Design and Synthesis of Novel Thiazolo[5,4‐d]pyrimidine Derivatives as Potential Angiogenesis Inhibitors

Vascular endothelial growth factor receptor‐2 (VEGFR‐2) plays an important role in both vasculogenesis and angiogenesis. Inhibition of VEGFR‐2 has been demonstrated as a key method against tumor‐associated angiogenesis. Thiazolopyrimidine is an important analog of the purine ring, and we choose the thiazolopyrimidine scaffold as the mother nucleus. Two series of thiazolo[5,4‐d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity. In HUVEC inhibition assay, compounds 3l (=1‐(5‐{[2‐(4‐chlorophenyl)‐5‐methyl[1,3]thiazolo[5,4‐d]pyrimidin‐7‐yl]amino}pyridin‐2‐yl)‐3‐(3,4‐dimethylphenyl)urea) and 3m (=1‐(5‐{[2‐(4‐chlorophenyl)‐5‐methyl[1,3]thiazolo[5,4‐d]pyrimidin‐7‐yl]amino}pyridin‐2‐yl)‐3‐(4‐methoxyphenyl)urea) exhibited the most potent inhibitory effect (IC₅₀=1.65 and 3.52 μm , respectively). Compound 3l also showed the best potency against VEGFR‐2 at 50 μm (98.5 %). These results suggest that further investigation of compound 3l might provide potential angiogenesis inhibitors.     

Chemical Composition of Bawei Longzuan Granule and Its Anti‐Arthritic Activity on Collagen‐Induced Arthritis in Rats by Inhibiting Inflammatory Responses

Bawei Longzuan granule (BLG) is a representative Zhuang medicine preparation. The present work aims to characterize the chemical constituents of BLG and evaluate its anti‐arthritic activity. The major chemical constituents of BLG were tentatively identified by ultra‐performance liquid chromatography‐quadrupole time‐of‐flight mass spectrometry (UPLC‐Q‐TOF/MS), which revealed the presence of some alkaloids (e. g., magnoflorine, sinomenine and nitidine) and flavonoids (e. g., hesperidin, diosmin and sinensetin) that may be partly responsible for the anti‐arthritic effect of BLG. In addition, the collagen‐induced arthritis (CIA) model in rats was induced by intradermal injection of bovine collagen‐II in complete Freund's adjuvant at the base of tail. The CIA rats received oral administration of BLG (1.25, 2.5 and 5 g/kg) for 30 days. Then, various indicators were determined to evaluate its anti‐arthritic activity, including paw swelling, arthritic score, body weight, knee joint pathology, thymus index and spleen index. Additionally, the serum levels of tumor necrosis factor (TNF)‐α, interferon (IFN)‐γ, interleukin (IL)‐1β, IL‐6, IL‐4 and IL‐10 were measured to determine the underlying mechanisms. The results showed that BLG efficiently ameliorated the severity of arthritis in CIA rats by decreasing paw swelling and arthritis score and improving the histological lesions of knee joint. Moreover, the serum levels of several pro‐inflammatory cytokines (i. e., IL‐1β, TNF‐α, IL‐6 and IFN‐γ) were downregulated, whereas two anti‐inflammatory factors (i. e., IL‐4 and IL‐10) were upregulated after BLG administration. These results indicated that BLG possessed promising therapeutic effect on collagen‐induced arthritis by inhibiting inflammatory responses. BLG can be used as a complementary or alternative traditional medicine to treat rheumatoid arthritis.     

Cytotoxic Spliceostatin Analogs from Pseudomonas sp.

Two new spliceostatin analogs, designed as spliceostatins J and K ( 1 and 2 ), were isolated and identified from the culture of Pseudomonas sp., along with two known ones, FR901464 ( 3 ) and spliceostatin E ( 4 ). Their structures were elucidated by detailed interpretation of their spectroscopic data, especially 2D‐NMR and HR‐ESI‐MS. Spliceostatin J ( 1 ) represented the first example of spliceostatins bearing an unusual hexahydrofuro[3,4‐b]furan moiety. Biological assay showed all the isolated compounds except 1 displayed potent cytotoxic activities against two cancer cell lines (MDA‐MB‐231 and A‐549). Structure‐activity‐relationship studies revealed that the tetrahydropyran ring in spliceostatin analogs was necessary for their bioactive retention.     

Synthesis and Anti‐HIV Activity of Guanine Modified Fluorinated Acyclic Nucleoside Phosphonate Derivatives

The preparation of an unprecedented series of nucleobase modified 3‐fluoro‐2‐(phosphonomethoxy)propyl (FPMP) acyclic nucleosides in both their (R) and (S) enantiomerically pure forms is described. The synthesis focuses on a Mitsunobu alkylation reaction to construct the C?N(9) bond between a chiral fluorinated side‐chain residue and 6‐ or 7‐modified guanine analogs. Prodrugs of FPMP‐7‐deazaguanine were also synthesized by derivatization of the corresponding phosphonic acid functionality with (bis)diamyl aspartate amidate groups, leading to moderate activity against human immunodeficiency virus type 1 (HIV‐1).     

Stilbene Glycoside Oligomers from the Roots of Polygonum multiflorum

Five new trans‐2,3,5,4′‐tetrahydroxystilbene 2‐O‐β‐d ‐glucopyranoside (TSG)‐based stilbene glycoside oligomers ( 1 – 5 ) were isolated from the roots of Polygonum multiflorum. Their structures were elucidated by comprehensive spectroscopic analyses and chemical evidences. The absolute configurations of 1 , 2 , 4 , and 5 were established by quantum‐chemical electronic circular dichroism (ECD) calculations. Putative biosynthetic pathways of 1–5 were proposed using TSG as the key precursor. In addition, compounds 1 (multiflorumiside H) and 3 (multiflorumiside J) exhibited moderate inhibitory activities against NO production in LPS‐stimulated RAW264.7 cells.     

Chemical and Morphological Inter‐ and Intrapopulation Variability in Natural Populations of Gentiana pneumonanthe L.

Inter‐ and intrapopulation variability in six natural populations of the rare species Gentiana pneumonanthe was examined based on morphological and chemical data. Population size and linear morphometric parameters differed significantly among populations, but without a clear connection to habitat conditions, i. e. water supply and light availability. Leaf shape varied from ovate to lanceolate in all populations, and one population was distinctive in having the largest number of leaves of transitional shape. HPLC analyses of six secondary metabolites were performed separately for belowground parts, and aboveground vegetative and reproductive parts of individual plants (6 populations ×7 individuals ×3 plant parts, n=126) in order to examine differences at the population and individual levels. Three secoiridoids (swertiamarin (SWM), sweroside (SWZ), and gentiopicrin (GP)), one xanthone (mangiferin (MGF)), and two flavones (isoorientin (IO) and isovitexin (IV)) were detected and quantified in the analyzed samples: sweroside dominated in the aboveground reproductive part, mangiferin in the aboveground vegetative part, and gentiopicrin in the belowground part. At the population level, differences in contents of the analyzed chemicals among populations were significant only for a few metabolites. At the individual level, a pronounced organ‐dependent distribution of secondary metabolites was revealed. The results of this study contribute to a better understanding of natural variability within populations of the rare and threatened G. pneumonanthe, and provide data on the contents and within‐plant distribution of secondary metabolites, which are important as pharmacologically active compounds and may be useful for further biotechnological procedures regarding this species.     

New Immunomodulating Polyhydroxypregnane Glycosides from the Roots of Cynanchum otophyllum C.K.Schneid.

Seven new polyhydroxypregnane glycosides, named cynotophyllosides P–V, together with three known analogs were isolated from the roots of Cynanchum otophyllum C.K.Schneid . Their structures were elucidated by a variety of spectroscopic techniques, as well as acid‐catalyzed hydrolysis. All isolates were tested for their immunological activities in vitro against Con A‐ and LPS‐induced proliferation of mice splenocytes. Immunoenhancing (for 1 , 9 ) and immunosuppressive (for 2 ) activities were observed. Furthermore, cynotophylloside R ( 3 ) showed immunomodulatory as it enhanced the proliferation of splenocytes in low concentration and suppressed immune cells in concentration more than 1.0 μg/ml.     

Synthesis,Structural Characterization and Antimicrobial Evaluation of Ruthenium Complexes with Heteroaromatic Carboxylic Acids

The antibacterial and antibiofilm activities of two new ruthenium complexes against E. coli, S. aureus, P. aeruginosa PAO1 (laboratory strain) and P. aeruginosa LES B58 (clinical strain) were evaluated. Complexes, mer‐[Ru^III(2‐bimc)₃] ? H₂O ( 1 ) and cis‐[Ru^IVCl₂(2,3‐pydcH)₂] ? 4H₂O ( 2 ), were obtained using aromatic carboxylic acid ligands, namely, 1H‐benzimidazole‐2‐carboxylic acid (2‐bimcH) and pyridine‐2,3‐dicarboxylic acid (2,3‐pydcH₂). Compounds were physicochemically characterized using X‐ray diffraction, Hirshfeld surface analysis, IR and UV/VIS spectroscopies, as well as magnetic and electrochemical measurements. Structural characterization revealed that Ru(III) and Ru(IV) ions in the complexes adopt a distorted octahedral geometry. The intermolecular classical and weak hydrogen bonds, and π???π contacts significantly contribute to structure stabilization, leading to the formation of a supramolecular assembly. Biological studies have shown that the Ru complexes inhibit the growth of bacteria and biofilm formation by the tested strains and the complexes seem to be a potential as antimicrobial agents.     

Copper Oxide Nanomaterials Derived from Zanthoxylum armatum DC. and Berberis lycium Royle Plant Species: Characterization,Assessment of Free Radical Scavenging and Antibacterial Activity

Copper oxide nanomaterials were synthesized by a facile sustainable biological method using two plant species (Zanthoxylum armatum DC. and Berberis lycium Royle ). The formation of materials was confirmed by FT‐IR, ATR, UV‐visible, XRD, TEM, SEM, EDX, TGA and PL. The antibacterial activity was evaluated by agar well diffusion method to ascertain the efficacy of plant species extract and extract derived copper oxide nanomaterials against six Gram‐positive bacteria namely Staphylococcus aureus, Streptococcus mutans, Streptococcus pyogenes, Corynebacterium diphtheriae, Corynebacterium xerosis, Bacillus cereus and four Gram‐negative bacteria such as Klebsiella pneumonia, Escherichia coli, Pseudomonas aeruginosa and Proteus vulgaris against the standard drug, Ciprofloxacin for Gram‐positive and Gentamicin for Gram‐negative bacteria, respectively. In both cases, copper oxide nanomaterials were found to be sensitive in all the bacterial species. Sensitivity of copper oxide nanomaterials shows an be higher as compared to plant species extract against different bacteria. Scavenging activity of plant extracts along with nanomaterials have been accessed using previously reported protocols employing ascorbic acid as standard. Scavenging activity of copper oxide nanomaterials shows an increase with increase in concentration. The biological activity (bactericidal and scavenging efficiency) of plant derived copper oxide nanomaterials revealed that these materials can be used as potent antimicrobial agent and DPPH scavengers in industrial as well as pharmacological fields.