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1.
Eur J Med Chem ; 85: 418-37, 2014 Oct 06.
Article in English | MEDLINE | ID: mdl-25108359

ABSTRACT

The 2'-deoxynucleoside 5'-phosphate N-hydrolase 1 (DNPH1) has been proposed as a new molecular target for cancer treatment. Here, we describe the synthesis of a series of novel 6-aryl- and 6-heteroarylpurine riboside 5'-monophosphates via Suzuki-Miyaura cross-coupling reactions, and their ability to inhibit recombinant rat and human DNPH1. Enzymatic inhibition studies revealed competitive inhibitors in the low micromolar range. Crystal structures of human and rat DNPH1 in complex with one nucleotide from this series, the 6-naphthylpurine derivative, provided detailed structural information, in particular regarding the possible conformations of a long and flexible loop wrapping around the large hydrophobic substituent. Taking advantage of these high-resolution structures, we performed virtual docking studies in order to evaluate enzyme-inhibitor interactions for the whole compound series. Among the synthesized compounds, several molecules exhibited significant in vitro cytotoxicity against human colon cancer (HCT15, HCT116) and human promyelocytic leukemia (HL60) cell lines with IC50 values in the low micromolar range, which correlated with in vitro DNPH1 inhibitory potency.


Subject(s)
Drug Design , Molecular Targeted Therapy , N-Glycosyl Hydrolases/antagonists & inhibitors , Nuclear Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Purine Nucleotides/chemical synthesis , Purine Nucleotides/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chemistry Techniques, Synthetic , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , Molecular Docking Simulation , N-Glycosyl Hydrolases/chemistry , N-Glycosyl Hydrolases/metabolism , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Protein Conformation , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins/metabolism , Purine Nucleotides/chemistry , Purine Nucleotides/metabolism , Rats , Structure-Activity Relationship
2.
PLoS One ; 8(11): e80755, 2013.
Article in English | MEDLINE | ID: mdl-24260472

ABSTRACT

The gene dnph1 (or rcl) encodes a hydrolase that cleaves the 2'-deoxyribonucleoside 5'-monophosphate (dNMP) N-glycosidic bond to yield a free nucleobase and 2-deoxyribose 5-phosphate. Recently, the crystal structure of rat DNPH1, a potential target for anti-cancer therapies, suggested that various analogs of AMP may inhibit this enzyme. From this result, we asked whether N (6)-substituted AMPs, and among them, cytotoxic cytokinin riboside 5'-monophosphates, may inhibit DNPH1. Here, we characterized the structural and thermodynamic aspects of the interactions of these various analogs with DNPH1. Our results indicate that DNPH1 is inhibited by cytotoxic cytokinins at concentrations that inhibit cell growth.


Subject(s)
Adenosine Monophosphate/pharmacology , N-Glycosyl Hydrolases/metabolism , Nuclear Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Amino Acid Sequence , Animals , Catalytic Domain , Enzyme Activation/drug effects , Humans , Kinetics , Models, Molecular , Molecular Conformation , Molecular Sequence Data , N-Glycosyl Hydrolases/chemistry , N-Glycosyl Hydrolases/genetics , Nuclear Proteins/chemistry , Nuclear Proteins/genetics , Protein Binding , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins/genetics , Rats , Sequence Alignment , Thermodynamics
3.
Acta Crystallogr D Biol Crystallogr ; 69(Pt 2): 247-55, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23385460

ABSTRACT

Rcl is a novel N-glycoside hydrolase found in mammals that shows specificity for the hydrolysis of 5'-monophosphate nucleotides. Its role in nucleotide catabolism and the resulting production of 2-deoxyribose 5-phosphate has suggested that it might fuel cancer growth. Its expression is regulated by c-Myc, but its role as an oncoprotein remains to be clarified. In parallel, various nucleosides have been shown to acquire pro-apoptotic properties upon 5'-monophosphorylation in cells. These include triciribine, a tricyclic nucleoside analogue that is currently in clinical trials in combination with a farnesyltransferase inhibitor. Similarly, an N(6)-alkyl-AMP has been shown to be cytotoxic. Interestingly, Rcl has been shown to be inhibited by such compounds in vitro. In order to gain better insight into the precise ligand-recognition determinants, the crystallization of Rcl with these nucleotide analogues was attempted. The first crystal structure of Rcl was solved by molecular replacement using its NMR structure in combination with distantly related crystal structures. The structures of Rcl bound to two other nucleotides were then solved by molecular replacement using the previous crystal structure as a template. The resulting structures, solved at high resolution, led to a clear characterization of the protein-ligand interactions that will guide further rational drug design.


Subject(s)
N-Glycosyl Hydrolases/chemistry , N-Glycosyl Hydrolases/metabolism , Nucleotides/chemistry , Oncogene Proteins/chemistry , Oncogene Proteins/metabolism , Acenaphthenes/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/genetics , Amino Acid Sequence , Amino Acid Substitution/genetics , Animals , Crystallization , Ligands , Molecular Sequence Data , N-Glycosyl Hydrolases/genetics , Nucleotides/genetics , Oncogene Proteins/genetics , Organophosphonates/chemistry , Phosphorylation , Protein Binding/genetics , Protein Interaction Mapping/methods , Rats , Ribonucleotides/chemistry , Ribonucleotides/genetics , Thionucleotides/chemistry , Thionucleotides/genetics , Thymidine/analogs & derivatives , Thymidine/chemistry , Thymidine/genetics , X-Ray Diffraction
4.
Chem Commun (Camb) ; 47(1): 253-5, 2011 Jan 07.
Article in English | MEDLINE | ID: mdl-20601994

ABSTRACT

N-alkylation of a novel pyridine sensor results in pyridinium salts whose conformations are stabilised by pyridinium cation-π interactions resulting in a fluorescent response that can be used to sense the presence of alkylating agents in solution at low concentration.


Subject(s)
Fluorescence , Fluorescent Dyes/chemistry , Hydrocarbons, Halogenated/analysis , Pyridines/chemistry , Alkylation , Cations/chemistry , Crystallography, X-Ray , Fluorescent Dyes/chemical synthesis , Models, Molecular , Molecular Structure , Pyridines/chemical synthesis , Solutions , Spectrometry, Fluorescence
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