Synthesis of novel ferrocene-containing 1,3-thiazinan-2-imines: One-pot reaction promoted by ultrasound irradiation

A simple one-pot synthesis of new ferrocene-containing 1,3-thiazinan-2-imines from 3-arylamino-1-ferrocenylpropan-1-ols and phenyl isothiocyanate has been developed. The key intermediate β-hydroxy thioureas were generated in situ using ultrasound irradiation and subsequent cyclization was achieved by the addition of acetic acid. The scope of the reaction towards various 3-arylamino-1-ferrocenylpropan-1-ols has been explored and the corresponding 3-aryl-6-ferrocenyl-N-phenyl-1,3-thiazinan-2-imines were obtained in moderate to high yields (52–90%).     

Silver-catalyzed decarboxylative cross-coupling of α-keto acids with alkenes giving approach to chalcones

A silver-catalyzed decarboxylative cross-coupling of α-keto acids with alkenes is reported. The method, with a wide range of substrate tolerance and mild operational conditions, can produce various chalcone derivatives in moderate to high yields from easily available starting materials.     

Cleavage of Diethyl Chromonyl α-Aminophosponate with Nitrogen and Carbon Nucleophiles: A Synthetic Approach and Biological Evaluations of a Series of Novel Azoles,Azines, and Azepines Containing α-Aminophosphonate and Phosphonate Groups

A convenient synthetic approach leading to a series of novel substituted azoles, azines, and azepines linked to the α-aminophosphonate moiety was achieved. The methodology depends on ring opening and ring closure (RORC) of the chromone ring of diethyl chromonyl α-aminophosphonate 1 via its reaction with nitrogen nucleophiles such as primary amines and 1,2-, 1,3-, and 1,4-bi-nucleophiles in ethanolic sodium ethoxide. Also, treatment of compound 1 with some acyclic and cyclic active methylene compounds under the same reaction conditions afforded interesting novel isolated and fused pyridine systems bearing phosphonate groups at the α-position. The screening of antimicrobial activity for the synthesized compounds indicates that connection of pyrazole, oxazepine, and benzodiazepine rings with α-aminophosphonate moiety exhibited good antimicrobial effects. Also, evaluation of their antioxidant properties shows that the compounds having 1,5-benzoxazepinyl and 1,5-benzodiazepinyl units in combination with α-aminophosphonic diester moiety are the most powerful antioxidant agents.     

One-pot synthesis of 2-amino-4H-chromen-4-yl phosphonate derivatives using β-cyclodextrin as reusable catalyst in water

Various 2-amino-4H-chromen-4-yl phosphonate derivatives were synthesized in good yields by condensation of salicylaldehyde, malononitrile or ethylcyanoacetate, and triethyl phosphite using β-cyclodextrin as a reusable catalyst under neutral conditions, in water.     

Metabolomic-based investigation of Yinlan alleviating hyperlipidemia by inhibiting blood stasis and phlegm turbidity through the PXR-CYP3A4-ABCB1-FXR pathway

Yinlan lipid regulatory capsule (YL) is a composite traditional Chinese medicine (TCM) new drug to alleviate hyperlipidemia, while its therapeutic mechanism in vivo was not clarified with nontargeted metabolomics investigation. An animal model was established in rats fed a high-fat diet, and their body weights, body mass index (BMI) and blood cholesterol levels were measured. Serum, liver and kidney tissue samples were also extracted for PXR-CYP3A4-ABCB1-FXR signaling pathway research using PCR and UHPLC–MS. The obtained plasma samples were analyzed by UHPLC-Q-TOF-MS metabolomic investigation, which revealed PXR-CYP3A4-related metabolites and changes induced by YL. Finally, the key metabolites were chosen as index components, and their levels in the serum, liver, small intestine and bile were used for simultaneous UHPLC–MS-MS determination. The results indicated that YL was effective in rebalancing blood TG and TC levels (compared to controls). With respect to the PXR-CYP3A4-ABCB1 pathway, as a result of YL’s effect, gene expression or activity of the two targets decreased significantly in both the liver and kidney. The same trend was observed in the serum samples mentioned above. Metabolomics screening and data revealed that 44 metabolites can be regarded as biomarkers related to hyperlipidemia, fatty acids synthesis, and body energy consumption, as well as synthesis, transportation and exertion of cholesterol. YL’s treatment focused on 26 of them, primarily bile acids, indicating that the antihyperlipidemic effect of this drug lies in its inhibitory activity of cholesterol metabolism. Subsequent analysis of those in vivo components revealed that significant increases (compared to the model group) occurred in the blood, liver, small intestine and bile in groups that received medium and high doses of YL (while the low dose was relatively unchanged). Those target components exhibit a close relationship with PXR and/or CYP3A4. The use of YL repressed PXR expression and subsequently decreased CYP3A4 activity. As a result, synthesis of related bile acids increased, while cholesterol levels decreased, consequently leading to the attenuation of hyperlipidemia. This study comprehensively investigated the antihyperlipidemia mechanism of YL based on its repression of PXR-CYP3A4 activity and related metabolite yield, establishing an accurate method for evaluating the therapeutic effect of YL.     

Effect of Alkynyl Group on Reactivity in Photoaffinity Labeling with 2-Thienyl-Substituted α-Ketoamide

Minimalist photo-reactive probes, which consist of a photo-reactive group and a tag for detection of target proteins, are useful tools in chemical biology. Although several diazirine-based and aryl azide-based minimalist probes are available, no keto-based minimalist probe has yet been reported. Here we describe minimalist probes based on a 2-thienyl-substituted α-ketoamide bearing an alkyne group on the thiophene ring. The 3-alkyne probe showed the highest photo-affinity labeling efficiency.     

Millettia ferruginea extract attenuates cisplatin-induced alterations in kidney functioning,DNA damage,oxidative stress,and renal tissue morphology

This study aimed to investigate the beneficial role of Millettia ferruginea extract (MF) in preventing cisplatin (Cisp) induced nephrotoxicity in rats. A total of 55 metabolites were identified using LC-MS analysis. The in vivo results indicated that MF pretreatment for 4 weeks (20 mg/kg b.w.) remarkably attenuated the altered renal biomarkers by decreasing the levels of plasma creatinine, urea, and uric acid when compared to the Cisp-group. The nephroprotective capacity of MF was further strengthened by histopathological observations, where Cisp + MF treated rats showed lower number of inflammatory cells and tubular degenerative changes than the Cisp-group. The harmful effects of cisplatin on renal oxidative stress indicators (MDA, SOD, CAT, and GPx), were restored by the treatment of MF. In addition, the reduction of inflammatory markers (IL-6 and TNF-α), associated with alleviating DNA fragmentation, highlighted the preventive effect of MF in kidney tissue. Additionally, MF components presented lower binding energies when docked into the active site of TNF-α and IL-6. The present findings concluded that M. ferruginea extract exhibited nephroprotective potential, which may be attributed to its antioxidant and anti-inflammatory properties. Further work is recommended to confirm the current results, explore the involved mechanism of action, and determine the therapeutic doses and time.     

Design,synthesis and evaluation of novel dehydroabietic acid-dithiocarbamate hybrids as potential multi-targeted compounds for tumor cytotoxicity

In the present study, novel representatives of the important group of biologically-active, dehydroabietic acid-bearing dithiocarbamate moiety, were synthesized and characterized by ¹H NMR, ¹³C NMR, HR-MS. The in vitro antiproliferative activity evaluation (MTT) indicated that these compounds exhibited potent inhibitory activities in various cancer cell lines (HepG-2, MCF-7, HeLa, T-24, MGC-803). Particularly, compound III-b possessed extraordinary cytotoxicity with low micromolar IC₅₀ values ranging from 4.07 to 38.84 µM against tested cancer cell lines, while displayed weak cytotoxicity on two normal cell lines (LO-2 and HEK 293 T). Subsequently, the potential mechanisms of representative compound III-b were elementarily investigated by Transwell experiment, which showed III-b can inhibit cancer cells migration. Annexin-V/PI dual staining showed that the compound can induce HepG-2 cells apoptosis in a dose-dependent manner. Meanwhile this apoptosis may be related to the upregulated protein expression of cleaved-caspase 3, cleaved-caspase 9, Bax and downregulated of Bcl-2 indicated by Western Blot. Later study further confirmed that ROS levels in HepG-2 cells increased significantly with the rise of concentrations. In addition, through the network pharmacology data analyzing, the core targets and signaling pathways of compound III-b for treatment of liver neoplasms were forecasted. Molecular docking model showed that compound III-b had high affinity with hub targets (CASP3, EGFR, HSP90AA1, MAPK1, ERBB2, MDM2), suggesting that compound III-b might target the hub protein to modulate signaling activity. Taken together, these data indicated that dehydroabietic acid structural modification following the “Molecular hybridization” principle is a feasible way to discover the potential multi-targeted antitumor compounds.     

Simultaneous determination of mitotane,its metabolite,and five steroid hormones in urine samples by capillary electrophoresis using β-CD2SDS1 complexes as hydrophobic compounds solubilizers

Mitotane is a cytotoxic drug used in the treatment of inoperable adrenocortical carcinoma, it inhibits steroidogenesis as well, and therefore monitoring the level of steroid hormones in patients treated with mitotane is a crucial point of therapy. Hence, we have developed a simple, fast, and efficient electrophoretic method combined with reverse polarity sweeping as online preconcentration technique and dispersive liquid–liquid microextraction for the simultaneous determination of mitotane, its main metabolite DDA, and five steroid hormones (progesterone, testosterone, epitestosterone, cortisol, and corticosterone) in urine samples. In addition, a new sample matrix consisting of β-CD₂SDS₁ complexes for a high hydrophobic compounds solubilization was developed. Approach based on the application of β-cyclodextrin and SDS complex of a ratio 2:1 allowed for hydrodynamic injection into the capillary of a solution containing both mitotane and other analytes. The detection limits of the analytes for the reverse polarity sweeping-dispersive liquid–liquid microextraction method were found to be in the range of 1.5–3 ng/mL, which were approximately 1000 times lower than in the conventional hydrodynamic injection (5 s, 0.5 psi) without any preconcentration procedure. All analytes were completely resolved in less than 13 min by uncoated silica capillary with an inner diameter of 75 μm (ID) × 60 cm. Electrophoretic separation was performed in reverse polarity with a voltage of –25 kV with a background electrolyte (BGE) consisting of 100 mM SDS, 25% ACN, 25 mM phosphate buffer (pH 2.5), and 7 mM β-cyclodextrin.