ABSTRACT
In this study, the synthetic way to new N-pyridinyl(methyl)indolylpropanamides acting as non acidic NSAIDs has been described. Pharmacomodulation was carried out at N(1) and C(5) of the indole ring and at the level of the propanamide chain. N(3)-pyridinylmethyl-[1(4-chlorobenzyl-5-chloroindol-3-yl)propanamide represents one of the most potent compounds in the TPA-induced mouse ear swelling assay, with a level of activity higher than that of ibuprofen and comparable to that of dexamethasone.
Subject(s)
Amides/chemical synthesis , Indoles/chemical synthesis , Inflammation/drug therapy , Amides/pharmacology , Animals , Dexamethasone , Ibuprofen , Indoles/pharmacology , Inflammation/prevention & control , Mice , Structure-Activity RelationshipABSTRACT
Structural analogues of Ilomastat (Galardin), containing unsaturation(s) and chain extension carrying bulky phenyl group or alkyl moieties at P'1 were synthesized and purified by centrifugal partition chromatography. They were analyzed for their inhibitory capacity towards MMP-1, MMP-2, MMP-3, MMP-9 and MMP-14, main endopeptidases involved in tumour progression. Presence of unsaturation(s) decreased the inhibitory potency of compounds but, in turn increased their selectivity for gelatinases. 2b and 2d derivatives with a phenyl group inhibited preferentially MMP-9 with IC50 equal to 45 and 38 nM, respectively, but also display activity against MMP-2 (IC50 equal to 280 and 120 nM, respectively). Molecular docking computations confirmed affinity of these substances for both gelatinases. With aims to obtain a specific gelatinase A (MMP-2) inhibitor, P'1 of Ilomastat was modified to carry one unsaturation coupled to an alkyl chain with pentylidene group. Docking studies indicated that MMP-2, but not MMP-9, could accommodate such substitution; indeed 2a proved to inhibit MMP-2 (IC50=123 nM), while displaying no inhibitory capacity towards MMP-9.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Matrix Metalloproteinase Inhibitors , Models, Molecular , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Alkylation , Circular Dichroism , Computer Simulation , Hydrogen Bonding , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Indoles/chemical synthesis , Indoles/isolation & purification , Matrix Metalloproteinase 2/chemistry , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/chemistry , Matrix Metalloproteinase 9/metabolism , Molecular Structure , Protease Inhibitors/chemical synthesis , Protease Inhibitors/isolation & purification , Protein Binding , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We report the synthesis of collagen related peptides containing the peptide sequence Lys-Hyp-Gly-Glu-Hyp-Gly-Pro-Lys. The alpha-triple helix peptides behave as type III collagen analogues supporting platelet aggregation, while the homotrimer which does not exhibit a triple-helical conformation inhibits type III collagen-induced human platelet aggregation. The incorporation of the octapeptide sequence in type III collagen mimetic peptides may lead to the loss of the anti-thrombotic activity for a pro-thrombotic one.
Subject(s)
Collagen Type III/pharmacology , Platelet Aggregation/drug effects , Amino Acid Sequence , Circular Dichroism , Collagen Type III/chemistry , Humans , Molecular Mimicry , Molecular Sequence Data , Nuclear Magnetic Resonance, Biomolecular , Spectrometry, Mass, Electrospray IonizationABSTRACT
Several N-pyridinyl(methyl)-indol-3-ylpropanamides were synthesized and pharmacological evaluations of their immunosuppressive potential were performed. Among thirteen compounds tested in vitro on murine T proliferation, three showed interesting inhibiting activity. For the most active compound (propanamide 18), immunosuppressive activity was documented both in vitro on human T lymphocytes proliferation and in vivo on mice delayed-type hypersensitivity. These experimental data demonstrated that these compounds hold potential as immunosuppressive agents.
Subject(s)
Immunosuppressive Agents/pharmacology , Indoles/pharmacology , Pyridines/pharmacology , Amides/chemistry , Animals , Cell Proliferation , Female , Humans , Hypersensitivity, Delayed , Indoles/chemistry , Mice , Mice, Inbred BALB C , Pyridines/chemistry , T-Lymphocytes/drug effectsABSTRACT
Cell cycle progression is dependent on intracellular iron level and chelators lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of new synthetic calix[4]arene podands bearing two aspartic/glutamic acid, ornithine groups or hydrazide function at the lower rim, designed as potential iron chelators. The synthesis only afforded calix[4]arenes in the cone conformation. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670A (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in the rat hepatoma cell line Fao by measuring mitochondrial succinate dehydrogenase activity. Their cytotoxicity was evaluated by extracellular LDH activity. Preliminary results indicated that among all tested compounds, monohydrazidocalix[4]arene 2 which is not cytotoxic in Fao cells exhibits interesting antiproliferative activity. This effect, independent on iron depletion, remains to be further explored. Moreover, it also shows that new substituted calix[4]arenes could open the way to new valuable medicinal chemistry scaffolding.
Subject(s)
Calixarenes/pharmacology , Carcinoma, Hepatocellular/drug therapy , Cell Proliferation/drug effects , Iron Chelating Agents/pharmacology , Phenols/pharmacology , Animals , Benzoates/pharmacology , Calixarenes/chemical synthesis , Calixarenes/chemistry , Carcinoma, Hepatocellular/enzymology , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Deferasirox , Drug Screening Assays, Antitumor , Hydroxyl Radical/antagonists & inhibitors , Hydroxyl Radical/metabolism , Iron Chelating Agents/chemical synthesis , Iron Chelating Agents/chemistry , Molecular Structure , Phenols/chemical synthesis , Phenols/chemistry , Rats , Solubility , Structure-Activity Relationship , Triazoles/pharmacology , Tumor Cells, CulturedABSTRACT
The authors have described the synthetic way to new N-pyridinyl(methyl)indolylpropanamides acting as non acidic NSAIDs. Pharmacomodulation was carried out at N-1 and C-5 of the indole ring and at the level of the propanamide chain. N-(pyridin-3-ylmethyl)-3-[5-chloro-1-(4-chlorobenzyl)-indol-3-yl]propanamide 32 represents one of the most potent compounds evaluated in the TPA-induced mouse ear swelling assay, with a level of activity higher than that of ibuprofen and comparable to that of dexamethasone.
Subject(s)
Amides/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Indoles/chemical synthesis , Propane/analogs & derivatives , Propane/chemical synthesis , Pyridines/chemical synthesis , Administration, Cutaneous , Administration, Oral , Amides/chemistry , Amides/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Ear, External , Edema/chemically induced , Edema/drug therapy , Indoles/chemistry , Indoles/pharmacology , Mice , Polyunsaturated Alkamides , Propane/chemistry , Propane/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Structure-Activity Relationship , Tetradecanoylphorbol AcetateABSTRACT
A series of novel N-substituted-(indol-2-yl)carboxamides (12-18) and (indol-3-alkyl)carboxamides (25-31) were synthesized and evaluated as inhibitors of the inflammation process. Pharmacomodulation at the level of the amidic nitrogen by incorporation of the previously described pharmacophoric moieties 6-aminolutidine, beta-picolylamine, 4-aminopyridine and piperazine was investigated; only two compounds (12) and (31) exhibited significant (approximately 40%) inhibitory effect in the carrageenan-induced rat paw edema after oral administration of a dose of 0.1 mM kg(-1). Replacement of the indole core by indazole failed to increase activity. Incorporation of an alkyl chain spacer led to more efficient compounds (46-52) especially in the indolepropanamide sub-series. Determination of the efficiency of the most active compounds on topical inflammation, by measuring reduction of ear thickness in the acute tetradecanoyl phorbol acetate (TPA)-induced mouse ear swelling assay, confirmed the high potency of propanamides (49) and (51) after oral administration: ID50 = 0.041 +/- 0.013 and 0.042 +/- 0.016 mM kg(-1) respectively. The less toxic propanamide (51) exerted a high level of inhibitory activity after topical application of 2 x 100 microg/ear: 78 +/- 2%.
