1,2,3-Triazole-Containing Uracil Derivatives with Excellent Pharmacokinetics as a Novel Class of Potent Human Deoxyuridine Triphosphatase Inhibitors

Miyakoshi, Hitoshi; Miyahara, Seiji; Yokogawa, Tatsushi; Endoh, Kanji; Muto, Toshiharu; Yano, Wakako; Wakasa, Takeshi; Ueno, Hiroyuki; Chong, Khoon Tee; Taguchi, Junko; Nomura, Makoto; Takao, Yayoi; Fujioka, Akio; Hashimoto, Akihiro; Itou, Kenjirou; Yamamura, Keisuke; Shuto, Satoshi; Nagasawa, Hideko; Fukuoka, Masayoshi

doi:10.1021/jm3004174

Cited by 53 publications

(30 citation statements)

References 27 publications

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“…A diverse set of 1,5-triazole products can be found in these reports which cover a wide range of targets and target classes including various enzyme inhibitors, [203][204][205][206][207][208][209][210][211][212][213] kinases, [214][215][216][217] proteases, 110,112 antivirals 218 (see also chapter 5.3) G-protein coupled receptors (GPCRs), 219 ion channels, [220][221][222] heat shock proteins, 95 and tRNA ligands. 223 1,5-Triazole derivatives have shown activity against numerous cancer cell lines, 205,215,[224][225][226][227] and against the parasites Trypanosoma cruzi 70,228 and Plasmodium falciparum.…”

Section: Target-oriented Medicinal Chemistrymentioning

confidence: 99%

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

et al. 2016

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The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the 1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry and the construction of 2 electronic devices. This review discusses the mechanism, scope and applications of the RuAAC reaction, covering the literature during the last 10 years. CONTENTS

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Section: Target-oriented Medicinal Chemistrymentioning

confidence: 99%

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

et al. 2016

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“…Another example of augmenting the efficacy of antimetabolites is the use of small molecule inhibitors targeting dUTPase, which hydrolyses dUTP and 5-FdUTP, an active metabolite of 5-FU, to their monophosphate forms, thereby limiting their toxic incorporation into nascent DNA 58,77,78 . Hence, inhibitors of dUTPase can increase the efficacy of 5-FU 79,80 . A more recent target to improve cytotoxic therapies with thiopurines has emerged by discovering that the nudix enzyme family member NUDT15 can hydrolyse triphosphates of 6-thioguanine and mercaptopurine 81,82 .…”

Section: Future Perspectives–samhd1 and Beyondmentioning

confidence: 99%

SAMHD1 protects cancer cells from various nucleoside-based antimetabolites

et al. 2017

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Recently, we demonstrated that sterile α motif and HD domain containing protein 1 (SAMHD1) is a major barrier in acute myelogenous leukemia (AML) cells to the cytotoxicity of cytarabine (ara-C), the most important drug in AML treatment. Ara-C is intracellularly converted by the canonical dNTP synthesis pathway to ara-CTP, which serves as a substrate but not an allosteric activator of SAMHD1. Using an AML mouse model, we show here that wild type but not catalytically inactive SAMHD1 reduces ara-C treatment efficacy in vivo. Expanding the clinically relevant substrates of SAMHD1, we demonstrate that THP-1 CRISPR/Cas9 cells lacking a functional SAMHD1 gene showed increased sensitivity to the antimetabolites nelarabine, fludarabine, decitabine, vidarabine, clofarabine, and trifluridine. Within this Extra View, we discuss and build upon both these and our previously reported findings, and propose SAMHD1 is likely active against a variety of nucleoside analog antimetabolites present in anti-cancer chemotherapies. Thus, SAMHD1 may constitute a promising target to improve a wide range of therapies for both hematological and non-haematological malignancies.

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“…The interest in these enzymes is highly motivated on the one hand by the peculiar active site architecture and, on the other hand, by the possibility of using these dUTPases as targets for developing drugs against neoplastic, as well as infectious diseases [31,[56][57][58][59][60][61][62][63][64][65] [100]. All-b dUTPases also include monomeric dUTPases [40].…”

Section: All-b Dutpasementioning

confidence: 99%

Preventive DNA repair by sanitizing the cellular (deoxy)nucleoside triphosphate pool

2014

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The occurrence of modified bases in DNA is attributed to some major factors: incorporation of altered nucleotide building blocks and chemical reactions or radiation effects on bases within the DNA structure. Several enzyme families are involved in preventing the incorporation of noncanonical bases playing a 'sanitizing' role. The catalytic mechanism of action of these enzymes has been revealed for a number of representatives in clear structural and kinetic detail. In this review, we focus in detail on those examples where clear evidence has been produced using high-resolution structural studies. Comparing the protein fold and architecture of the enzyme active sites, two main classes of sanitizing deoxyribonucleoside triphosphate pyrophosphatases can be assigned that are distinguished by the site of nucleophilic attack. In enzymes associated with attack at the a-phosphorus, it is shown that coordination of the c-phosphate group is also ensured by multiple interactions. By contrast, enzymes catalyzing attack at the b-phosphorus atom mainly coordinate the a-and the b-phosphate only. Characteristic differences are also observed with respect to the role of the metal ion cofactor (Mg 2+ ) and the coordination of nucleophilic water. Using different catalytic mechanisms embedded in different protein folds, these enzymes present a clear example of convergent evolution.

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1,2,3-Triazole-Containing Uracil Derivatives with Excellent Pharmacokinetics as a Novel Class of Potent Human Deoxyuridine Triphosphatase Inhibitors

Cited by 53 publications

References 27 publications

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

SAMHD1 protects cancer cells from various nucleoside-based antimetabolites

Preventive DNA repair by sanitizing the cellular (deoxy)nucleoside triphosphate pool

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