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ABSTRACT: The present study describes the synthesis and pharmacological profiles of new olivacine related compounds, possessing a modified D ring. The impact of this modification has been evaluated with respect to the cytotoxic and in vivo antitumoral effects of these molecules and in comparison with parent S 16020-2 previously prepared and investigated in our laboratory. The D ring size and number of nitrogen atoms as well as the position of the aminoalkyl substituent have a profound impact on the cytotoxic and antitumoral profiles. Thus out of the prepared pyrazinocarbazole compounds, 2 is devoid of any substantial cytotoxic and antitumoral activities while the pyrimidocarbazole 3 has a similar profile compared to 1 (S 16020-2). L1210 and P388 in vivo antitumoral effects are lost for both imidazocarbazoles 4 and 5, but the former conserves an in vivo antitumoral effect on B16 melanoma, this effect being the largest in the series. Structural similarities and differences amongst the studied compounds could be evidenced by calculation of global properties such as molecular electrostatic potentials (MEP maps) and partition coefficients (logP), thus adding information on the impact of chemical changes on these two parameters known to influence biological behavior.
Bioorganic & Medicinal Chemistry 02/2005; 13(1):175-84. · 2.92 Impact Factor
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Biochimica et Biophysica Acta 04/2004; 1644(2-3):251-60. · 4.66 Impact Factor
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ABSTRACT: A structure-activity study was performed by synthesis on N,N'-disubstitution of 3-aminobenzo[c] and [d]azepin-2-one 2 and 3 to afford potent and specific farnesyl transferase inhibitors with low nM enzymatic and cellular activities.
Bioorganic & Medicinal Chemistry Letters 03/2004; 14(3):767-71. · 2.55 Impact Factor
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ABSTRACT: The synthesis and structure-activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16-F10 metastasis model and display very good pharmacokinetic parameters.
Journal of Medicinal Chemistry 09/2003; 46(18):3840-52. · 5.25 Impact Factor
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ABSTRACT: Three-dimensional models of ligand-receptor complexes based on site-directed mutagenesis experiments of the monoamine G protein-coupled receptors reveal the existence of three distinct drug binding sites inside the receptors. Here, we develop this “three-site” hypothesis and outline its implications for the modular design of ligands for monoamine GPCRs. Molecular models of receptor-ligand complexes are built for the 5-HT1A receptor where mutagenesis studies map three spatially distinct binding regions which correspond to the binding sites of the “small, one site-filling” ligands 5-HT, propranolol and 8-OH-DPAT, respectively. The models of the 5-HT1A ligand-receptor complexes provide a frame for the discussion of other ligand-receptor interactions, including α1 and β2 adrenoceptors, D1 and D2 dopamine, and 5-HT1D and 5-HT2A receptors, where mutagenesis and modelling studies also showed occupation of the corresponding three binding locations. All three binding sites are located within the highly conserved seven helix transmembrane domain of the receptor and overlap partially at the prominent Asp residue in TM3 which constitutes the benchmark anchor site for monoamine ligands. The analysis of the sequence similarity, for each binding site, among the monoamine GPCR superfamily shows that the three loci display different degrees of evolutionary conservation. This result suggests different roles for each of the binding sites in intrinsic receptor functions and provides additional insights for the design of ligand functionality and selectivity. The existence of three distinct binding sites is also reflected by the architecture of known high affinity ligands which crosslink two or three “one site-filling” fragments around a basic amino group. Typical ligands reported in the Cipsline/MDDR portfolio illustrate this point despite the occasional difficulty of attributing the individual ligand fragments to a specific receptor site. The database exploration illustrates the binding site promiscuity of some fragments which is particularly evident for symmetrical ligands and which has implications for 3D QSAR methods dependent on alignments. We propose to generate by deconvolution of known ligands three distinct databases of site-specific bioisosters which should provide keystones for the design of novel recomposed monoamine GPCR ligands. The systematic exploration of the “three site” hypothesis should open novel perspectives for the understanding of ligand recognition for this class of therapeutically important receptors.
Quantitative Structure-Activity Relationships 12/1999; 18(6):561 - 572.
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ABSTRACT: We report here on the synthesis and pharmacological properties of a new series of small linear and cyclic peptides derived from the five C-terminal amino acid residues of second-generation bradykinin receptor antagonists. Variations of the two first residues of the pentapeptide (Thi-Ser-d-Tic-Oic-Arg) were shown to modulate the biological activities of the analogs on bradykinin-induced smooth muscle contractions in rabbit jugular vein (RJV), a tissue preparation specific of the B2 bradykinin receptor. Several analogs showed pA2 values around 7 on this tissue preparation, and one cyclic compound, c[-Gly-Thi-d-Tic-Oic-Arg-], 24, in which Thi-Ser was replaced by Gly-Thi, displayed a pA2 of 7.4 on RJV. On the basis of these results, three cyclic molecules and their linear counterparts (compounds 22−24 and 4−6, respectively) were tested on human umbilical vein, a tissue specific of the human B2 receptor. The pKB values obtained for these compounds on these tissue preparations were equivalent to those obtained for the decapeptide NPC 567 (4.8 < pA2 < 5.1). NMR and molecular modeling studies performed on compound 24 clearly demonstrated a type II‘ β-turn structure. This analog may serve as a new lead for the design of nonpeptide ligands of the bradykinin B2 receptor subtype.
05/1996;
