Nucleosides and nucleotides. 94. Radical deoxygenation of tert-alcohols in 1-(2-C-alkylpentofuranosyl)pyrimidines: synthesis of (2'S)-2'-deoxy-2'-C-methylcytidine, an antileukemic nucleoside

Matsuda, Akira; Takenuki, Kenji; Sasaki, Takuma; Ueda, Tohru

doi:10.1021/jm00105a037

Cited by 51 publications

(27 citation statements)

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“…We have synthesized (2′S)-2′-deoxy-2′-C-methylcytidine (SMDC), (2′R)-2′-deoxy-2′-C-methylcytidine (RMDC), and (2′S)-2′-deoxy-2′-C-ethylcytidine (SEDC) from uridine to elucidate the steric requirement of the substituent at the 2′β-position of 2′-deoxycytidine. 15) Against mouse leukemic L1210 cells in vitro, SMDC was as potent as araC (Table 1) but RMDC was 150-fold less effective than SMDC, and SECD was ineffective at concentrations up to 100 µg/ml. Additionally, 2′deoxy-2′-(methylthio)-β-D-arabinofuranosylcytosine did not show any cytotoxicity toward mouse leukemic L5178Y cells in vitro at up to 100 µg/ml.…”

Section: (2′mentioning

confidence: 99%

Antitumor activity of sugar‐modified cytosine nucleosides

2004

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ucleoside antimetabolites, such as 1-β-D-arabinofuranosylcytosine (araC), 2-chloro-2′-deoxyadenosine (CldA), 9-β-D-arabinofuranosyl-2-fluoroadenine 5′-monophosphate (fludarabine, FaraAMP) and 2′-deoxy-2′,2′-difluorocytidine (gemcitabine, dFdC) ( Fig. 1), have been widely used not only as antileukemic agents, but also as antitumor agents against solid tumors.1) Like other nucleoside antimetabolites, such as antiviral agents, these nucleosides are not active components themselves, but have to be metabolically activated by phosphorylation. Therefore, two of the most important factors for effective clinical use are the substrate specificities of nucleoside kinases and the expression levels of the kinases in tumor tissues of patients. The target enzymes of the metabolized nucleotides are different. AraC 5′-triphosphate (araCTP) is incorporated into DNA, and becomes a trigger for apoptosis. 2-Chloro-2′-deoxyadenosine 5′-triphosphate (CldATP) is incorporated into DNA by DNA polymerase and also potently inhibits ribonucleotide reductase (RDR) in place of dATP.2) Fludarabine 5′-triphosphate (FaraATP) is incorporated into both DNA and RNA, causing inhibition of DNA and RNA polymerases. Moreover, FaraATP inhibits RDR as well as DNA ligase 1 and DNA primase.2) Gemcitabine 5′-diphosphate (dFdCDP) is a very potent inhibitor of RDR, and its corresponding 5′-triphosphate (dFdCTP) inhibits DNA polymerase.3) Such differences in target enzymes of nucleotide antimetabolites must be important for the activity against the target diseases. Therefore, further development of new types of nucleoside antimetabolites could be a very effective strategy for fighting tumors. In this review, we describe the design, in vitro cytotoxicity, in vivo antitumor activity, metabolism and mechanism of action of new sugarmodified cytosine nucleosides, such as (2′S)-2′-deoxy-2′-C-methylcytidine (SMDC), 1-(2-deoxy-2-methylene-β-D-erythropentofuranosyl)cytosine (DMDC), 1-(2-C-cyano-2-deoxy-1-β-D-arabino-pentofuranosyl)cytosine (CNDAC) and 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (ECyd), which we have been developing in our labs. 4) Deoxycytidine kinase-dependent chemotherapyIn mammalian cells and tissues, there are four nucleoside kinases, deoxycytidine kinase (dCK), thymidine kinase-1 (TK1), adenosine kinase (AK) and uridine/cytidine kinase (UCK), in cytosol and two nucleoside kinases, thymidine kinase-2 (TK2) and deoxyguanosine kinase (dGK), in mitochondria.5-7) Many of the antitumor nucleosides in clinical use, such as araC, CldA, dFdC and araG derivatives are phosphorylated by dCK to afford the corresponding 5′-monophosphates, which are further phosphorylated by nucleoside monophosphate kinases and then nucleoside diphosphate kinases (NDPK) (Fig. 2). Among the nucleoside kinases, dCK seems most suitable for activation of the above-described nucleosides to exhibit antitumor efficacy: 1) dCK is constitutively expressed at both the protein and mRNA levels, being unrelated to cell cycle regulation. 2) dCK has the broadest substrate specificity among...

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Section: (2′mentioning

confidence: 99%

Antitumor activity of sugar‐modified cytosine nucleosides

2004

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“…The CX bond (X CH 2 , O) at C(2') of 5',3'-blocked nucleosides is preferably attacked from the a-face due to steric hindrance of the heterocyclic base. It was demonstrated for 2'-oxo nucleosides by reduction [20] or nucleophilic addition [22] and for 2'-deoxy-2'-methyleneuridine by cis-hydroxylation [25]. We obtained also predominantly the (S)-isomer of the protected 2'-deoxy-2'-[(2-methoxyethoxy)amino]cytidine after 2'-oxime reduction.…”

Section: Results Andmentioning

confidence: 72%

“…synthesis of the key compound, 5',3'-protected 2'-oxocytidine 1. Oxidation of 5',3'-blocked ribonucleosides is usually carried out with CrO 3 /Py/AcOH [20], DessÀMartin periodinane [21] or under conditions of Swern oxidation [22]. DessÀMartin periodinane provides excellent results, but is not cost-effective.…”

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confidence: 99%

Synthesis of (2′S)‐ and (2′R)‐2′‐Deoxy‐2′‐[(2‐methoxyethoxy)amino] Pyrimidine Nucleosides and Oligonucleotides

Zatsepin¹,

Ivanova²,

Oretskaya

2004

Chemistry & Biodiversity

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Syntheses of specified 2'-modified nucleosides were achieved: a) via oximation of the 5',3'-blocked 2'-oxocytidine, followed by reduction, or b) by intramolecular nucleophilic addition of 3'-(2-methoxyethoxy)carbamate to the 2'-position with opening of O(2),2'-anhydrouridine. For the first time, 3'-phosphoroamidites of these 2'-modified nucleosides were successfully incorporated into oligonucleotides by solid-phase synthesis. Incorporation of 2'-modified nucleotides into oligodeoxyribonucleotides had a negative effect on the duplex T(m) values with the DNA or RNA complements. Nevertheless, modified nucleotides have shown good target recognition; the (S)-isomer binds preferably to RNA and the (R)-isomer to DNA. Both modified nucleosides significantly increased nuclease resistance of the oligodeoxyribonucleotides.

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“…8,9) Considerable attention has been focused on branched chain sugar nucleosides because of their biological importance. During the course of synthetic studies aiming to develop antitumor agents, our group has found that branched-chain sugar nucleosides [10][11][12][13][14][15][16] are promising antitumor drug candidates 17) such as 1-(2-deoxy-2-methylene-b-Derythro-pentofuranosyl)cytosine [18][19][20][21] (DMDC, Fig. 1, 1) and 1-(2-C-cyano-2-deoxy-b -D-arabino-pentofuranosyl)cytosine [22][23][24][25][26][27] (CNDAC, 2).…”

Section: Introductionmentioning

confidence: 99%

Fine Synthetic Nucleoside Chemistry Based on Nucleoside Natural Products Synthesis

Ichikawa

2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Synthetic nucleoside chemistry based on nucleoside natural products synthesis were described. First, a samarium diiodide (SmI 2 )-promoted aldol reaction with the use of a a-phenylthioketone as an enolate was developed. The characteristics of this reaction are that the enolate can be regioselectively generated and the aldol reaction proceeds under near neutral condition. This reaction is proved to be a powerful reaction for the synthesis of complex nucleoside natural products, and herbicidin B and fully protected tunicaminyluracil, which were undecose nucleoside natural products, were synthesized. Next, the synthetic methodology of the caprazamycins, which are promising antibacterial nucleoside natural products, was also developed by the strategy including b bselective ribosylation without using a neighboring group participation. Our synthetic route provided a range of key analogues with partial structures to define the pharmacophore. Simplification of the caprazamycins was further pursued to develop diketopiperazine analogs.

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Nucleosides and nucleotides. 94. Radical deoxygenation of tert-alcohols in 1-(2-C-alkylpentofuranosyl)pyrimidines: synthesis of (2'S)-2'-deoxy-2'-C-methylcytidine, an antileukemic nucleoside

Cited by 51 publications

References 4 publications

Antitumor activity of sugar‐modified cytosine nucleosides

Antitumor activity of sugar‐modified cytosine nucleosides

Synthesis of (2′S)‐ and (2′R)‐2′‐Deoxy‐2′‐[(2‐methoxyethoxy)amino] Pyrimidine Nucleosides and Oligonucleotides

Fine Synthetic Nucleoside Chemistry Based on Nucleoside Natural Products Synthesis

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