Publications by authors named "D Hockova"
Article Synopsis
- MYC is a critical driver of cancer that enhances gene expression and increases RNA production, contributing to tumor growth and survival.
- The study reveals that MYC triggers RNA degradation, leading to toxic byproducts that cause cancer cell death, indicating a new mechanism for targeting MYC-driven cancers.
- Therapeutic strategies that intensify the breakdown of RNA could serve as effective treatments for aggressive cancers like triple-negative breast cancer (TNBC) that rely on MYC.
Twelve N2'-branched acyclic nucleoside phosphonates and bisphosphonates were synthesized as potential inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT), the key enzyme in the purine salvage pathway for production of purine nucleotides. The chemical structures were designed with the aim to study selectivity of the inhibitors for PfHGXPRT over human HGPRT. The newly prepared compounds contain 9-deazahypoxanthine connected to a phosphonate group via a five-atom-linker bearing a nitrogen atom (N2') as a branching point.
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- - A new series of N-branched acyclic nucleoside phosphonates (aza-ANPs) was created using a specific chemical reaction, but the final versions were ineffective at entering cells and did not directly show anti-trypanosomal activity.
- - These compounds were found to inhibit a specific enzyme related to Trypanosoma brucei, with effective concentration (K values) ranging from 1.7-14.1 μM.
- - The prodrugs derived from these compounds showed promising anti-trypanosomal effects, particularly one derivative that was highly effective with an EC of 0.58 μM and also demonstrated some cytotoxic effects against cancer cell lines.
Article Synopsis
- Pathogens like certain spp. cannot produce purine nucleobases on their own and depend on host cells to acquire them for DNA/RNA synthesis, utilizing purine phosphoribosyltransferases (PRTs) as key enzymes in this process.
- Researchers synthesized 16 new acyclic nucleoside phosphonates, including several with unique chiral centers, to test their inhibitory effects on PRTs.
- The most effective inhibitor, bisphosphonate (,)-, demonstrated exceptional potency against both human and parasite 6-oxopurine PRTs, with a very low inhibition constant (2 nM), and its varying binding conformations explain its effectiveness and preference for targeting parasite enzymes over human ones (35-fold select
Some pathogens, including parasites of the genus Trypanosoma causing Human and Animal African Trypanosomiases, cannot synthesize purines de novo and they entirely rely on the purine salvage pathway (PSP) for their nucleotide generation. Thus, their PSP enzymes are considered as promising drug targets, sparsely explored so far. Recently, a significant role of acyclic nucleoside phosphonates (ANPs) as inhibitors of key enzymes of PSP, namely of 6-oxopurine phosphoribosyltransferases (PRTs), has been discovered.
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