Helicobacter pylori (Hp) is a human pathogen that lives in the gastric mucosa of approximately 50% of the world's population causing gastritis, peptic ulcers, and gastric cancer. An increase in resistance to current drugs has sparked the search for new Hp drug targets and therapeutics. One target is the disruption of nucleic acid production, which can be achieved by impeding the synthesis of 6-oxopurine nucleoside monophosphates, the precursors of DNA and RNA. These metabolites are synthesized by Hp xanthine-guanine-hypoxanthine phosphoribosyltransferase (XGHPRT). Here, nucleoside phosphonates have been evaluated, which inhibit the activity of this enzyme with Ki values as low as 200 nM. The prodrugs of these compounds arrest the growth of Hp at a concentration of 50 μM in cell-based assays. The kinetic properties of HpXGHPRT have been determined together with its X-ray crystal structure in the absence and presence of 9-[(N-3-phosphonopropyl)-aminomethyl-9-deazahypoxanthine, providing a basis for new antibiotic development.
- MeSH
- antibakteriální látky chemie metabolismus farmakologie terapeutické užití MeSH
- bakteriální proteiny chemie metabolismus MeSH
- gastrointestinální nemoci farmakoterapie mikrobiologie patologie MeSH
- Helicobacter pylori účinky léků enzymologie MeSH
- hypoxanthinfosforibosyltransferasa chemie metabolismus MeSH
- hypoxanthiny chemie metabolismus farmakologie terapeutické užití MeSH
- infekce vyvolané Helicobacter pylori farmakoterapie patologie MeSH
- kinetika MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- organofosfonáty chemie metabolismus farmakologie terapeutické užití MeSH
- pentosyltransferasy chemie metabolismus MeSH
- prekurzory léčiv chemie metabolismus farmakologie terapeutické užití MeSH
- sekvence aminokyselin MeSH
- sekvenční seřazení MeSH
- simulace molekulární dynamiky MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The gold(I) mixed-ligand complexes involving O-substituted derivatives of 9-deazahypoxanthine (HLn) and triphenylphosphine (PPh3) with the general formula [Au(Ln)(PPh3)] (1-5) were prepared and thoroughly characterized by elemental analysis, FT-IR and multinuclear NMR spectroscopy, ESI+ mass spectrometry, single crystal X-ray (HL5 and complex 2) and TG/DTA analyses. Complexes 1-5 were evaluated for their in vitro antitumor activity against nine human cancer lines, i.e. MCF7 (breast carcinoma), HOS (osteosarcoma), A549 (adenocarcinoma), G361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) and THP-1 (monocytic leukaemia), for their in vitro anti-inflammatory activity using a model of LPS-activated macrophages, and for their in vivo antiedematous activity by λ-carrageenan-induced hind paw edema model on rats. The results showed that the complexes 1-5 exhibit selective in vitro cytotoxicity against MCF7, HOS, 22Rv1, A2780 and A2780R, with submicromolar IC50 values for 2 against the MCF7 (0.6 µM) and HOS (0.9 µM). The results of in vitro cytotoxicity screening on primary culture of human hepatocytes (HEP220) revealed up to 30-times lower toxicity of compounds against healthy cells as compared with cancer cells. Additionally, the complexes 1-5 significantly influence the secretion and expression of pro-inflammatory cytokines TNF-α and IL-1β by a similar manner as a commercially used anti-arthritic drug Auranofin. The tested complexes also significantly influence the rate and overall volume of the edema, caused by the intraplantar application of λ-carrageenan polysaccharide to rats. Based on these promising results, the presented compounds could qualify to become feasible candidates for advanced testing as potential antitumor and anti-inflammatory drug-like compounds.
- MeSH
- antiflogistika chemie farmakologie terapeutické užití MeSH
- antitumorózní látky chemie farmakologie terapeutické užití MeSH
- edém farmakoterapie MeSH
- hepatocyty účinky léků MeSH
- hypoxanthiny chemie farmakologie terapeutické užití MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- zánět farmakoterapie MeSH
- zlato chemie farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
