Oleanolic acid derivative alleviates cardiac fibrosis through inhibiting PTP1B activity and regulating AMPK/TGF-ß/Smads pathway.

Cardiac fibrosis (CF) in response to persistent exogenous stimuli or myocardial injury results in cardiovascular diseases (CVDs). Protein tyrosine phosphatase 1B (PTP1B) can promote collagen deposition through regulating AMPK/TGF-ß/Smads signaling pathway, and PTP1B knockout improves cardiac dysfunction against overload-induced heart failure. Oleanolic acid (OA) has been proven to be an inhibitor of PTP1B, and its anti-cardiac remodeling effects have been validated in different mouse models. To improve the bioactivity of OA and to clarify whether OA derivatives with stronger inhibition of PTP1B activity have greater prevention of cardiac remodeling than OA, four new OA derivatives were synthesized and among them, we found that compound B had better effects than OA in inhibiting cardiac fibrosis both in vivo in the isoproterenol (ISO)-induced mouse cardiac fibrosis and in vitro in the TGF-ß/ISO-induced 3T3 cells. Combining with the results of molecular docking, surface plasmon resonance and PTP1B activity assay, we reported that OA and compound B directly bound to PTP1B and inhibited its activity, and that compound B showed comparable binding capability but stronger inhibitory effect on PTP1B activity than OA. Moreover, compound B presented much greater effects on AMPK activation and TGF-ß/Smads inhibition than OA. Taken together, OA derivative compound B more significantly alleviated cardiac fibrosis than OA through much greater inhibition of PTP1B activity and thus much stronger regulation of AMPK/TGF-ß/Smads signaling pathway.

Synthesis and In Vitro Anti-Influenza Virus Evaluation of Novel Sialic Acid (C-5 and C-9)-Pentacyclic Triterpene Derivatives.

The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-pentacyclic triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with pentacyclic triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-pentacyclic triterpene conjugates. Their structures were confirmed by ESI-HRMS, ¹H-NMR, and 13C-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 µM. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 µM (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 µM, ~53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 µM, ~20-30%), and no significant anti-influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold.

Elucidation of the pharmacophore of echinocystic acid, a new lead for blocking HCV entry.

To elucidate the pharmacophore of echinocystic acid (EA), an oleanane-type triterpene displaying substantial inhibitory activity on HCV entry, two microbial strains, Rhizopus chinensis CICC 3043 and Alternaria alternata AS 3.4578, were utilized to modify the chemical structure of EA. Eight new metabolites with regio- and stereo-selective introduction of hydroxyl and lactone groups at various inert carbon positions were obtained. The anti-HCV entry activity of the metabolites 2-13, along with their parental compound EA and other analogs 14-15, were evaluated. Most of the metabolites showed no improvement but detrimental effect on potency except compound 5 and 6, which showed similar and even a litter higher anti-HCV entry activity than that of EA. The results demonstrated that ring A, B, C and the left side of ring E of EA are highly conserved, while ring D and the right side of ring E of EA are flexible. Introduction of a hydroxyl group at C-16 enhanced the triterpene potency. Further analysis indicated that the hemolytic effect of EA disappeared upon such modifications.

Conjugation of cyclodextrin with fullerene as a new class of HCV entry inhibitors.

An α-cyclodextrin-[60]fullerene conjugate with a flexible linker at the secondary face of α-cyclodextrin has been prepared, which displays significant water solubility and, more importantly, acts as a new class of HCV entry inhibitor with IC(50) at 0.17 µM level.

Novel peptide derivatives of bleomycin A5: synthesis, antitumor activity and interaction with DNA.

A series of novel amino acid and peptide derivatives of bleomycin (BLM) A(5) were synthesized. All the compounds possessed significant antitumor activities in vitro against HL-60, BGC-823, PC-3MIE8, and MDA-MB-435 cell lines. Their antitumor activities against MDA-MB-435 were 10-fold higher than BLM A5. The DNA cleavage studies indicated that the hydrophobic amino acid or peptide derivatives of BLM A5 could induce higher cleavage ratio of double to single strand DNA than BLM A5. From the DNA binding studies, we found that the derivatives containing either D-conformation amino acid or basic amino acid could facilitate DNA binding of BLM.

Synthesis, biological evaluation and DNA binding properties of novel bleomycin analogues.

A series of bleomycin analogues was prepared with a facile synthetic method. All the compounds were shown to display significant antitumor activity against HeLa and BGC-823 cell lines in vitro. The binding properties with CT-DNA and cleavage efficiency to pBR322 DNA were investigated, the results indicate that there is a positive relationship between DNA cleavage efficiency and the binding affinity to DNA, and the antitumor activity of the bleomycin analogues is enhanced as the hydrophobicity of the C-terminus substituent side chain increased.

Manganese(II) complex of 6,7-dicycanodipyridoquinoxaline with antitumor activities: synthesis, crystal structure and binding with DNA.

A new Mn(II) complex with the planar ligand 6,7-dicycanodipyrido[2,2-D:2',3'-f]quinoxaline (L) [MnL(NO(3))(H(2)O)(3)]NO(3).CH(3)OH (1) has been synthesized and characterized by elemental analysis, IR, TG-DTA and molar conductance. Its crystal structure was determined by X-ray diffraction, crystal data: yellow, triclinic, space group P1;, Z=2, a=7.3743(8) A, b=11.2487(15) A, c=14.1655(15) A, alpha=79.412(2) degrees, beta=83.208(2) degrees, gamma=80.466(2) degrees. The Mn atom was hexa-coordinated to form a distorted octahedral geometry by two nitrogen atoms of L and four oxygen atoms of three H(2)O and NO(3)(-) in the complex. The binding mode of the complex with calf thymus DNA has also been investigated with spectrophotometric methods, viscosity and thermal denaturation measurements. The experimental results indicate that the complex intercalated into DNA base pairs via the ligand L. The intrinsic binding constant K(b) values for 1 (5.00 x 10(5) M(-1)) and L (1.65 x 10(5) M(-1)) were determined by absorption titration and calculated with the model of McGhee and Von Hippel. Biological tests against four different cell lines (HL-60, KB, Hela and BGC-823) in vitro showed that the complex had significant antitumor properties since the 50% inhibition concentrations (IC(50)) of the complex were within a microM range similar to those of antitumor drug 5-fluorouracil.

Synthesis, crystal structure, antitumor activity and DNA-binding study on the Mn(II) complex of 2H-5-hydroxy-1,2,5-oxadiazo[3,4-f]1,10-phenanthroline.

The complex [Mn(L)(NO(3))(2)(H(2)O)(2)] (1) (L=2H-5-hydroxy-1,2,5-oxadiazo[3,4-f]1,10-phenanthroline) was synthesized and characterized by elemental analysis, IR and UV. The crystal and molecular structure of 1 was determined by single-crystal X-ray diffraction; crystal data: light yellow, monoclinic, space group P2(1)/n, Z=4, a=7.432(2) A, b=9.582(3) A, c=23.445(7) A, beta=90.519(5) degrees. The Mn atom in 1 is hexa-coordinated in a distorted octahedral arrangement by two N atoms of the ligand L and four O atoms of two water molecules and two nitrate anions. Biological tests in vitro showed that 1 has significant antitumor activity against HL-60, KB, Hela and BGC-823 cells. The interaction of 1 with calf thymus DNA was investigated by absorption titration, thermal denaturation and viscosity measurements. The results suggest that 1 binds with DNA by intercalating via the ligand L.