyridine and either zinc(II) and cadmium(II). Although the motivation for investigations of many of these systems is their luminescent behavior, we have chosen to focus mainly on structural details, and we assess to what extent assemblies are reproducible. We also consider cases where there is structural evidence for competitive product formation. A point that emerges is the lack of systematic investigations.     

A Study on Synthesis and Upscaling of 2′-O-AECM-5-methyl Pyrimidine Phosphoramidites for Oligonucleotide Synthesis

2′-O-(N-(Aminoethyl)carbamoyl)methyl-modified 5-methyluridine (AECM-MeU) and 5-methylcytidine (AECM-MeC) phosphoramidites are reported for the first time and prepared in multigram quantities. The syntheses of AECM-MeU and AECM-MeC nucleosides are designed for larger scales (approx. 20 g up until phosphoramidite preparation steps) using low-cost reagents and minimizing chromatographic purifications. Several steps were screened for best conditions, focusing on the most crucial steps such as N³ and/or 2′-OH alkylations, which were improved for larger scale synthesis using phase transfer catalysis (PTC). Moreover, the need of chromatographic purifications was substantially reduced by employing one-pot synthesis and improved work-up strategies.     

New Flavone C-Glycosides from Scleranthus perennis and Their Anti-Collagenase Activity

Three new flavone glycosides, one known flavone glycoside, and the phenolic derivative apiopaenonside were isolated and identified from the ethyl acetate fraction of the aerial parts of Scleranthus perennis. The planar structures were elucidated through extensive analysis of UV-Vis, IR, and ¹H NMR and ¹³C NMR spectral data, including the 2D techniques COSY, HSQC, and HMBC, as well as ESI mass spectrometry. The isolated compounds were established as 5,7,3′-trihydroxy-4′-acetoxyflavone-8-C-β-d-xylopyranoside-2′′-O-glucoside (1), 5,7,3′-trihydroxy-4′-methoxyflavone-8-C-β-d-xylopyranoside-2′′-O-glucoside (2), 5,7-dihydroxy-3′-methoxy-4′-acetoxyflavone-8-C-β-d-xylopyranoside-2′′-O-glucoside (3), 5,7-dihydroxy-3′-methoxy-4′-acetoxyflavone-8-C-β-d-xylopyranoside-2′′-O-(4′′′-acetoxy)-glucoside (4), and apiopaenonside (5). Moreover, all isolated compounds were evaluated for anti-collagenase activity. All compounds exhibited moderate inhibitory activity with IC₅₀ values ranging from 36.06 to 70.24 µM.     

Microextraction of Reseda luteola-Dyed Wool and Qualitative Analysis of Its Flavones by UHPLC-UV,NMR and MS

Detailed knowledge on natural dyes is important for agronomy and quality control as well as the fastness, stability, and analysis of dyed textiles. Weld (Reseda luteola L.), which is a source of flavone-based yellow dye, is the focus of this study. One aim was to reduce the required amount of dyed textile to ≤50 μg for a successful chromatographic analysis. The second aim was to unambiguously confirm the identity of all weld flavones. By carrying out the extraction of 50 μg dyed wool with 25 μL of solvent and analysis by reversed-phase UHPLC at 345 nm, reproducible chromatographic fingerprints could be obtained with good signal to noise ratios. Ten baseline separated peaks with relative areas ≥1% were separated in 6 min. Through repeated polyamide column chromatography and prepHPLC, the compounds corresponding with the fingerprint peaks were purified from dried weld. Each was unequivocally identified, including the position and configuration of attached sugars, by means of 1D and 2D NMR and high-resolution MS. Apigenin-4′-O-glucoside and luteolin-4′-O-glucoside were additionally identified as two trace flavones co-eluting with other flavone glucosides, the former for the first time in weld. The microextraction might be extended to other used dye plants, thus reducing the required amount of precious historical textiles.     

Nucleophilic substitution reactions of monofunctional nucleophilic reagents with cyclotriphosphazenes containing 2,2-dioxybiphenyl units

The nucleophilic substitution reactions of mono- and bis-spiro-2,2′ -dioxybiphenyl cyclotriphosphazenes (3 and 4) with cyclopropanemethylamine (5) and aniline (6) were performed in the presence of trimethylamine in THF. Five novel cyclopropanemethylamino- and anilino-substituted spiro-2,2′ -dioxybiphenyl cyclotriphosphazene derivatives (7–11) were obtained from these reactions. The molecular structures of the new cyclotriphosphazene derivatives (7–11) were characterized by elemental analysis, MALDI-TOF MS, FT-IR, and NMR ( ³¹ P and ¹ H) spectroscopies. The structure of the spiro-(2,2′ -dioxybiphenyl)-bis-(anilino)-cyclotriphosphazene (11) was also determined by single-crystal X-ray crystallography.     

Colorimetric Cyanide Chemosensor Based on 1′,3,3′,4-Tetrahydrospiro[chromene-2,2′-indole]

A new class of chemosensors based on the 1′,3,3′,4-tetrahydrospiro[chromene-2,2′-indole] ring system, which detects cyanide with high specificity, is described. These chemosensors show a distinct color change when treated with cyanide in acetonitrile solution buffered with sodium phosphate, and this procedure is not affected by the presence of other common anions. The chemisensors exhibit high sensitivity to low concentrations of cyanide, meeting the European Union water quality control criterion of sensitivity below 0.05 mg L⁻¹, and show a very fast response within tens of seconds. The mechanism for detection is rationalized by the nucleophilic substitution of the phenolic oxygen atom at the indoline C-2 atom by the cyanide anion to form a stable indolylnitrile adduct and to generate the colored 4-nitrophenolate chromophore. These chemosensors can be synthesized by a simple procedure from commercially available starting materials.     

Desymmetrizing Heteroleptic [Cu(P^P)(N^N)][PF6] Compounds: Effects on Structural and Photophysical Properties,and Solution Dynamic Behavior

The preparation, characterization and electrochemical and photophysical properties of a series of desymmetrized heteroleptic [Cu(P^P)(N^N)][PF₆] compounds are reported. The complexes incorporate the chelating P^P ligands bis(2-(diphenylphosphanyl)phenyl)ether (POP) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (xantphos), and 6-substituted 2,2′-bipyridine (bpy) derivatives with functional groups attached by –(CH₂)_n– spacers: 6-(2,2′-bipyridin-6-yl)hexanoic acid (1), 6-(5-phenylpentyl)-2,2′-bipyridine (2) and 6-[2-(4-phenyl-1H-1,2,3,triazol-1-yl)ethyl]-2,2′-bipyridine (3). [Cu(POP)(1)][PF₆], [Cu(xantphos)(1)][PF₆], [Cu(POP)(2)][PF₆], [Cu(xantphos)(2)][PF₆], and [Cu(xantphos)(3)][PF₆] have been characterized in solution using multinuclear NMR spectroscopy, and the single crystal structure of [Cu(xantphos)(3)][PF₆]^.0.5Et₂O was determined. The conformation of the 6-[2-(4-phenyl-1H-1,2,3,triazol-1-yl)ethyl]-substituent in the [Cu(xantphos)(3)]⁺ cation is such that the α- and β-CH₂ units reside in the xanthene ‘bowl’ of the xantphos ligand. The 6-substituent desymmetrizes the structure of the [Cu(P^P)(N^N)]⁺ cation and this has consequences for the interpretation of the solution NMR spectra of the five complexes. The NOESY spectra and EXSY cross-peaks provide insight into the dynamic processes operating in the different compounds. For powdered samples, emission maxima are in the range 542–555 nm and photoluminescence quantum yields (PLQYs) lie in the range 13–28%, and a comparison of PLQYs and decay lifetimes with those of [Cu(xantphos)(6-Mebpy)][PF₆] indicate that the introduction of the 6-substituent is not detrimental in terms of the photophysical properties.     

Validation of the Antioxidant and Enzyme Inhibitory Potential of Selected Triterpenes Using In Vitro and In Silico Studies,and the Evaluation of Their ADMET Properties

The antioxidant and enzyme inhibitory potential of fifteen cycloartane-type triterpenes’ potentials were investigated using different assays. In the phosphomolybdenum method, cycloalpioside D (6) (4.05 mmol TEs/g) showed the highest activity. In 1,1-diphenyl-2-picrylhydrazyl (DPPH*) radical and 2,2′-azino-bis(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) cation radical scavenging assays, cycloorbicoside A-7-monoacetate (2) (5.03 mg TE/g) and cycloorbicoside B (10) (10.60 mg TE/g) displayed the highest activities, respectively. Oleanolic acid (14) (51.45 mg TE/g) and 3-O-β-d-xylopyranoside-(23R,24S)-16β,23;16α,24-diepoxycycloart-25(26)-en-3β,7β-diol 7-monoacetate (4) (13.25 mg TE/g) revealed the highest reducing power in cupric ion-reducing activity (CUPRAC) and ferric-reducing antioxidant power (FRAP) assays, respectively. In metal-chelating activity on ferrous ions, compound 2 displayed the highest activity estimated by 41.00 mg EDTAE/g (EDTA equivalents/g). The tested triterpenes showed promising AChE and BChE inhibitory potential with 3-O-β-d-xylopyranoside-(23R,24S)-16β,23;16α,24-diepoxycycloart-25(26)-en-3β,7β-diol 2′,3′,4′,7-tetraacetate (3), exhibiting the highest inhibitory activity as estimated from 5.64 and 5.19 mg GALAE/g (galantamine equivalent/g), respectively. Compound 2 displayed the most potent tyrosinase inhibitory activity (113.24 mg KAE/g (mg kojic acid equivalent/g)). Regarding α-amylase and α-glucosidase inhibition, 3-O-β-d-xylopyranoside-(23R,24S)-16β,23;16α,24-diepoxycycloart-25(26)-en-3β,7β-diol (5) (0.55 mmol ACAE/g) and compound 3 (25.18 mmol ACAE/g) exerted the highest activities, respectively. In silico studies focused on compounds 2, 6, and 7 as inhibitors of tyrosinase revealed that compound 2 displayed a good ranking score (−7.069 kcal/mole) and also that the ΔG free-binding energy was the highest among the three selected compounds. From the ADMET/TOPKAT prediction, it can be concluded that compounds 4 and 5 displayed the best pharmacokinetic and pharmacodynamic behavior, with considerable activity in most of the examined assays.     

DNA Intercalating Near-Infrared Luminescent Lanthanide Complexes Containing Dipyrido[3,2-a:2′,3′-c]phenazine (dppz) Ligands: Synthesis,Crystal Structures,Stability, Luminescence Properties and CT-DNA Interaction

In order to create near-infrared (NIR) luminescent lanthanide complexes suitable for DNA-interaction, novel lanthanide dppz complexes with general formula [Ln(NO₃)₃(dppz)₂] (Ln = Nd³⁺, Er³⁺ and Yb³⁺; dppz = dipyrido[3,2-a:2′,3′-c]phenazine) were synthesized, characterized and their luminescence properties were investigated. In addition, analogous compounds with other lanthanide ions (Ln = Ce³⁺, Pr³⁺, Sm³⁺, Eu³⁺, Tb³⁺, Dy³⁺, Ho³⁺, Tm³⁺, Lu³⁺) were prepared. All complexes were characterized by IR spectroscopy and elemental analysis. Single-crystal X-ray diffraction analysis of the complexes (Ln = La³⁺, Ce³⁺, Pr³⁺, Nd³⁺, Eu³⁺, Er³⁺, Yb³⁺, Lu³⁺) showed that the lanthanide’s first coordination sphere can be described as a bicapped dodecahedron, made up of two bidentate dppz ligands and three bidentate-coordinating nitrate anions. Efficient energy transfer was observed from the dppz ligand to the lanthanide ion (Nd³⁺, Er³⁺ and Yb³⁺), while relatively high luminescence lifetimes were detected for these complexes. In their excitation spectra, the maximum of the strong broad band is located at around 385 nm and this wavelength was further used for excitation of the chosen complexes. In their emission spectra, the following characteristic NIR emission peaks were observed: for a) Nd³⁺: ⁴F_3/2 → ⁴I_9/2 (870.8 nm), ⁴F_3/2 → ⁴I_11/2 (1052.7 nm) and ⁴F_3/2 → ⁴I_13/2 (1334.5 nm); b) Er³⁺: ⁴I_13/2 → ⁴I_15/2 (1529.0 nm) c) Yb³⁺: ²F_5/2 → ²F_7/2 (977.6 nm). While its low triplet energy level is ideally suited for efficient sensitization of Nd³⁺ and Er³⁺, the dppz ligand is considered not favorable as a sensitizer for most of the visible emitting lanthanide ions, due to its low-lying triplet level, which is too low for the accepting levels of most visible emitting lanthanides. Furthermore, the DNA intercalation ability of the [Nd(NO₃)₃(dppz)₂] complex with calf thymus DNA (CT-DNA) was confirmed using fluorescence spectroscopy.