35959-38-7

Usage

Chemical class

Pyrimidines

Analog of

Nucleoside thymidine

Use

Chemotherapeutic agent

Cancer types treated

Leukemia and lymphoma

Mechanism of action

Interferes with DNA synthesis in cancer cells

Potential use

Antiviral therapy against certain viruses (e.g., HIV)

Research status

Further research needed to understand mechanisms of action and potential applications in medicine

Upstream product

• 35959-37-6 5’-azido-2’,5’-dideoxyuridine 
• 1336-21-6 ammonium hydroxide 
• 964-26-1 2'-deoxyuridine-5'-monophosphate 
• 27999-47-9 ((2R,3S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate 
• 951-78-0 2'-deoxyuridine 

Downstream Products

• 859206-66-9 1-{(2R,4S,5R)-4-Hydroxy-5-[(trityl-amino)-methyl]-tetrahydro-furan-2-yl}-1H-pyrimidine-2,4-dione 
• 864948-86-7 [(2R,3S,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3-hydroxy-tetrahydro-furan-2-ylmethyl]-phosphoramidic acid diphenyl ester 
• 1277164-76-7 5'-[diphenyl-(5-pyrimidyl)methyl]amino-2',5'-dideoxyuridine 
• 859206-74-9 5'-(2-chlorotrityl)amino-2',5'-dideoxyuridine 
• 859206-63-6 5'-[diphenyl(4-pyridyl)methyl]amino-2',5'-dideoxyuridine 
• 859206-73-8 5'-(4-methoxytrityl)amino-2',5'-dideoxyuridine 
• 1340593-25-0 5'-(bis(4-fluorophenyl)methylamino)-2',5'-dideoxyuridine 
• 66-22-8 uracil 
• 1327273-80-2 UDP-5''-amino-2'',5''-dideoxy-α-D-ribose 
• 58-98-0 UDP 
• 56045-73-9 AIdUrd 
• 106929-02-6 2',5'-dideoxy-5'-(4-(fluorosulfonyl)benzamido)uridine 

Relevant academic research and scientific papers

Norepinephrine-Transporter-Targeted and DNA-Co-Targeted Theranostic Guanidines

High risk neuroblastoma often recurs, even with aggressive treatments. Clinical evidence suggests that proliferative activities are predictive of poor outcomes. This report describes syntheses, characterization, and biological properties of theranostic guanidines that target norepinephrine transporter and undergo intracellular processing, and subsequently their catabolites are efficiently incorporated into DNA of proliferating neuroblastoma cells. Radioactive guanidines are synthesized from 5-radioiodo-2′-deoxyuridine, a molecular radiotherapy platform with clinically proven minimal toxicities and DNA-targeting properties. The transport of radioactive guanidines into neuroblastoma cells is active as indicated by the competitive suppression of cellular uptake by meta-iodobenzylguanidine. The rate of intracellular processing and DNA uptake is influenced by the agent's catabolic stability and cell population doubling times. The radiotoxicity is directly proportional to DNA uptake and duration of exposure. Biodistribution of 5-[125I]iodo-3′-O-(?-guanidinohexanoyl)-2′-deoxyuridine in a mouse neuroblastoma model shows significant tumor retention of radioactivity. Neuroblastoma xenografts regress in response to the clinically achievable doses of this agent.

TARGETED PROTEIN DEGRADATION

This invention provides pharmaceutical protein degraders and E3 ubiquitin ligase binders for therapeutic applications as described further herein.

Functionalized C-nucleosides as remarkable RNA binders: Targeting of prokaryotic ribosomal A-site RNA

RNA represents an extremely promising and yet challenging therapeutic target. Here, we report the design of a series of C-nucleosides as original RNA binders. Some of them bind strongly and selectively to A-site prokaryotic ribosomal RNA.

Enzymatic Synthesis of the Ribosylated Glycyl-Uridine Disaccharide Core of Peptidyl Nucleoside Antibiotics

Muraymycins belong to a family of nucleoside antibiotics that have a distinctive disaccharide core consisting of 5-amino-5-deoxyribofuranose (ADR) attached to 6′-N-alkyl-5′-C-glycyluridine (GlyU). Here, we functionally assign and characterize six enzymes from the muraymycin biosynthetic pathway involved in the core assembly that starts from uridine monophosphate (UMP). The biosynthesis is initiated by Mur16, a nonheme Fe(II)- and α-ketoglutarate-dependent dioxygenase, followed by four transferase enzymes: Mur17, a pyridoxal-5′-phosphate (PLP)-dependent transaldolase; Mur20, an aminotransferase; Mur26, a pyrimidine phosphorylase; and Mur18, a nucleotidylyltransferase. The pathway culminates in glycosidic bond formation in a reaction catalyzed by an additional transferase enzyme, Mur19, a ribosyltransferase. Analysis of the biochemical properties revealed several noteworthy discoveries including that (i) Mur16 and downstream enzymes can also process 2′-deoxy-UMP to generate a 2-deoxy-ADR, which is consistent with the structure of some muraymycin congeners; (ii) Mur20 prefers l-Tyr as the amino donor source; (iii) Mur18 activity absolutely depends on the amine functionality of the ADR precursor consistent with the nucleotidyltransfer reaction occurring after the Mur20-catalyzed aminotransfer reaction; and (iv) the bona fide sugar acceptor for Mur19 is (5′S,6′S)-GlyU, suggesting that ribosyltransfer occurs prior to N-alkylation of GlyU. Finally, a one-pot, six-enzyme reaction was utilized to generate the ADR-GlyU disaccharide core starting from UMP.

MIBG ANALOGS AND USES THEREOF

Compounds and compositions for targeting cells expressing norepinephrine transporter, and methods of making and using the same. The compounds comprise MIBG analogs conjugated to active agents for treatment and/or diagnosis of various conditions, including neuroblastoma.

Modified 5'-Trityl Nucleosides as Inhibitors of Plasmodium falciparum dUTPase

2'-Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this Plasmodium falciparum enzyme. Herein we report further structure-activity studies; in particular, variations of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base. Compounds were tested against both the enzyme and the parasite. Variations of the 5'-trityl group and of the 3'-substituent were well tolerated and yielded active compounds. However, there is a clear requirement for the uracil base for activity, because modifications of the uracil ring result in loss of enzyme inhibition and significant decreases in antiplasmodial action. Fewer trips to the dUMP: dUTPase is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this P.falciparum enzyme. Herein we report further structure-activity studies of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base.

Biosynthetic origin and mechanism of formation of the aminoribosyl moiety of peptidyl nucleoside antibiotics

Several peptidyl nucleoside antibiotics that inhibit bacterial translocase I involved in peptidoglycan cell wall biosynthesis contain an aminoribosyl moiety, an unusual sugar appendage in natural products. We present here the delineation of the biosynthetic pathway for this moiety upon in vitro characterization of four enzymes (LipM-P) that are functionally assigned as (i) LipO, an l-methionine:uridine-5′-aldehyde aminotransferase; (ii) LipP, a 5′-amino-5′-deoxyuridine phosphorylase; (iii) LipM, a UTP:5-amino-5-deoxy-α-d-ribose-1-phosphate uridylyltransferase; and (iv) LipN, a 5-amino-5-deoxyribosyltransferase. The cumulative results reveal a unique ribosylation pathway that is highlighted by, among other features, uridine-5′-monophosphate as the source of the sugar, a phosphorylase strategy to generate a sugar-1-phosphate, and a primary amine-requiring nucleotidylyltransferase that generates the NDP-sugar donor.

Solid-phase synthesis and evaluation of TAR RNA targeted β-carboline-nucleoside conjugates

Four types of β-carboline-nucleoside conjugates were synthesized. The binding affinities of these β-carboline-nucleoside conjugates 4-11, 13 and 15 to TAR RNA were evaluated by affinity capillary electrophoresis. The data of binding affinities to TAR RNA show that conjugates 9 and 13 are stronger binders than the parent compound MC3. Computer modeling indicates that the β-carboline-nucleoside conjugate 13 can fit to the UCU three-nucleotide bulge region of TAR RNA. The Royal Society of Chemistry 2008.

Deoxyuridine triphosphate nucleotidohydrolase as a potential antiparasitic drug target

This paper describes a structure-activity study to identify novel, small-molecule inhibitors of the enzyme deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) from parasitic protozoa. The successful synthesis of a variety of analogues of dUMP is de

Synthesis of 2'-deoxyuridine and 5-fluoro-2'-deoxyuridine derivatives and evaluation in antibody targeting studies

Derivatives of 2'-deoxyuridine and of the anticancer agent 5-fluoro-2'- deoxyuridine (FdUR) were linked indirectly via a human serum albumin carrier (HSA) to the murine antiosteosarcoma monoclonal antibody 791T/36. Starting from the 2'-deoxyuridines 1a an