Abstract
Our genomic DNA is under constant assault from endogenous and exogenous sources, which needs to be resolved to maintain cellular homeostasis. The eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1) catalyzes the hydrolysis of phosphodiester bonds that covalently link adducts to DNA-ends. Tdp1 utilizes two catalytic histidines to resolve a growing list of DNA-adducts. These DNA-adducts can be divided into two groups: small adducts, including oxidized nucleotides, RNA, and non-canonical nucleoside analogs, and large adducts, such as (drug-stabilized) topoisomerase- DNA covalent complexes or failed Schiff base reactions as occur between PARP1 and DNA. Many Tdp1 substrates are generated by chemotherapeutics linking Tdp1 to cancer drug resistance, making a compelling argument to develop small molecules that target Tdp1 as potential novel therapeutic agents. Tdp1’s unique catalytic cycle, which is centered on the formation of Tdp1-DNA covalent reaction intermediate, allows for two principally different targeting strategies: (1) catalytic inhibition of Tdp1 catalysis to prevent Tdp1-mediated repair of DNA-adducts that enhances the effectivity of chemotherapeutics; and (2) poisoning of Tdp1 by stabilization of the Tdp1- DNA covalent reaction intermediate, which would increase the half-life of a potentially toxic DNA-adduct by preventing its resolution, analogous to topoisomerase targeted poisons such as topotecan or etoposide. The catalytic Tdp1 mutant that forms the molecular basis of the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy best illustrates this concept; however, no small molecules have been reported for this strategy. Herein, we concisely discuss the development of Tdp1 catalytic inhibitors and their results.
Highlights
Tyrosyl-DNA phosphodiesterase I (Tdp1) is a eukaryotic DNA repair enzyme which is a member of the phospholipase D superfamily and hydrolyzes the phosphodiester bond that links an adduct to the end of a nicked DNA strand[1,2,3]
Tdp1 natural substrates can be divided into two groups: small adducts consisting of damaged nucleotides, DNA inserted ribonucleotides, and non-canonical nucleotide/nucleoside analogs, and large adducts including covalent protein-DNA adducts that are generated as a transient reaction intermediate by, for example, DNA topoisomerases and Tdp1, or protein fragments as a result of failed Schiff base linked proteins such as proteolytically processed poly (ADP-ribose) polymerase 1 (PARP1)-DNA adducts [Table 1]
These transient protein-DNA adducts can be stabilized by chemotherapeutics including camptothecins (CPT), epipodophyllotoxins, and local DNA perturbations introduced by, for example, irradiation and endogenously generated reactive oxygen species [Table 1]
Summary
Tyrosyl-DNA phosphodiesterase I (Tdp1) is a eukaryotic DNA repair enzyme which is a member of the phospholipase D superfamily and hydrolyzes the phosphodiester bond that links an adduct to the end of a nicked DNA strand[1,2,3]. These researchers synthesized their derivatives and evaluated the compounds in: (1) Tdp catalytic assay; (2) in silico docking; and (3) cell toxicity/growth inhibition studies They identified a wide variety of chemical scaffolds that include the Benzopentathiepines derivative 2-(Dibutylamino)-N(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)acetamide, which inhibits catalysis at high nanomolar concentrations and induces MCF7 cytotoxicity (IC50 ~ 28 μmol/L) via DNA fragmentation and apoptosis[62]. They combined a 7-hydroxycoumarin with monoterpenoid moieties resulting in 7-(((1S,5R)6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-2,3-dihydrocyclopenta[c]chromen-4(1H)-one that exhibits a high nanomolar catalytic inhibition (IC50 = 675 ± 7 nmol/L), a MCF7 CC50 of 180 nmol/L (in combination with CPT) and increased MCF7 CPT sensitivity, but had no effect on RPMI-8226 human multiple melanoma cells that maintain lower Tdp levels than MCF7 cells[63].
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