ABSTRACT
DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-phthaloyl-l-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to understand its interaction with DNMT. The indole, carboxylate, and phthalimide moieties were modified. Homologated and conformationally constrained analogues were prepared. The latter were synthesized from prolinohomotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found to be at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , Phthalimides/chemical synthesis , Tryptophan/analogs & derivatives , Catalytic Domain , Cell Line, Tumor , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/chemistry , Humans , Molecular Docking Simulation , Phthalic Acids/chemical synthesis , Phthalic Acids/chemistry , Phthalic Acids/pharmacology , Phthalimides/chemistry , Phthalimides/pharmacology , Stereoisomerism , Structure-Activity Relationship , Tryptophan/chemical synthesis , Tryptophan/chemistry , Tryptophan/pharmacologyABSTRACT
Hydrolysis of TA photoproduct leads to two derivatives presenting different formation kinetic profiles depending on the oligomer content. The formation efficiency of TA photoproducts in UV-C-irradiated DNA slightly exceeds the formation of the trans,syn cyclobutane pyrimidine dimer at TT sites.
Subject(s)
DNA/chemistry , Pyrimidine Dimers/chemistry , Hydrolysis , Photochemical Processes , Ultraviolet RaysABSTRACT
Using the analogue of TpT methylated at the 3'-end N3 position (Tpm3T), we demonstrate that when the oxetane/(6-4) pathway is precluded, water addition occurs at the 3'-end C6 position of the oxetane intermediate to provide its opening. Photoreversal of this (6-4) photoproduct C6 hydrate brings the first experimental evidence that the (6-4) photolyase repair can proceed through an oxetane intermediate.
Subject(s)
Deoxyribodipyrimidine Photo-Lyase/chemistry , Ethers, Cyclic/chemistry , Pyrimidine Dimers/chemistry , DNA/chemistry , DNA/metabolism , Deoxyribodipyrimidine Photo-Lyase/metabolism , Ethers, Cyclic/metabolism , Glycosides/chemistry , Glycosides/metabolism , Imines/chemistry , Imines/metabolism , Photochemistry , Pyrimidine Dimers/metabolismABSTRACT
Polycationic derivatives of polynorbornene with different non-cytotoxic counterions, have been prepared by organometallic polymerization of methyleneammonium norbornene and subsequent exchange of the counterion. In this paper the effect of the counterion on the polycationic polymer binding onto plasmid DNA was studied via different ethidium bromide assays, heparin displacement and protection against degradation by DNAse. According to the nature of the counterions and consequently the size of the polymer particles, their complexation with the DNA led to aggregates with variable binding affinity for the plasmid. The relative transfection efficiency of each polyplex was compared, on the basis of reporter gene expression, in cells in culture. The nature of the counterion was seen to affect gene delivery. The order of transfection efficiency of the counterions studied at equivalent charge ratios (NH3+/PO4-) is lactobionate, acetate, chloride. The results obtained with the polynorbornene methyleneammonium lactobionate and acetate are particularly encouraging.
