Deoxyuridine Analogs Research Articles

Fluorescent 2′-Deoxyuridine (dU) Analogue: Tropolonyl triazolyl-dU (tt-dU) Exhibits Solvatochromism/HeLa Cell Internalization and Its Triphosphate (tt-dUTP) Is Incorporated into DNA Enzymatically

AbstractThis era has witnessed the development and extensive application of modified nucleosides, including fluorescent nucleosides that clinically served humankind. Most fluorescent nucleoside analogues are derived from benzenoid aromatic scaffolds. However, the non-benzenoid aromatic moiety, tropolone, which exhibits unique hydrogen bonding and metal chelating properties, also occurs in nature. Recently, we introduced the tropolone unit at deoxyuridine through an ethyne linker and prepared its DNA analogues, which are fluorescent. This report describes the synthesis of a new troponyl triazolyl-dU (tt-dU) analogue, possessing a triazolyl linker, through click chemistry. tt-dU exhibits fluorescence with solvatochromism and enters into Hela cells without any cytotoxicity. Its triphosphate (tt-dUTP) was also synthesized and incorporated enzymatically into DNA, as shown in primer extension experiments. The unique photophysical properties and metal-chelating ability of the tropolone group make tt-dU a promising modified nucleoside.

Palladium-Catalyzed C-H Olefination for Nucleic Acid Production.

The palladium-catalyzed direct C-H olefination of unprotected uridine, 2'-deoxyuridine, uridine monophosphate, and uridine analogues are described here. This protocol provides an efficient, atom-economical, and environmentally friendly method for the introduction of an alkenyl group at the C5 position of the uracil without pre-functionalization. A series of C5-alkenylated uridine analogues, including some biologically significant compounds and potential pharmaceutical candidates, were synthesized with exposed hydroxyl groups on the ribose. © 2023 Wiley Periodicals LLC. Basic Protocol 1: The reaction of uridine, 2'-deoxyuridine, and sofosbuvir for the C-H olefination with methyl acrylate Basic Protocol 2: The reaction of uridine and 2'-deoxyuridine for the C-H olefination with styrene.

Why 6-Iodouridine Cannot Be Used as a Radiosensitizer of DNA Damage? Computational and Experimental Studies

Previous density functional theory (DFT) studies on 6-brominated pyrimidine nucleosides suggest that 6-iodo-2'-deoxyuridine (6IdU) should act as a better radiosensitizer than its 5-iodosubstituted 2'-deoxyuridine analogue. In this work, we show that 6IdU is unstable in an aqueous solution. Indeed, a complete disappearance of the 6IdU signal was observed during its isolation by reversed-phase high-performance liquid chromatography (RP-HPLC). As indicated by the thermodynamic characteristics for the SN1-type hydrolysis of 6IdU obtained at the CAM-B3LYP/DGDZVP++ level and the polarizable continuum model (PCM) of water, 6-iodouracil (6IU) was already released quantitatively at ambient temperatures. The simulation of the hydrolysis kinetics demonstrated that a thermodynamic equilibrium was reached within seconds for the title compound. To assess the reliability of the calculations carried out, we synthesized 6-iodouridine (6IUrd), which was, unlike 6IdU, sufficiently stable in an aqueous solution at room temperature. The activation barrier for the N-glycosidic bond dissociation in 6IUrd was estimated experimentally using an Arrhenius plot. The stabilities in water calculated for 6IdU, 6IUrd, and 5-iodo-2'-deoxyuridine (5IdU) could be explained by the electronic and steric effects of the 2'-hydroxy group present in the ribose moiety. Our studies highlight the issue of the hydrolytic stability of potentially radiosensitizing nucleotides which, besides having favorable dissociative electron attachment (DEA) characteristics, must be stable in water to have any practical application.

Synthesis of Aminotroponyl-/Difluoroboronyl Aminotroponyl Deoxyuridine Phosphoramidites.

This report describes the chemical synthesis of aminotroponyl-conjugated deoxyuridine analog (at-dU) and its difluoroboron complex (dfbat-dU) and their phosphoramidites by using the versatile phosphorylating reagent 2-Cyanoethyl N,N-diisopropylchlorophosphoramidite. Tropolone is a non-benzenoid aromatic bioactive natural fluorescent molecule, possessing intramolecular charge transfer and metal chelating properties with transition metal ions such as Cu2+/ Zn2+/ Ni2+ . Its synthetic derivatives, 2-aminotropones also exhibit unique bioactivities and are considered potential therapeutic drug candidate. Recently, the fluorescence properties of aminotropone has improved by complexing with difluoroboron residue that generates aminotroponyl-BODIPY analog. These could be employed for the synthesis of at-dU/dfbat-dU containing DNA oligonucleotides for designing the 11 B/19 F-NMR/fluorescence-based DNA probes. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of N-propargyl-2-aminotropone (2) and difluoroboronyl N-propargyl-2-aminotropone (3) molecules. Basic Protocol 2: Synthesis of N-propargyl-2-aminotroponyl deoxyuridinyl (at-dU) phosphoramidites (7). Basic Protocol 3: Synthesis of difluoroboronyl N-propargyl-2-aminotroponyl deoxyuridinyl (dfbat-dU) phosphoramidites (10).

The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2'-Deoxyuridine and Tubercidin Analogues.

Among the scarce validated drug targets against Chagas disease (CD), caused by Trypanosoma cruzi, the parasite's nucleoside salvage system has recently attracted considerable attention. Although the trypanocidal activity of tubercidin (7-deazapurine) has long been known, the identification of a class of 7-substituted tubercidin analogs with potent in vitro and in vivo activity and much-enhanced selectivity has made nucleoside analogs among the most promising lead compounds against CD. Here, we investigate the recently identified TcrNT2 nucleoside transporter and its potential role in antimetabolite chemotherapy. TcrNT2, expressed in a Leishmania mexicana cell line lacking the NT1 nucleoside transporter locus, displayed very high selectivity and affinity for thymidine with a Km of 0.26 ± 0.05 µM. The selectivity was explained by interactions of 2-oxo, 4-oxo, 5-Me, 3'-hydroxy and 5'-hydroxy with the transporter binding pocket, whereas a hydroxy group at the 2' position was deleterious to binding. This made 5-halogenated 2'-deoxyuridine analogues good substrates but 5-F-2'-deoxyuridine displayed disappointing activity against T. cruzi trypomastigotes. By comparing the EC50 values of tubercidin and its 7-substituted analogues against L. mexicana Cas9, Cas9ΔNT1 and Cas9ΔNT1+TcrNT2 it was shown that TcrNT2 can take up tubercidin and, at a minimum, a subset of the analogs.

Abstract B039: Development of a selective therapeutic intervention for p53 mutant for pancreatic adenocarcinoma

Abstract Genetic alterations in the tumor suppressor p53 gene (TP53) are found in over 70% of Pancreatic Adenocarcinoma (PAAD) and contribute to poor prognosis, cancer progression and metastasis. Existing treatment options for p53 mutant (p53mut) cancer are limited and there is an urgent need for better therapeutic interventions that can be greatly beneficial to a large proportion of patients with PAAD. Here we present a novel therapeutic strategy for selective targeting p53mut pancreatic tumors. Genomic data revealed that p53-deficient PAADs express high levels of DNA replication genes as well as genes involved in Base Excision (BER) and Mismatch (MMR) Repair, indicating activation of these mechanisms. Evaluation of BER activity by a novel methodology with a modified deoxyuridine analogue showed a significant dysregulation in BER mediated repair in p53mut cancer cells leading to accumulation of p53mut tumor cells in late S/G2 phase. By exploiting this defect, we found that treatment with a deoxyuridine analogue such as trifluorothymidine (TFT, a component of TAS102) resulted in accumulation of DNA breaks selectively in p53mut cells. A deoxyuridine analogue (TFT) did not block DNA replication but rather activated DNA repair leading to DNA breaks in p53mut cells whereas p53 wild type cells accumulated in G1 with minimal DNA damage. Further, we found that inhibition of poly (ADP) ribose polymerase (PARP) enhanced DNA damage and increased cell death selectively in p53mut tumor cells although PARP inhibitor alone was not effective. In contrast, the TAS102-PARPi did not induce DNA damage in the normal cells such as hTERT-immortalized Human Pancreatic Nestin Expressing cells (HPNE). A new TAS102-PARPi combination regimen demonstrated greater inhibition of tumor growth and improved the survival rates in p53mut PAAD xenograft models including Cell-Derived Xenograft (CDX) and Patient-Derived xenograft (PDX) models, compared to either drug alone without adverse effects in mice. Thus, this preclinical work identified a novel and immediately feasible strategy for p53mut disease that may improve treatment and the quality of life for a significant proportion of patients with PAAD while limiting toxic effects on normal tissues. Citation Format: Mohammed M. Alruwaili, Justin Zonneville, Mohammed A. Alqarni, Priyanka Rajan, Hannah Serio, Robert Straubinger, Christos Fountzilas, Andrei Bakin. Development of a selective therapeutic intervention for p53 mutant for pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B039.

Fluorescent DNA analog: 2-aminotroponyl-pyrrolyl-2’-deoxyuridinyl DNA oligo enhance fluorescence in DNA-duplex as compared to 2-aminotroponyl-ethynyl-2’-deoxyuridinyl DNA oligo

The nucleobase modified fluorescent DNA and RNA analogs are synthesized by the conjugation of aromatic scaffolds through linkers, comprising mostly ethyne/ethene or fused ring residues at the pyrimidine/purine ring. These scaffolds are mainly derived from the benzenoid aromatic molecules comprising electron withdrawing/donating characters. However, non-benzenoid aromatic scaffolds such as tropolone and related derivatives are constituents of various troponoid natural products. The conjugation of nucleobases with a troponyl moiety is underutilized for the synthesis of fluorescent DNA analogs. This report describes the synthesis and photophysical studies of 2-aminotroponyl conjugated deoxyuridine nucleosides and their DNA analogs. 2-Aminotropone derivatives are conjugated at the C-5 position of uridine through an ethynyl linker/pyrrolyl ring fusion and their DNA analogs. Their photophysical studies reveal that aminotroponyl deoxyuridine analogs exhibit solvent-dependent fluorescence properties. Moreover, pyrrolyl ring-fused aminotroponyl DNA oligonucleotides enhance the fluorescence after formation of duplexation with complementary sequences of native DNA oligonucleotides. Hence, these modified nucleosides and DNA are promising fluorescent analogs which could be useful to design the sequence-specific DNA probes.

Abstract P1-16-07: A synthetic lethality treatment strategy for p53 mutant breast cancer

Abstract Breast carcinomas commonly carry mutations in the tumor suppressor p53, while therapeutic efforts to target mutant p53 were largely unfruitful. Here we report preclinical data supporting a novel combination therapy strategy for treatment of p53-mutant cancers. Genomic data revealed a high expression activity of Base-Excision Repair (BER) pathways in p53-mutant breast cancers. We designed a new methodology for testing BER in live cells. The BER studies revealed a significant dysregulation in BER-mediated repair in p53-mutant cancer cells. Taken advantage in the BER defect, we developed a novel treatment strategy that specifically targets p53-mt cancers. We found that treatment with deoxyuridine analogues induced accumulation of DNA damage selectively in p53-mutant cells. Further, inhibitors of poly (ADP-ribose) polymerase (PARPi) greatly enhanced this response and increased cell death, although PARPi as a single agent was not effective. In contrast, normal cells responded to PARPi with activation of the p53-p21 axis and cell cycle arrest. Inactivation of p53 in p53 wild-type cell lines conferred the p53-mutant phenotype. Preclinical breast cancer studies revealed that the combination of deoxyuridine analogue with PARPi was more effective in inhibition of tumor growth and metastases than either drug alone. This work illustrates a novel combination therapy strategy that may improve survival rates and outcomes for thousands of breast cancer patients. Citation Format: Andrei Bakin, Justin Zonneville, Moyi Wang, Mohammed Alruwaili, Kevin Eng, Renuka Iyer, Ben Park, Christos Fountzilas. A synthetic lethality treatment strategy for p53 mutant breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-07.

Palladium-catalyzed C-H olefination of uridine, deoxyuridine, uridine monophosphate and uridine analogues.

The palladium-catalyzed oxidative C–H olefinations of uridine, deoxyuridine, uridine monophosphate and uridine analogues are reported herein. This protocol provides an efficient, atom-economic and environmentally friendly approach to the synthesis of biologically important C5-alkene modified uracil/uridine-containing derivatives and pharmaceutical candidates.

Selective therapeutic strategy for p53-deficient cancer by targeting dysregulation in DNA repair

Breast carcinomas commonly carry mutations in the tumor suppressor p53, although therapeutic efforts to target mutant p53 have previously been unfruitful. Here we report a selective combination therapy strategy for treatment of p53 mutant cancers. Genomic data revealed that p53 mutant cancers exhibit high replication activity and express high levels of the Base-Excision Repair (BER) pathway, whereas experimental testing showed substantial dysregulation in BER. This defect rendered accumulation of DNA damage in p53 mutant cells upon treatment with deoxyuridine analogues. Notably, inhibition of poly (ADP-ribose) polymerase (PARP) greatly enhanced this response, whereas normal cells responded with activation of the p53-p21 axis and cell cycle arrest. Inactivation of either p53 or p21/CDKN1A conferred the p53 mutant phenotype. Preclinical animal studies demonstrated a greater anti-neoplastic efficacy of the drug combination (deoxyuridine analogue and PARP inhibitor) than either drug alone. This work illustrates a selective combination therapy strategy for p53 mutant cancers that will improve survival rates and outcomes for thousands of breast cancer patients.

Abstract 1180: A novel synthetic lethality treatment strategy for metastatic breast cancer

Abstract Breast carcinomas commonly carry mutations in the tumor suppressor p53, while therapeutic efforts to target mutant p53 were largely unfruitful. Here we present preclinical data supporting a novel combination therapy strategy for treatment of p53-deficient cancers. Genomic data revealed a high expression activity of Base-Excision Repair (BER) pathways in p53-deficient breast cancers. However, we found that BER-mediated repair was significantly dysregulated in p53-mutant cancer cells. Treatment with deoxyuridine analogues induced accumulation of DNA damage in p53-mutant cells and inhibitors of poly (ADP-ribose) polymerase (PARPi) greatly enhanced this response. In contrast, normal cells responded to PARPi with activation of the p53-p21 axis and cell cycle arrest. Inactivation of either p53 or p21/CDKN1A in p53 wild-type cells conferred the p53-mutant phenotype. Preclinical breast cancer studies revealed that the combination of deoxyuridine analogue with PARPi was more effective in inhibition of tumor growth and metastases than either drug alone. This work illustrates a novel combination therapy strategy that may improve survival rates and outcomes for thousands of breast cancer patients. Citation Format: Justin Zonneville, Moyi Wang, Mohammed Alruwaili, Kevin Eng, Thomas Melendy, Ben Ho Park, Renuka Iyer, Christos Fountzilas, Andrei V. Bakin. A novel synthetic lethality treatment strategy for metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1180.

Validation of Plasmodium falciparum dUTPase as the target of 5\u2032-tritylated deoxyuridine analogues with anti-malarial activity

BackgroundMalaria remains as a major global problem, being one of the infectious diseases that engender highest mortality across the world. Due to the appearance of resistance and the lack of an effective vaccine, the search of novel anti-malarials is required. Deoxyuridine 5′-triphosphate nucleotido-hydrolase (dUTPase) is responsible for the hydrolysis of dUTP to dUMP within the parasite and has been proposed as an essential step in pyrimidine metabolism by providing dUMP for thymidylate biosynthesis. In this work, efforts to validate dUTPase as a drug target in Plasmodium falciparum are reported.MethodsTo investigate the role of PfdUTPase in cell survival different strategies to generate knockout mutants were used. For validation of PfdUTPase as the intracellular target of four inhibitors of the enzyme, mutants overexpressing PfdUTPase and HsdUTPase were created and the IC50 for each cell line with each compound was determined. The effect of these compounds on dUTP and dTTP levels from P. falciparum was measured using a DNA polymerase assay. Detailed localization studies by indirect immunofluorescence microscopy and live cell imaging were also performed using a cell line overexpressing a Pfdut-GFP fusion protein.ResultsDifferent attempts of disruption of the dut gene of P. falciparum were unsuccessful while a 3′ replacement construct could recombine correctly in the locus suggesting that the enzyme is essential. The four 5′-tritylated deoxyuridine analogues described are potent inhibitors of the P. falciparum dUTPase and exhibit antiplasmodial activity. Overexpression of the Plasmodium and human enzymes conferred resistance against selective compounds, providing chemical validation of the target and confirming that indeed dUTPase inhibition is involved in anti-malarial activity. In addition, incubation with these inhibitors was associated with a depletion of the dTTP pool corroborating the central role of dUTPase in dTTP synthesis. PfdUTPase is mainly localized in the cytosol.ConclusionThese results strongly confirm the pivotal and essential role of dUTPase in pyrimidine biosynthesis of P. falciparum intraerythrocytic stages.

Design and Development of a Two-Color Emissive FRET Pair Based on a Photostable Fluorescent Deoxyuridine Donor Presenting a Mega-Stokes Shift.

We report the synthesis and site-specific incorporation in oligodeoxynucleotides (ODNs) of an emissive deoxyuridine analog electronically conjugated on its C5-position with a 3-methoxychromone moiety acting as a fluorophore. When incorporated in ODNs, this fluorescent deoxyuridine analog exhibits remarkable photostability and good quantum yields. This deoxyuridine analog also displays a mega-Stokes shift, which allows for its use as an efficient donor for FRET-based studies when paired with the yellow emissive indocarbocyanine Cy3 acceptor.

3′-O- and 5′-O-Propargyl Derivatives of 5-Fluoro-2′-Deoxyuridine: Synthesis, Cytotoxic Evaluation and Conformational Analysis

ABSTRACTA series of new 3′-O- and 5′-O-propargyl derivatives of 5-fluoro-2′-deoxyuridine (1–4) was synthesized by means of propargyl reaction of properly blocked nucleosides (2,4), followed by the deprotection reaction with ammonium fluoride. The synthesized propargylated 5-fluoro-2′-deoxyuridine analogues (1–4) were evaluated for their cytotoxic activity in three human cancer cell lines: cervical (HeLa), oral (KB) and breast (MCF-7), using the sulforhodamine B (SRB) assay. The highest activity and the best SI coefficient in all of the investigated cancer cells were displayed by 3′-O-propargyl-5-fluoro-2′-deoxyuridine (1), and its activity was higher than that of the parent nucleoside. The other new compounds exhibited moderate activity in all of the used cell lines.

Synthesis and evaluation of C-5 modified 2′-deoxyuridine monophosphates as inhibitors of M. tuberculosis thymidylate synthase

A series of 5′-monophosphates of 5-substituted 2′-deoxyuridine analogs, which recently demonstrated in vitro substantial suppression of two strains of Mycobacterium tuberculosis growth (virulent laboratory H37Rv and multiple resistant MS-115), has been synthesized and evaluated as potential inhibitors of M. tuberculosis thymidylate synthases: classical (ThyA) and flavin dependent thymidylate synthase (ThyX). A systematic SAR study and docking revealed 5-undecyloxymethyl-2′-deoxyuridine 5′-monophosphate 3b, displaying an IC50 value against ThyX of 8.32μM. All derivatives lack activity against the ThyA. It can be assumed that the mechanism of action of 3b may be partially associated with the inhibition of the ThyX.

Conformation-sensitive nucleoside analogues as topology-specific fluorescence turn-on probes for DNA and RNA G-quadruplexes.

Development of probes that can discriminate G-quadruplex (GQ) structures and indentify efficient GQ binders on the basis of topology and nucleic acid type is highly desired to advance GQ-directed therapeutic strategies. In this context, we describe the development of minimally perturbing and environment-sensitive pyrimidine nucleoside analogues, based on a 5-(benzofuran-2-yl)uracil core, as topology-specific fluorescence turn-on probes for human telomeric DNA and RNA GQs. The pyrimidine residues of one of the loop regions (TTA) of telomeric DNA and RNA GQ oligonucleotide (ON) sequences were replaced with 5-benzofuran-modified 2′-deoxyuridine and uridine analogues. Depending on the position of modification the fluorescent nucleoside analogues distinguish antiparallel, mixed parallel-antiparallel and parallel stranded DNA and RNA GQ topologies from corresponding duplexes with significant enhancement in fluorescence intensity and quantum yield. Further, these GQ sensors enabled the development of a simple fluorescence binding assay to quantify topology- and nucleic acid-specific binding of small molecule ligands to GQ structures. Together, our results demonstrate that these nucleoside analogues are useful GQ probes, which are anticipated to provide new opportunities to study and discover efficient G-quadruplex binders of therapeutic potential.

Synergistic enhancement of 5-fluorouracil cytotoxicity by deoxyuridine analogs in cancer cells.

5-Fluorouracil (FU) is a halogenated nucleobase analog that is widely used in chemotherapy. Here we show that 5-hydroxymethyl-2'-deoxyuridine (hmUdR) synergistically enhances the activity of FU in cell lines derived from solid tumors but not normal tissues. While the cytotoxicity of FU and hmUdR was not directly related to the amount of the modified bases incorporated into cellular DNA, incubation with this combination resulted in dramatic increase in the number of single strand breaks in replicating cancer cells, leading to NAD-depletion as consequence of poly(ADP-ribose) synthesis and S phase arrest. Cell death resulting from the base/nucleoside combination did not occur by apoptosis, autophagy or necroptosis. Instead, the cells die via necrosis as a result of NAD depletion. The FU-related nucleoside analog, 5-fluoro-2'-deoxyuridine, also displayed synergy with hmUdR, whereas hmUdR could not be replaced by 5-hydroxymethyluracil. Among other 5-modified deoxyuridine analogs tested, 5-formyl-2'-deoxyuridine and, to a lesser extent, 5-hydroxy-2'-deoxyuridine, also acted synergistically with FU, whereas 5-hydroxyethyl-2'-deoxyuridine did not. Together, our results have revealed an unexpected synergistic interaction between deoxyuridine analogs and FU in a cancer cell-specific manner, and suggest that these novel base/nucleoside combinations could be developed into improved FU-based chemotherapies.

Development of environmentally sensitive fluorescent and dual emissive deoxyuridine analogues

We designed and developed fluorescent deoxyuridine analogues with strong sensitivity to hydration for the major groove labelling of DNA.

Synthesis and evaluation of 5′-modified thymidines and 5-hydroxymethyl-2′-deoxyuridines as Mycobacterium tuberculosis thymidylate kinase inhibitors

We report the synthesis of 5′-modified thymidines (16, 18, 21, 23) and 5,5′-bis-substituted 2′-deoxyuridine analogues (30, 47) as inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). These analogues were evaluated for their capacity to inhibit TMPKmt and solely two 5′-modified thymidines were found to possess moderate inhibitory activity. In addition, a feasibility study of protecting groups for the 5-CH2OH moiety of 2′-deoxyuridines is described that enables to introduce the desired 5′-modification.

Design, Synthesis, and Evaluation of 5′‐Diphenyl Nucleoside Analogues as Inhibitors of the Plasmodium falciparum dUTPase

Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for malaria. We previously reported some 5'-tritylated deoxyuridine analogues (both cyclic and acyclic) as selective inhibitors of the Plasmodium falciparum dUTPase. Modelling studies indicated that it might be possible to replace the trityl group with a diphenyl moiety, as two of the phenyl groups are buried, whereas the third is exposed to solvent. Herein we report the synthesis and evaluation of some diphenyl analogues that have lower lipophilicity and molecular weight than the trityl lead compound. Co-crystal structures show that the diphenyl inhibitors bind in a similar manner to the corresponding trityl derivatives, with the two phenyl moieties occupying the predicted buried phenyl binding sites. The diphenyl compounds prepared show similar or slightly lower inhibition of PfdUTPase, and similar or weaker inhibition of parasite growth than the trityl compounds.