Synthesis and biological evaluation of novel 4,5-bis(dialkylaminoalkyl)-substituted acridines as potent telomeric G-quadruplex ligands.

Several 4,5-bis(dialkylaminoalkyl)-substituted acridines have been prepared starting from acridine and their telomeric G-quadruplex stabilizing properties were evaluated using FRET melting and TRAP (Telomerase Repeat Amplification Protocol Assay) experiments.

Introduction of the 4-(4-bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with improved selectivity.

Hydrazide derivatives of Ilomastat, carrying either aryl groups or distinct alkyl and arylsulfonyl moieties were synthesized and evaluated for their MMP inhibitory activity. Potent and selective MMP-9 inhibition (IC(50)=3 nM) was observed for compound 3m (arylsulfonyl group: 4-(4-Br-C6H4)-C6H4-SO(2)-). Interaction with the S2 enzyme subsite is mainly responsible for the inhibitory properties of this derivative as confirmed by molecular docking computation.

Collagen-binding domains of gelatinase A and thrombospondin-derived peptides impede endocytic clearance of active gelatinase A and promote HT1080 fibrosarcoma cell invasion.

Gelatinase A (matrix metalloproteinase-2, MMP-2) binds to several proteins through its collagen-binding domains (CBDs). Surface plasmon resonance analysis revealed a strong interaction between CBD123 and thrombospondin-1 (TSP-1), with a K(D) value of 2x10(-9) M. CBD123, as well as individual domains, behave as competitive inhibitors of the TSP-1-directed endocytic clearance of active MMP-2, but not of its latent form, by HT1080 fibrosarcoma cells.

Non-covalent complexes between bis-beta-carbolines and double-stranded DNA: A study by electrospray ionization FT-ICR mass spectrometry (I).

The non-covalent complexes of five bis-beta-carbolines alkaloids with three different double-stranded oligodeoxynucleotides d(GCGCGATCGCGC)(2), d(GCGCAATTGCGC)(2), and d(GCGAAATTTCGC)(2) were investigated by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. These five antitumor compounds all showed DNA-binding abilities. Binding affinities in the order of 2>3, 4>5, and 1 with double-stranded DNA were obtained, which mean that the length of the linkage chain between two beta-carbolines has a remarkable effect on the formation of the non-covalent complexes.

The NC1 domain of type XIX collagen inhibits in vivo melanoma growth.

Type XIX collagen is a minor collagen that localizes to basement membrane zones, together with types IV, XV, and XVIII collagens. Because several NC1 COOH-terminal domains of other chains from basement membrane collagens were reported to exhibit antitumor activity, we decided to study the effects of the NC1(XIX) collagen domain on tumor progression using an experimental in vivo model of mouse melanoma. We observed a 70% reduction in tumor volume in NC1(XIX)-treated mice compared with the corresponding controls.

N-arylsulfonyl-2-vinyltryptamines as new 5-HT6 serotonin receptor ligands.

Several new 2-vinyl-Nb,Nb-dimethyltryptamines were prepared using Fischer indole synthesis followed by simple functional group transformations and evaluated on 5-HT4, 5-HT5, 5-HT6 and 5-HT7 serotonin receptors. It was found that 2-vinyl substitution conferred a potent and selective 5-HT6 binding activity to these molecules which could be enhanced by Na-arylsulfonyl substituents.

A novel strategy for designing specific gelatinase A inhibitors: potential use to control tumor progression.

Matrix metalloproteases (MMPs) are zinc endopeptidases deeply implicated in tumor progression. MMP inhibitors are attractive potential anti-cancer agent. Unfortunately, until now, clinical trials remain disappointing, that could be the result of a lack of selectivity.

The antitumor properties of the alpha3(IV)-(185-203) peptide from the NC1 domain of type IV collagen (tumstatin) are conformation-dependent.

Tumor progression may be controlled by various fragments derived from noncollagenous 1 (NC1) C-terminal domains of type IV collagen. We demonstrated previously that a peptide sequence from the NC1 domain of the alpha3(IV) collagen chain inhibits the in vitro expression of matrix metalloproteinases in human melanoma cells through RGD-independent binding to alpha(v)beta(3) integrin. In the present paper, we demonstrate that in a mouse melanoma model, the NC1 alpha3(IV)-(185-203) peptide inhibits in vivo tumor growth in a conformation-dependent manner.

Upregulation of MMPs by soluble E-cadherin in human lung tumor cells.

Loss of E-cadherin/catenin mediated cell-cell adhesion and overexpression of matrix metalloproteinases (MMPs) are largely involved in tumor invasion. It has been recently shown that high levels of a soluble 80 kDa fragment of E-cadherin, resulting from a cleavage by MMPs, are found in serum and in urine from cancer patients. Additionally, this soluble E-cadherin (sE-CAD) promotes cell invasion into chick heart and into collagen type I gels.

Improved gelatinase a selectivity by novel zinc binding groups containing galardin derivatives.

The synthesis of several analogues of galardin, a MMP inhibitor, are presented with their in vitro inhibitory activity against MMP-1 and MMP-2. These compounds contain a distinct Zinc Binding Group (ZBG). Those having a 2-acylated-heterocycle as well as a 2-arylamide function do not exhibit a good inhibition/selectivity against the enzymes tested.

Cytotoxic bis-3,4-dihydro-beta-carbolines and bis-beta-carbolines.

Ten bis-beta-carboline 1, 2 and bis-3,4-dihydro-beta-carboline 3, 4 derivatives, linked between carbons 1 and 1' by a polymethylene spacer, were synthesized from bistryptamine amides 9, 10. Some of them display a micromolar IC50 towards L-1210 cells.