Preclinical antitumor activity of 4′-thio-β-d-arabinofuranosylcytosine (4′-thio-ara-C)

Waud, William R.; Gilbert, Karen S.; Shepherd, R; Montgomery, John A.; Secrist, John A.

doi:10.1007/s00280-003-0589-9

Cited by 26 publications

(9 citation statements)

References 6 publications

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“…Typically, a stereoselective 1′,2′- cis relationship between the nucleobase and the C2′–F group in the furanoside series ( A ) is obtained through displacement of anomeric halo sugars (Scheme ). , However, to the best of our knowledge, no approach has been reported to provide high 1′,2′- cis selectivity in the corresponding thiofuranoside ( B ) series. − Thio scaffolds improve the pharmacokinetic profile of nucleoside analogues, as seen with T-AraC versus AraC, for solid tumors. , …”

Section: Introductionmentioning

confidence: 99%

“…5−7 Thio scaffolds improve the pharmacokinetic profile of nucleoside analogues, as seen with T-AraC versus AraC, for solid tumors. 8,9 Controlling the 1′,2′-trans stereochemistry (C) for C2′monofluorinated NAs is also particularly challenging due to the lack of possible C2-neighboring group participation. Nucleo-base addition results in variable 1′,2′-trans selectivity, 10−12 and their synthesis often relies on fluorination of preformed nucleoside analogues.…”

Section: ■ Introductionmentioning

confidence: 99%

“…This substitution reaction could be performed at 0 °C in DMSO instead of 25 °C in THF (entries 1 and 4 and entries 5 and 6) with a slight increase in selectivity. Different activating agents were examined to perform the substitution reaction with 9). The 1,2syn/anti ratio for nucleobase coupling to 2,3-anti-dithioacetal 14 could therefore be improved with a variation of the activating agent and solvent from 2:1 to 6:1 (entries 5 and 9) albeit with lower yields.…”

Section: ■ Introductionmentioning

confidence: 99%

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Diastereoselective Synthesis of C2′-Fluorinated Nucleoside Analogues Using an Acyclic Approach

et al. 2016

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Nucleoside analogues bearing a fluorine in the C2'-position have been synthesized by S2-like cyclizations of acyclic thioaminal precursors. This strategy provides access to two scaffolds, d-1',2'-cis-thiofuranosides and d-1',2'-trans-furanosides, which are difficult to generate using the standard approach for nucleoside synthesis. The addition of silylated nucleobases onto model C2-fluorinated dithioacetal substrates resulted in 1,2-syn diastereoselectivity, which is consistent with the C2-F and S-alkyl moiety being in close proximity. A new series of analogues bearing a C3' all-carbon quaternary center along with a C2'-F atom have also been synthesized using this approach and are being investigated as potential antimetabolites.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Diastereoselective Synthesis of C2′-Fluorinated Nucleoside Analogues Using an Acyclic Approach

et al. 2016

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“…OSI-7836 is most structurally similar to ara-C, differing only by a sulfur moiety in place of the oxygen in the arabinose sugar ring (Figure 1). However, OSI-7836 is functionally similar to gemcitabine, demonstrating broad spectrum activity in a variety of solid tumor mouse xenograft models, including lung, colon, renal, prostate, and breast cancers (Waud et al 1999(Waud et al , 2001). OSI-7836 has demonstrated inhibition of DNA polymerases and induction of G2/M arrest of the cell cycle (Blajeski et al 2002).…”

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confidence: 99%

Safety Assessment of 4′-Thio-β-d-Arabinofuranosylcytosine in the Beagle Dog Suggests a Drug-Induced Centrally Mediated Effect on the Hypothalamic-Pituitary-Adrenal Axis

Colagiovanni¹,

Drolet²,

Dihel³

et al. 2006

Int J Toxicol

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4'-Thio-beta-D-arabinofuranosylcytosine (OSI-7836) is a nucleoside analogue with structural similarity to gemcitabine and cytarabine (ara-C). Myelosuppression, reversible transaminase elevations, and flu-like symptoms are common side effects associated with human use of gemcitabine and ara-C. Fatigue is also associated with the use of gemcitabine and OSI-7836 in humans. To better understand the toxicity of OSI-7836, subchronic studies were conducted in dogs. OSI-7836 was administered on days 1 and 8 or on days 1, 2, and 3 of a 21-day dose regimen. These schedules attempted to match clinical trial dosing regimens. Routine toxicity study end points demonstrated that OSI-7836 was primarily cytotoxic to the gastrointestinal tract, bone marrow, and testes; the myelotoxicity was mild and reversible. Plasma pharmacokinetics were dose-linear with an elimination half-life of 2.2 h. Follow-up single dose experiments in dogs assessed drug effects on lymphocyte subpopulations and on adrenal and thyroid function. Populations of T and B cells were equally reduced following OSI-7836 administration. There were no adverse effects on thyroid function, but there were marked reductions in circulating cortisol and adrenocorticotropic hormone concentrations suggesting a centrally mediated impairment of the hypothalamic-pituitary-adrenal axis. These findings show a toxicological profile with OSI-7836 similar to other nucleoside analogues and suggest that the beagle is a model for studying one possible cause of OSI-7836-related fatigue, impaired function of the hypothalamic-pituitary-adrenal axis.

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“…Τέλος, η ένωση 1-(4΄-θείο-β-Dαραβινοφουρανοζυλο)κυτοσίνη (4΄-thio-araC) (Tiwari et al 2000, Waud et al 2003, Someya et al 2003, Secrist 2005, είναι στην παρούσα φάση σε στάδιο κλινικών μελετών.…”

Section: αντικαρκινικοί νουκλεοζίτεςunclassified

Βιοδραστικοί Ακόρεστοι Κετονουκλεοζίτες

Manta¹,

Μαντά²

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Preclinical antitumor activity of 4′-thio-β-d-arabinofuranosylcytosine (4′-thio-ara-C)

Cited by 26 publications

References 6 publications

Diastereoselective Synthesis of C2′-Fluorinated Nucleoside Analogues Using an Acyclic Approach

Diastereoselective Synthesis of C2′-Fluorinated Nucleoside Analogues Using an Acyclic Approach

Safety Assessment of 4′-Thio-β-d-Arabinofuranosylcytosine in the Beagle Dog Suggests a Drug-Induced Centrally Mediated Effect on the Hypothalamic-Pituitary-Adrenal Axis

Βιοδραστικοί Ακόρεστοι Κετονουκλεοζίτες

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