Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase

Ferraris, Dana; Duvall, Bridget; Delahanty, Greg; Mistry, Bipin; Alt, Jesse; Rojas, Camilo; Rowbottom, Christopher; Sanders, Kristen M.; Schuck, Edgar; Huang, Kuan Chun; Redkar, Sanjeev; Slusher, Barbara; Tsukamoto, Takashi

doi:10.1021/jm401856k

Cited by 49 publications

(45 citation statements)

References 21 publications

(44 reference statements)

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“…45 In the case of nucleosides, a C-2′ fluoro group improves the stability of the anomeric linkage, which can be important for some nucleosides that degrade by anomeric cleavage under the acidic conditions of gastric fluids. 54 We have shown 1 and its derivatives to be extremely stable under strongly acidic conditions, while microsomal stability studies revealed little metabolism of 1 . Thus, we hypothesize that the C-2′ fluoro group likely decreases renal clearance.…”

Section: Resultsmentioning

confidence: 90%

Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

et al. 2015

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MbtA catalyzes the first committed biosynthetic step of the mycobactins, which are important virulence factors associated with iron acquisition in Mycobacterium tuberculosis. MbtA is a validated therapeutic target for antitubercular drug development. 5′-O-[N-(salicyl)sulfamoyl]adenosine (1) is a bisubstrate inhibitor of MbtA and exhibits exceptionally potent biochemical and antitubercular activity. However, 1 suffers from sub-optimal drug disposition properties resulting in a short half-life (t1/2), low exposure (AUC), and low bioavailability (F). Four strategies were pursued to address these liabilities including the synthesis of prodrugs, increasing the pKa of the acyl-sulfonyl moiety, modulation of the lipophilicity, and strategic introduction of fluorine into 1. Complete pharmacokinetic (PK) analysis of all compounds was performed. The most successful modifications involved fluorination of the nucleoside that provided substantial improvements in t1/2 and AUC. Increasing the pKa of the acyl-sulfonyl linker yielded incremental enhancements while modulation of the lipophilicity and prodrug approaches led to substantially poorer PK parameters.

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Section: Resultsmentioning

confidence: 90%

Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

et al. 2015

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“…Retroviral overexpression of CDA caused significant resistance to DAC in vitro (Eliopoulos et al, 1998 ), and increased CDA expression/activity in human males in vivo has been linked with a reduced half-life of AZA and DAC, and possibly worse outcomes in MDS patients (Mahfouz et al, 2013 ). In rhesus monkeys, co-administration of CDA inhibitors with DAC improved pharmacokinetic profile and boosted plasma levels (Ferraris et al, 2014 ). Thus, a rational to combine inhibitors of CDA with HMA exists (Karahoca & Momparler, 2013 ).…”

Section: Azanucleosides In Mds/amlmentioning

confidence: 99%

“…Thus, a rational to combine inhibitors of CDA with HMA exists (Karahoca & Momparler, 2013 ). The CDA inhibitor tetrahydrouridine (THU) was assessed in humans in the 1990s and is being revived in clinical trials, with or without second generation DNMT inhibitors (Ferraris et al, 2014 ; Marsh et al, 1993 ) ( Table 1 ). However, much care needs to be taken in titrating the dose of CDA inhibitors, as CDA downregulation was reported to be associated with toxic death in a patient exposed to the nucleoside analogue gemcitabine (Mercier et al, 2007 ).…”

Section: Azanucleosides In Mds/amlmentioning

confidence: 99%

Digging deep into “dirty” drugs – modulation of the methylation machinery

Pleyer

Greil

2015

Drug Metabolism Reviews

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DNA methylation and histone modification are epigenetic mechanisms that result in altered gene expression and cellular phenotype. The exact role of methylation in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remains unclear. However, aberrations (e.g. loss-/gain-of-function or up-/down-regulation) in components of epigenetic transcriptional regulation in general, and of the methylation machinery in particular, have been implicated in the pathogenesis of these diseases. In addition, many of these components have been identified as therapeutic targets for patients with MDS/AML, and are also being assessed as potential biomarkers of response or resistance to hypomethylating agents (HMAs). The HMAs 5-azacitidine (AZA) and 2′-deoxy-5-azacitidine (decitabine, DAC) inhibit DNA methylation and have shown significant clinical benefits in patients with myeloid malignancies. Despite being viewed as mechanistically similar drugs, AZA and DAC have differing mechanisms of action. DAC is incorporated 100% into DNA, whereas AZA is incorporated into RNA (80–90%) as well as DNA (10–20%). As such, both drugs inhibit DNA methyltransferases (DNMTs; dependently or independently of DNA replication) resulting in the re-expression of tumor-suppressor genes; however, AZA also has an impact on mRNA and protein metabolism via its inhibition of ribonucleotide reductase, resulting in apoptosis. Herein, we first give an overview of transcriptional regulation, including DNA methylation, post-translational histone-tail modifications, the role of micro-RNA and long-range epigenetic gene silencing. We place special emphasis on epigenetic transcriptional regulation and discuss the implication of various components in the pathogenesis of MDS/AML, their potential as therapeutic targets, and their therapeutic modulation by HMAs and other substances (if known). The main focus of this review is laid on dissecting the rapidly evolving knowledge of AZA and DAC with a special focus on their differing mechanisms of action, and the effect of HMAs on transcriptional regulation.

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“…To increase their potency, cytidine analogs have been studied in combination with inhibitors of cytidine deaminase (CDA), an enzyme mainly found in the gastrointestinal tract and liver involved in their inactivation by deamination, limiting their bioavailability. These compounds are tetrahydrouridine (THU) ( 9 ) or its improved deoxy- and difluorinated derivatives ( 10 and 11 ) [35]. Compound E7727 (structure not yet disclosed) is a CDA inhibitor tested in clinical trials (NCT02103478) in a combined formulation with ( 2 ) under the name ASTX727.…”

Section: Inhibition Of Dna Methylationmentioning

confidence: 99%

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

et al. 2017

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Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action.

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Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase

Cited by 49 publications

References 21 publications

Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

Digging deep into “dirty” drugs – modulation of the methylation machinery

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

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