Design a syntéza 5,6-disubstituovaných uracilových derivátů jako účinných inhibitorů thymidinfosforylasy

We report on a series of novel 5,6-disubstituted uracils with significant inhibitory activity against human and Escherichia coli thymidine phosphorylases

Metalace 6-halo-2,4-dimethoxypyrimidinů jako klíčový krok pro syntézu biologicky aktivních sloučenin

Introduction of carbon substituents to the position C-5 and C-6 of uracil ring was performed by reaction of organometallic derivatives of uracil with electrophiles or by transition metal catalyzed cross-coupling reaction. Especially lithiathion was studied intensively

Karbocyklická analoga nukleosidů a nenukleosidové inhibitory thymidin fosforylasy

!ntroduction Analogues ofnucleic acid components belong to the most successful classes oftherapeutics. Extensive modifications ofnucreobases, nucreosides and nucleotides led to the discovery ofa huge group of compounds with remarkable biological activity. The most important are perhaps the effects on various severe diseases such as cancer, leukemia or viral infectrons. The essential aim ofthis Thesis was the preparation ofbiologically active compounds related to the nucleic acid components. Since the carbocyclic anďogues ofnucleosides have been a long-time interest of our group, the first part of this work was devoted to the development of practical synthetic routes towards their new derivatives and to the synthesis of the novel analogues for further biological activity screening. However, the preliminary biological tests of the prepared compounds uncovered very promising lead to the compretely different field than it was expected. During the primer studies, I synthesized several 5,6-disubstituted uracils, initially prepared just as moder compounds for development of nover synthetic approaches towards carbocyclic nucleosides, that showed to posses outstanding inhibitory activity against thymidine phosphorylase. Therefore, the development of novel derivatives based on these findings was estabrished as a new...Uvod Anďoga nukleových kyselin patří bezesporu k nejúspěšnějšímťídámléčiv.Rozsáhlé obměny přirozených nukleobází, nukleosidů i nukleotidů ved|y k objevu řady sloučenin s mimořádnou biologickou aktivitou. Některé ztéchto|átek se uplatňují při léčbětakzávažnýchonemocněni jakoje rakovin4 leukemie nebo nemoci virového původu ZáMadnim cílem této dizertačnípráce byla příprava biologicky účinných|túek na báni komponent nuk|eových kyse'in. Prvníčást by|a věnována výoji účinnýchmetod syntézy karbocykliclcých analogů nukleosidů a jejich vyuŽití k získánínových derivatů ur&ných k předběžným testům bio'ogické aktivity. V pruběhu řešení této problematiky jsem přrpravil několik jednoduchých 5'.-substituovaných uracilových derivátů, zpÍvu pouzemodetoqých Iátek při zavádění noých syntetických metod pro připra* karbocyk|ických derrvátů nukleosidů, které vykazova|y značnouinhibiění aktivifu vůčithynidin fosforylfue. Příprava vhodných nových látek s touto strukurou se proto stala nov],Ím prioritním cíIem této priíce. s tímby|a přirozeně spojena také nutnost vývoje nových synteticlcýcb metod přípravy rozsáh|ejších skupin takovýchto sloučenin.Department of Organic ChemistryKatedra organické chemieFaculty of SciencePřírodovědecká fakult

Carbocyclic analogues of nucleosides and nonnucleoside inhibitors of thymidine phosphorylase

!ntroduction Analogues ofnucleic acid components belong to the most successful classes oftherapeutics. Extensive modifications ofnucreobases, nucreosides and nucleotides led to the discovery ofa huge group of compounds with remarkable biological activity. The most important are perhaps the effects on various severe diseases such as cancer, leukemia or viral infectrons. The essential aim ofthis Thesis was the preparation ofbiologically active compounds related to the nucleic acid components. Since the carbocyclic anďogues ofnucleosides have been a long-time interest of our group, the first part of this work was devoted to the development of practical synthetic routes towards their new derivatives and to the synthesis of the novel analogues for further biological activity screening. However, the preliminary biological tests of the prepared compounds uncovered very promising lead to the compretely different field than it was expected. During the primer studies, I synthesized several 5,6-disubstituted uracils, initially prepared just as moder compounds for development of nover synthetic approaches towards carbocyclic nucleosides, that showed to posses outstanding inhibitory activity against thymidine phosphorylase. Therefore, the development of novel derivatives based on these findings was estabrished as a new..

Novel conformationally locked nucleosides and nucleotides

We report on a synthesis of two novel types of conformationally locked nucleoside analogues. We prepared 7 membered ring 3’,5’-bridged nucleoside analogs locked in a Southern conformation. These nucleoside analogues were converted in one pot to appropriate phosphoramidate prodrugs using boronate methodology. We also devised and prepared a novel carbocyclic nucleoside by replacing furanose with cyclohexene that resulted in a locked Northern conformation similar to LNA monomers. Further details on the biological activity and application for oligonucleotide synthesis will be discussed in detail

Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin

SARS-CoV-2 expresses a 2′-O RNA methyltransferase (MTase) that is involved in the viral RNA cap formation and therefore a target for antiviral therapy. Here the authors provide the structure of nsp10-nsp16 with the panMTase inhibitor sinefungin and report that the development of MTase inhibitor therapies that target multiple coronoaviruses is feasible

High-Throughput Fluorescent Assay for Inhibitor Screening of Proteases from RNA Viruses

Spanish flu, polio epidemics, and the ongoing COVID-19 pandemic are the most profound examples of severe widespread diseases caused by RNA viruses. The coronavirus pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demands affordable and reliable assays for testing antivirals. To test inhibitors of viral proteases, we have developed an inexpensive high-throughput assay based on fluorescent energy transfer (FRET). We assayed an array of inhibitors for papain-like protease from SARS-CoV-2 and validated it on protease from the tick-borne encephalitis virus to emphasize its versatility. The reaction progress is monitored as loss of FRET signal of the substrate. This robust and reproducible assay can be used for testing the inhibitors in 96- or 384-well plates

Synthesis of C-6-substituted uridine phosphonates through aerobic ligand-free Suzuki-Miyaura cross-coupling

An efficient protocol for the construction of C-6-(hetero)aryl-substituted uridine phosphonate analogues utilizing an aerobic, ligand-free Suzuki-Miyaura cross-coupling reaction of a 6-iodo-precursor in aqueous media has been established. The method presents a modular approach toward the target compounds as demonstrated by the synthesis of a small library comprising 14 novel nucleoside phosphonates