Fluorouridine Derivatives Research Articles

4’-fluorouridine and its derivatives as potential COVID-19 oral drugs: a review

Background: Although vaccination is underway, antiviral drugs against coronavirus disease 2019 (COVID-19) are lacking. Remdesivir, a nucleoside analog that works by inhibiting the viral RNA-dependent RNA polymerase (RdRp), is the only fully approved antiviral for the treatment of COVID-19. However, it is limited to intravenous use and is usually recommended only for hospitalized patients with severe COVID-19; therefore, oral drugs that can be prescribed even to non-hospitalized patients are required. According to a recent study, 4′-fluoruridine, a nucleoside analog similar to remdesivir, is a promising candidate for COVID-19 oral therapy due to its ability to stall viral RdRp. Methods: We examined the antiviral activity of 4′-fluorouridine and compared it to other drugs currently in development. The current literature on 4′-fluorouridine's antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been compiled and discussed in this review. Results: The 4'-fluorouridine has antiviral activity against the respiratory syncytial virus, hepatitis C virus, lymphocytic choriomeningitis virus, and other RNA viruses, including SARS-CoV-2. In vitro studies have shown that SARS-CoV-2 is susceptible to 4'-fluorouridine, with the half-maximal effective concentration (EC50) of 0.2 to 0.6 M, and that the 4′-fluorouridine derivative, 4′-fluorouridine-5′-triphosphate, inhibited RdRp via a mechanism distinct from that of the already approved COVID-19 oral drug, molnupiravir. In addition, an in vivo study revealed that SARS-CoV-2 is highly susceptible to 4'-fluorouridine and was effective with a single daily dose versus molnupiravir administered twice daily. Conclusions: Concerns about the genetic effects of molnupiravir may be resolved by the use of 4′-fluorouridine and its derivative, which, unlike molnupiravir, do not alter genetics, but inhibit RdRp instead. Although they are currently considered as strong candidates, further studies are required to determine the antiviral activity of 4′-fluorouridine and its derivative against SARS-CoV-2 and their genetic effects on humans.

Synthesis and Conformational Analysis of Fluorinated Uridine Analogues Provide Insight into a Neighbouring-Group Participation Mechanism.

Fluorinated nucleoside analogues have attracted much attention as anticancer and antiviral agents and as probes for enzymatic function. However, the lack of direct synthetic methods, especially for 2′,3′-dideoxy-2′,3′-difluoro nucleosides, hamper their practical utility. In order to design more efficient synthetic methods, a better understanding of the conformation and mechanism of formation of these molecules is important. Herein, we report the synthesis and conformational analysis of a 2′,3′-dideoxy-2′,3′-difluoro and a 2′-deoxy-2′-fluoro uridine derivative and provide an insight into the reaction mechanism. We suggest that the transformation most likely diverges from the SN1 or SN2 pathway, but instead operates via a neighbouring-group participation mechanism.

Studies toward the oxidative and reductive activation of C–S bonds in 2′-S-aryl-2ʹ-thiouridine derivatives

Studies directed toward the oxidative and reductive desulfurization of readily available 2′-S-aryl-2′-thiouridine derivatives were investigated with the prospect to functionalize the C2′-position of nucleosides. The oxidative desulfurization-difluorination strategy was successful on 2-(arylthio)alkanoate surrogates, while extension of the combination of oxidants and fluoride sources was not an efficient fluorination protocol when applied to 2′-S-aryl-2′-thiouridine derivatives, resulting mainly in C5-halogenation of the pyrimidine ring and C2′-monofluorination without desulfurization. Cyclic voltammetry of 2′-arylsulfonyl-2′-deoxyuridines and their 2′-fluorinated analogues showed that cleavage of the arylsulfone moiety could occur, although at relatively high cathodic potentials. While reductive-desulfonylation of 2′-arylsulfonyl-2′-deoxyuridines with organic electron donors (OEDs) gave predominantly base-induced furan type products, chemical (OED) and electrochemical reductive-desulfonylation of the α-fluorosulfone derivatives yielded the 2′-deoxy-2′-fluorouridine and 2′,3′-didehydro-2′,3′-dideoxy-2′-fluorouridine derivatives. These results provided good evidence of the generation of a C2′-anion through carbon-sulfur bond cleavage, opening new horizons for the reductive-functionalization approaches in nucleosides.

Rapid Microwave‐Assisted Fluorination Yielding Novel 5′‐Deoxy‐5′‐fluorouridine Derivatives.

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The first synthesis of 1′-fluoronucleosides

The first synthesis of 1'-fluoronucleosides, which has long been synthetic targets as the potential antimetabolites, was achieved. Electrophilic fluorination of the 1'-position of a 1'-ketouridine derivative, followed by reduction of the 2'-keto-moiety, gave the protected 1'-fluorouridine derivative and its arabino-type congener. Alternatively, nucleophilic fluorination of a 1'-phenyselenouridine derivative with DAST/NBS produced the protected 1'-fluorouridine and its alpha-anomer.

Rapid microwave-assisted fluorination yielding novel 5′-deoxy-5′-fluorouridine derivatives

The preparation of 18F-labeled ligands for positron emission tomography (PET) and the subsequent imaging have to be completed within a half-life of the neutron-deficient isotope ( 18F = 110 min). In this paper, we report a rapid fluorination approach to obtain 5′-deoxy-5′-fluoro-substituted uracil nucleoside analogues. Nucleophilic substitution at the 5′-position of the nucleosides was achieved within 45 min providing excellent yields of 75–92% by application of microwaves.

Synthesis of 1′-fluorouracil nucleosides as potential antimetabolites

The first synthesis of 1′-fluoronucleosides, which has long been synthetic targets as the potential antimetabolites, was achieved. Electrophilic fluorination of the 1′-position occurred to form an anomeric mixture of 1′-fluorouridine derivatives, when the lithium enolate, prepared from 3′,5′- O-tetraisopropyldisiloxane-1,3-diyl (TIPDS)-protected 2′-ketouridine ( 10) and LiHMDS, was treated with an electrophilic fluorinating agent such as NFSI ( 13). Subsequent reduction of the 2′-keto-moiety of the resulting β-nucleoside gave the protected 1′-fluorouridine 16 and its arabino-type congener 17. Alternatively, nucleophilic fluorination was also successful. Thus, treatment of 2′,3′,5′-tri- O-acetyl-1′-phenylselenouridine ( 20) with DAST/NBS produced the 1′-fluorouridine triacetate ( 21) and its α-anomer 22.

Synthesis of pyrimidine 1′-fluoronucleosides

Treatment of the 1′-lithium enolate, prepared from a 2′-ketouridine derivative, with NFSI, followed by reduction of the 2′-keto-moiety gave the corresponding 1′-fluorouridine derivative and its arabino-type congener. Thus, the first synthesis of 1′-fluoronucleosides was achieved.

A Comparative Study of Uracil-DNA Glycosylases from Human and Herpes Simplex Virus Type 1

Uracil-DNA glycosylase (UNG) is the key enzyme responsible for initiation of base excision repair. We have used both kinetic and binding assays for comparative analysis of UNG enzymes from humans and herpes simplex virus type 1 (HSV-1). Steady-state fluorescence assays showed that hUNG has a much higher specificity constant (k(cat)/K(m)) compared with the viral enzyme due to a lower K(m). The binding of UNG to DNA was also studied using a catalytically inactive mutant of UNG and non-cleavable substrate analogs (2'-deoxypseudouridine and 2'-alpha-fluoro-2'-deoxyuridine). Equilibrium DNA binding revealed that both human and HSV-1 UNG enzymes bind to abasic DNA and both substrate analogs more weakly than to uracil-containing DNA. Structure determination of HSV-1 D88N/H210N UNG in complex with uracil revealed detailed information on substrate binding. Together, these results suggest that a significant proportion of the binding energy is provided by specific interactions with the target uracil. The kinetic parameters for human UNG indicate that it is likely to have activity against both U.A and U.G mismatches in vivo. Weak binding to abasic DNA also suggests that UNG activity is unlikely to be coupled to the subsequent common steps of base excision repair.

Irreversible cytotoxic effect of a novel lowly immunosuppressive antitumor fluorouridine derivative, UK-21.

Previously, we reported that the 5-fluorouridine derivative, 2',3',5'-tris-O-[N(2-n-propyl-n-pentanoylglycyl]-5-fluorouridine (UK-21), is a newly synthesized lowly immunosuppressive and potent antitumor drug in comparison with other fluorouridine derivatives such as 5-fluorouracil (5-FU), 5-fluorouridine (5-FUR) and 5-fluorodeoxyuridine (5-FUDR). In order to elucidate the molecular mechanism of antitumor activity of UK-21, we compared the effect of the four drugs on cell proliferation, cell cycle progression and macromolecular syntheses. When KB cells were subjected to a colony-forming inhibition assay designed to expose the cells to the drugs for 4-96 h and wash out, UK-21 and 5-FUR inhibited the colony formation at concentrations ranging from 0.01 to 0.1 microM, whereas 1-100 microM was needed for the cytotoxicity of 5-FU and 5-FUDR. By exposure for 24-48 h, all these drugs inhibited cell growth and caused accumulation of the cells in S or G2 phase at almost the same concentrations of 0.32-8 microM. These results suggest that the cytotoxic effects of UK-21 and 5-FUR are irreversible, while those of 5-FU and 5-FUDR are reversible. To confirm this, KB cells were treated with UK-21 and/or 5-FU for 1 h, and continued to be cultured for 1-7 days, resulting in the inhibition of the cell growth by UK-21 in a dose-dependent manner at concentrations of 10-100 microM, but not by 5-FU even at 100 microM. UK-21, 5-FUR and 5-FU showed a linear relationship between exposure time and IC50 in the colony formation assay with a slope of almost -1, but 5-FUDR did not, suggesting that UK-21, 5-FUR and 5-FU are cell cycle non-specific inhibitors, while 5-FUDR is a cell cycle-specific inhibitor. UK-21 and 5-FUR, but not 5-FU and 5-FUDR inhibited the incorporation of [3H]uridine into the acid insoluble fraction, while UK-21 and 5-FUDR, but not 5-FUR and 5-FU inhibited the incorporation of [3H]thymidine. These results suggest that irreversible cytotoxic effects of UK-21 like 5-FUR are exerted through inhibition of RNA synthesis.

Distribution to the brain, protein binding and physico-chemical properties of 5-substituted 3′-fluoro-uridine derivatives, studied by microdialysis

Distribution to the brain, protein binding and physico-chemical properties of 5-substituted 3′-fluoro-uridine derivatives, studied by microdialysis

Novel lowly immunosuppressive antitumor fluorouridine derivative, UK-21: antitumor activity and effect on humoral immune response in mice

Novel lowly immunosuppressive antitumor fluorouridine derivative, UK-21: antitumor activity and effect on humoral immune response in mice

Novel lowly immunosuppressive antitumor fluorouridine derivative, UK-21: antitumor activity and effect on humoral immune response in mice.

Our previous studies indicated that a newly synthesized 5-fluorouridine derivative, 2',3',5'-tris-O-[N-(2-n-propyl-n-pentanoyl)glycyl]-5-fluorouridine (UK-21), revealed its antitumor activity by being converted to 5-fluorouridine (5-FUR) and showed a low level of immunological side effects. However, the bioavailability of UK-21 given orally did not seem to be good. In the present study, we focused on the antitumor and immunosuppressive activities of UK-21 given i.p. to mice. UK-21 suppressed the growth of L-1210, P388 and EL4 leukemias inoculated i.v. into corresponding syngeneic mice and both the growth of Lewis lung carcinoma transplanted s.c. and its subsequent metastasis to the lung. UK-21 showed antitumor activity at doses almost 10 times lower than those of 5-fluorouracil (5-FU). The side effects of UK-21, especially on immune functions, were examined in comparison with those of 5-FUR, 5-FU, and cyclophosphamide (CY) at doses producing comparable antitumor activity. The suppressive effect of UK-21 on IgM and IgG antibody formation in mice immunized with ovalbumin was clearly weaker than that of 5-FUR, 5-FU, and CY. The suppressive effect of UK-21 on thymus weight was markedly weaker than that of 5-FU and CY. The reduction of WBC counts induced by UK-21 was also lower than that produced by any other agent. The results reported herein suggest the strong possibility of UK-21 being developed as a novel anticancer drug with cytotoxic mechanisms different from those of 5-FU. Our study also points to the chemical modification of 5-FUR as a feasible way of developing new anticancer drugs.

ChemInform Abstract: Synthesis and γ‐Radiolysis of 2′‐Deoxy‐5‐fluorouridine and 5‐ Fluorouridine Derivatives.

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4'-substituted nucleosides. 3. Synthesis of some 4'-fluorouridine derivatives.

4'-substituted nucleosides. 3. Synthesis of some 4'-fluorouridine derivatives.