Design and synthesis of 3-benzylaminocoumarin-7-O-sulfamate derivatives as steroid sulfatase inhibitors.

Steroid sulfatase (STS) is a sulfatase enzyme that catalyzes the conversion of sulfated steroid precursors to free steroid. The inhibition of STS could abate estrogenic steroids that stimulate the proliferation and development of breast cancer, and therefore STS is a potential target for adjuvant endocrine therapy. In this study, a series of 3-benzylaminocoumarin-7-O-sulfamate derivatives targeting STS were designed and synthesized. Structure-relationship activities (SAR) analysis revealed that attachment of a benzylamino group at the 3-position of coumarin improved inhibitory activity. Compound 3j was found to have the highest inhibition activity against human placenta isolated STS (IC50  0.13 µM) and MCF-7 cell lines (IC50 1.35 µM). Kinetic studies found compound 3j to be an irreversible inhibitor of STS, with KI and kinact value of 86.9 nM and 158.7 min-1, respectively.

Discovery of monocarbonyl curcumin-BTP hybrids as STAT3 inhibitors for drug-sensitive and drug-resistant breast cancer therapy.

Signal transducer and activator of transcription 3 (STAT3) is a well-known antitumor target. Exogenous ROS insult can lead to selective cytotoxicity against cancer cells. A combination of STAT3 inhibition and "oxidation therapy" may be a new strategy to address the multidrug-resistance issue due to their important roles in the survival and drug resistance of cancer cells. Here, a series of novel curcumin-BTP hybrids were designed and evaluated as STAT3 inhibitors with ROS production activity. Compound 6b exerted the best antitumor activity and selectivity for MCF-7 and MCF-7/DOX cells (IC50 = 0.52 µM and 0.40 µM, respectively), while its IC50 value for MCF-10A breast epithelial cells was 7.72 µM. Furthermore, compound 6b suppressed STAT3 phosphorylation, nuclear translocation and DNA-binding activity and the expression of STAT3 specific oncogenes. Increases in the level of IL-6-induced p-STAT3 were also inhibited by 6b without influencing IFN-γ-induced p-STAT1 expression. Additionally, 6b effectively promoted intracellular ROS accumulation, induced cancer cell apoptosis and cell cycle arrest, abolished the colony formation ability of breast cancer cells, and inhibited P-gp expression in MCF-7/DOX cells. Finally, 6b suppressed the growth of implanted human breast cancer in vivo. Our findings highlight that 6b may be a promising therapeutic agent for drug-sensitive and drug-resistant breast cancers.

Discovery of a synthetic Aminopeptidase N inhibitor LB-4b as a potential anticancer agent.

APN inhibitors have been considered as potential anticancer agents for years. LB-4b is the first synthetic APN inhibitor to be evaluated for both of its anti-invasion and anti-angiogenesis effects. As a potent synthetic APN inhibitor (IC50=850 nM, versus bestatin of 8.1 µM), LB-4b was determined to have more significant block effects to cancer cell invasion and angiogenesis than bestatin. Besides, it is able to be easily synthesized with a high total yield, while the reported synthetic methods of bestatin are much more complex.

An iminosugar N-pentafluorobenzyl-1-deoxynojirimycin as a novel potential immunosuppressant for the treatment of Th2-related diseases.

Increased levels of Th2 cytokine interleukin-4 (IL-4) have been reported to be involved in the pathogenesis of the parasite Schistosoma japonicum (S. japonicum) infection or detected in the serum of the causative agent of acquired immunodeficiency syndrome (AIDS) patients. This correlates with a worsened outcome of AIDS. The inhibition of a Th2 type response might aid in the treatment of these Th2-related diseases. Previously, we found that N-pentafluorobenzyl-1-deoxynojirimycin (5F-DNM), a new derivative of 1-deoxynojirimycin (DNM) (an inhibitor of the glycoprotein processing enzymes, glucosidase I and II), had specific inhibition effects on human CD4(+) T cells. In this study, we further found that 5F-DNM not only markedly inhibited in vitro IL-4 production from human PBMCs, CD4(+) T cells and mouse splenocytes but also strongly inhibited the production of IL-4 in splenocytes from a mouse model of S. japonicum infection. The numbers of S. japonicum worms were significantly decreased in vivo upon the treatment of mice with 5F-DNM. We demonstrated the mechanism of 5F-DNM effects on CD4(+) T cells acts via the inhibition of the IL-4/JAK1/STAT6 signaling pathway. Moreover, 5F-DNM was found to induce CD4 internalization (transfer from the cellular surface to the cytoplasm) in CD4(+) T cells and had no significant effects on the overall expression levels of CD4. These findings indicate that 5F-DNM might be used as a potential candidate for the treatment of S. japonicum parasitic infection, AIDS and other Th2-related diseases.

Design, synthesis and pharmacological evaluation of alpha-substituted N-benzylamides of gamma-hydroxybutyric acid with potential GABA-ergic activity. Part 6. Search for new anticonvulsant compounds.

In the recent study we have extended our investigations to the new anticonvulsant derivatives of alpha-substituted N-benzylamides of gamma-hydroxybutyric acid (GHB). Among the obtained compounds N-benzylamide of alpha-(1,2,3,4-tetrahydroisoquinoline)-GHB (9) has demonstrated activity against maximal electroshock (MES) induced seizures in mice (at 100 mg/kg ip) and in rats (at 30 mg/kg, po dose). Lactone 8 and amide 9 have possessed a weak effect on [3H]-muscimol binding. Molecular modeling studies have revealed that anticonvulsant activity of the alpha-substituted amides of GHB might partially be explained by the orientation of the terminal benzylamide fragment.

Effects of ethyl and benzyl groups on the miscibility and properties of castor oil-based polyurethane/starch derivative semi-interpenetrating polymer networks.

Cornstarch derivative (ES), prepared using diethyl sulfate as an etherifying reagent, was blended with castor oil-based polyurethane (PU) prepolymer to obtain a series of semi-interpenetrating polymer network (semi-IPN) materials, named as UES films. Simultaneously, other kinds of semi-IPN (UBS2) were prepared from PU and benzyl starch (BS2) to compare the effects of the substitute groups. The differences in the miscibility and properties of the two series of materials were investigated using attenuated total reflection Fourier transform infrared spectroscopy, atomic force microscopy, dynamic mechanical thermal analysis, ultraviolet-visible spectroscopy, water-sensitivity and tensile testing. The experimental results revealed that UBS2 films exhibit stronger interfacial attraction and better phase mixing than the UES films, as a result of specific interactions between the PU hard segments and BS2 phenyl groups. The optical transmittance, water-resistivity, tensile strength, and elongation at break of the UBS2 films were clearly higher than those of the UES films containing the same concentration of PU. In particular, the miscibility and properties of the UES film with 40 wt.-% ES, were very poor, whereas the semi-IPN films containing 70 wt.-% benzyl starch still had a certain miscibility and good properties. Therefore, the phenyl groups play an important role in the improvement of the miscibility and properties of the semi-IPN materials.

Dihydrophenanthrenes from Bletilla formosana.

Three new dihydrophenanthrenes, 4-methoxy-9,10-dihydrophenanthrene-1,2,7-triol (1), 1-(4-hydroxybenzyl)-4,7-dimethoxy-9,10-dihydrophenanthrene-2-ol (2), and 1,3,6-tri(4-hydroxybenzyl)-4-methoxydihydrophenanthrene-2,7-diol (3) together with seven known phenanthrene derivatives, six known flavonoids, a bibenzyl and three phenolic compounds were isolated from the whole plant of Bletilla formosana. Their structures were elucidated by spectroscopic, mainly 2D NMR spectrometry and chemical methods.

Synthesis and biological activity of novel acridinylidene and benzylidene thiazolidinediones.

A novel set of acridinylidene thiazolidinediones and benzylidene thiazolidinediones was synthesized by nucleophilic addition of cyanoacrylates. Some of these compounds were evaluated for their glucose lowering capability and their effects on the triglyceride level in alloxan diabetic mice.

Synthesis of radioiodine labeled dibenzyl disulfide for evaluation of tumor cell uptake.

Benzyl 4-halobenzyl and ally benzyl disulfide were synthesized as diallyl disulfide analogues and their tumor growth inhibitory effects on the cancer cells (SNU C5 and MCF-7) were comparable to that of diallyl disulfide, indicating that the disulfide functional group was responsible for the tumor growth inhibitory effects. Cu(I)-assisted radioiodination of benzyl 4-bromobenzyl disulfide gave benzyl 4-[123I/125I]iodobenzyl disulfide in 30-40% radiochemical yield. The radiolabeled disulfide was taken up by the cancer cells in a time-dependent manner, and the uptake was inhibited by the pretreatment of S-methyl methanethiosulfonate (MMTS), phorone and diallyl disulfide. This study suggested that the radiolabeled dibenzyl disulfide was taken up by the cancer cells via thiol-disulfide exchange and retained inside the cells.

Anticonvulsant activity of benzylamides of some amino acids and heterocyclic acids.

A series of new potential anticonvulsants have been synthesized. They are N-methyl benzyl-amides of N-methyl Asp and N-methyl Glu (R and S), benzylamides of some heterocyclic acids and their N-oxides and benzylamides of two heteroalicyclic acids. The obtained compounds were evaluated in the Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH.

[Preparation and study of phytotoxicity of N-arylalkyl substituted amides. I. Benzylamides]. / Preparazione e studio dell'attività fitotossica di amidi N-aralchilsostituite. Nota I - Benzilamidi.

A series of N-benzyl substituted amides (substances I-CV) have been prepared and tested for phytotoxicity. Preliminary tests were carried out on various common plants using both pre- and post-emergence tests at doses of 6 kg/ha. Further tests using doses of 4 and 2 kg/ha were carried out on the most interesting compounds. Some of the compounds tested showed marked phytotoxic activity. This activity appears clearly different as regards mechanism from that of homologous anilides. The amides studied appear to be quite inactive as inhibitors of the Hill reaction.