Homodimerization is important in signal transduction and can play a crucial role in many other biological systems. To obtaining structural information for the design of molecules able to control the ...signalization pathways, the proteins involved will have to be crystallized in complex with ligands that induce dimerization. Bi-functional drugs have been generated by linking two ligands together chemically and the relative crystallizability of complexes with mono-functional and bi-functional ligands has been evaluated. There are problems associated with crystallization with such ligands, but overall, the advantages appear to be greater than the drawbacks. The study involves two matrix metalloproteinases, MMP-12 and MMP-9. Using flexible and rigid linkers we show that it is possible to control the crystal packing and that by changing the ligand-enzyme stoichiometric ratio, one can toggle between having one bi-functional ligand binding to two enzymes and having the same ligand bound to each enzyme. The nature of linker and its point of attachment on the ligand can be varied to aid crystallization, and such variations can also provide valuable structural information about the interactions made by the linker with the protein. We report here the crystallization and structure determination of seven ligand-dimerized complexes. These results suggest that the use of bi-functional drugs can be extended beyond the realm of protein dimerization to include all drug design projects.
The preparation of 3-substituted tetrahydropyrazinoisoquinolines using the tributyltin hydride mediated intramolecular radical cyclization of suitably protected 2-substituted 3,4-dihydropyrazines is ...reported. The compounds are obtained as single enantiomers, as the relative configuration of the new generated stereogenic center is driven by the stereochemistry of the 2-substituted carbon in the starting materials, which is in turn derived from naturally occurring amino acids.
During the lead optimization of NK₁/NK₃ receptor antagonists program, a focused exploration of molecules bearing a lactam moiety was performed. The aim of the investigation was to identify the ...optimal position of the carbonyl and hydroxy methyl group in the lactam moiety, in order to maximize the in vitro affinity and the level of insurmountable antagonism at both NK₁ and NK₃ receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK₁/NK₃ activity, were reported in this paper.
The 2,2-difluorobenzodioxole moiety has been proposed in medicinal chemistry research as a potential metabolically more stable derivative of the benzodioxole fragment. Herein we present, to the best ...of our knowledge, the first synthesis of 4-chloro-2,2-difluoro1,3dioxole4,5-
cpyridine, a 5-aza-derivative of the 2,2-difluorobenzodioxole, from simple and cheap starting materials. The chlorine atom in position 4 could be useful for further functionalisation by cross coupling reactions.
The 2,2-difluorobenzodioxole moiety has been introduced in medicinal chemistry research as a potential metabolically more stable derivative of the benzodioxole fragment. Herein we present, to the best of our knowledge, the first synthesis of 4-chloro-2,2-difluoro1,3dioxole4,5-
cpyridine, a 5-aza-derivative of the 2,2-difluorobenzodioxole, from simple and cheap starting materials. The chlorine atom in position 4 could be useful for further functionalisation by cross coupling reactions.
The Simmon–Smith cyclopropanation of enantiomerically enriched dehydropiperazines is reported. The reaction is highly stereoselective and allowed us to prepare new, enantiomerically enriched ...3-substituted 2,5-diazabicyclo4.1.0heptane cores with high diastereomeric purity and a relative anti-configuration, which was assigned by NMR analysis.
During the lead optimization of NK sub(1/NK) sub(3) receptor antagonists program, a focused exploration of molecules bearing a lactam moiety was performed. The aim of the investigation was to ...identify the optimal position of the carbonyl and hydroxy methyl group in the lactam moiety, in order to maximize the in vitro affinity and the level of insurmountable antagonism at both NK sub(1 and NK) sub(3) receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK sub(1/NK) sub(3) activity, were reported in this paper.
During the lead optimization of NK
1/NK
3 receptor antagonists program, a focused exploration of molecules bearing a lactam moiety was performed. The aim of the investigation was to identify the ...optimal position of the carbonyl and hydroxy methyl group in the lactam moiety, in order to maximize the in vitro affinity and the level of insurmountable antagonism at both NK
1 and NK
3 receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK
1/NK
3 activity, were reported in this paper.
Starting from the potent MMP-2/MMP-14 inhibitor (
R)-
1 we describe new dimeric compounds of type
2, which are able to give an inhibitor–enzyme interaction more complex than that allowed for ...monomeric compounds of type
1 potentially, thus influencing positively the potency and/or selectivity of the new compounds, if compared with those of (
R)-
1.
Starting from the observation that the CbzNH(CH
2)
2 side chain of the potent MMP-2/MMP-14 inhibitor, benzyl-(3
R)-4-(hydroxyamino)-3-isopropoxy(1,1′-biphenyl-4yl-sulfonyl)amino-4-oxobutylcarbamate, (
R)-
1 lies in a hydrophobic region (S1) exposed to the solvent of the protease active site, we hypothesized that an aminoethylcarboxamido chain structurally related to that of (
R)-
1 might be an useful tool to bind another linker stretching out from the protein. This would be able to interact either with a enzyme region adjacent to the active site, or with other molecules of matrix metalloproteinases (MMPs), or other proteins of the extracellular matrix (ECM) that may be involved in the enzyme activation. On these basis we describe new dimeric compounds of type
2, twin hydroxamic acids, obtained by the joint of two drug entities of (
R)-
1 linked in P1 by extendable semirigid linkers. Type
2 compounds are potentially able to undergo more complex inhibitor–enzyme interactions than those occurring with monomeric compounds of type
1, thus influencing positively the potency, selectivity and/or cytotoxicity of the new compounds.
