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1.
Int J Nanomedicine ; 6: 787-94, 2011.
Article in English | MEDLINE | ID: mdl-21589646

ABSTRACT

Nanotechnology is an exciting field of investigation for the development of new treatments for many human diseases. However, it is necessary to assess the biocompatibility of nanoparticles in vitro and in vivo before considering clinical applications. Our characterization of polyol-produced maghemite γ-Fe(2)O(3) nanoparticles showed high structural quality. The particles showed a homogeneous spherical size around 10 nm and could form aggregates depending on the dispersion conditions. Such nanoparticles were efficiently taken up in vitro by human endothelial cells, which represent the first biological barrier to nanoparticles in vivo. However, γ-Fe(2)O(3) can cause cell death within 24 hours of exposure, most likely through oxidative stress. Further in vivo exploration suggests that although γ-Fe(2)O(3) nanoparticles are rapidly cleared through the urine, they can lead to toxicity in the liver, kidneys and lungs, while the brain and heart remain unaffected. In conclusion, γ-Fe(2)O(3) could exhibit harmful properties and therefore surface coating, cellular targeting, and local exposure should be considered before developing clinical applications.


Subject(s)
Biocompatible Materials/chemistry , Ferric Compounds/chemistry , Magnetite Nanoparticles/chemistry , Analysis of Variance , Animals , Biocompatible Materials/administration & dosage , Biocompatible Materials/toxicity , Cell Line, Transformed , Cell Survival/drug effects , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Ferric Compounds/administration & dosage , Ferric Compounds/pharmacokinetics , Ferric Compounds/toxicity , Histocytochemistry , Humans , Intracellular Space/metabolism , Magnetite Nanoparticles/administration & dosage , Magnetite Nanoparticles/toxicity , Materials Testing , Particle Size , Rats , Tissue Distribution
2.
Bioorg Med Chem ; 18(10): 3588-600, 2010 May 15.
Article in English | MEDLINE | ID: mdl-20417107

ABSTRACT

The group IIA human non-pancreatic secretory phospholipase A(2) (hnp-sPLA(2)) is one of the enzymes implied in the inflammatory process. In the course of our work on inhibitors of this enzyme we investigated the influence of rigidity of the piperazine region on the biological activity. Several modifications were explored. Various linkers, such as amide, urea, carbamate, or alkoxyphenyl were inserted between the piperazine and the lipophilic chain. Also, modification of the piperazine core to incorporate carbonyl groups was studied. In an in vitro fluorimetric assay using the human GIIA (HPLA(2)) and porcine pancreatic GIB enzymes, compound 60a (Y=phenoxy, R=C(18)H(37), Z=CH(2)) had the optimal activity with an IC(50)=30nM on HPLA(2). By means of molecular modelling we attempted to get informations towards comprehension of differences in activity.


Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Phospholipases A/antagonists & inhibitors , Piperazines/chemistry , Piperazines/pharmacology , Animals , CHO Cells , Cell Line , Combinatorial Chemistry Techniques , Cricetinae , Cricetulus , Enzyme Inhibitors/pharmacology , Humans , Piperazine , Quantitative Structure-Activity Relationship , Structure-Activity Relationship
3.
J Med Chem ; 50(7): 1618-26, 2007 Apr 05.
Article in English | MEDLINE | ID: mdl-17335183

ABSTRACT

Secreted phospholipases A2 (sPLA2s) have been reported to play an important role in various inflammatory conditions and thus represent an attractive therapeutic target. Previous SAR studies from our laboratory have revealed certain important features of our recently discovered specific hGIIA sPLA2 inhibitors, and we report here the synthesis and biological activities of glycerol-containing derivatives of our lead compound III (Figure 1). Efficient and selective synthesis methods have been developed to make glycerol trisubstituted by different groups on desired positions. In terms of biological activities, the best compounds (A3, A6, and A15) are more active than III (Figure 1), as potent as Me-Indoxam, an sPLA2s inhibitor of reference, against hGIIA, hGV, and hGX sPLA2s and at least 10 times less active toward the GIB enzymes in two in vitro assay systems. By synthesis of enantiopure (S)-A6, we demonstrated that no important improvement of the inhibitory potency could be achieved by this approach. Furthermore, the results show that the global lipophilicity is likely responsible for the anti-PLA2 activity and two oxadiazolone moieties seem too big to be accommodated by the active site of the hGIIA enzyme.


Subject(s)
Glycerol/analogs & derivatives , Glycerol/chemical synthesis , Oxadiazoles/chemical synthesis , Phospholipases A/antagonists & inhibitors , Glycerol/pharmacology , Group II Phospholipases A2 , Humans , Hydrophobic and Hydrophilic Interactions , Oxadiazoles/pharmacology , Phospholipases A/chemistry , Phospholipases A2 , Stereoisomerism , Structure-Activity Relationship
4.
J Org Chem ; 69(8): 2888-91, 2004 Apr 16.
Article in English | MEDLINE | ID: mdl-15074948

ABSTRACT

We report the results of a study aimed at the diastereoselective synthesis of chiral 2-alkoxy-5-/6-methoxycarbonylmethylidenepyrrolidines/-piperidines by condensation of chiral amines onto omega-oxo alkynoates and omega-oxo beta-keto esters.

5.
Chem Pharm Bull (Tokyo) ; 51(6): 728-30, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12808255

ABSTRACT

5-Aryl-3-(4-hydroxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 3 were prepared by cyclocondensation of 1-(4-hydroxyphenyl)-2-aroylhydrazines with thiophosgene. All compounds exhibited antiproliferation activity in K562, IC(50) ranging from 24 to 94 micro M comparable efficacy with apigenin and genistein and showed more potent antiproliferation of K562/adr cells, highly expressing P-glycoprotein. Compounds 3g, 3e and 3a inhibited the function of P-glycoprotein with the alpha(0.5) equal to 10+/-3 micro M, 21+/-5 micro M and 34+/-7 micro M, respectively.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Oxazoles/chemical synthesis , Thiones/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Humans , Inhibitory Concentration 50 , K562 Cells , Magnetic Resonance Spectroscopy , Molecular Structure , Oxazoles/chemistry , Oxazoles/pharmacology , Thiones/chemistry , Thiones/pharmacology
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