Nucleosides and nucleotides. 83. Design, synthesis, and antineoplastic activity of 2'-deoxy-2'-methylidenecytidine

Takenuki, Kenji; Matsuda, Akira; Ueda, Tohru; Sasaki, Takuma; Fujii, Akihiro; Yamagami, Keiji

doi:10.1021/jm00401a001

Cited by 74 publications

(30 citation statements)

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“…The dose-limiting toxicities of DMDC observed in these studies were grade 3 leucopenia, neutropenia, and thrombocytopenia. No tumor regression was reported as a result of DMDC treatment but long-lasting stability of disease was noted in 5 patients (van der Gaast et al, 1998a).…”

Section: Introductionmentioning

confidence: 97%

“…DMDC was designed and synthesized as a novel deoxycytidine analog and is structurally related to cytosine arabinoside (Ara-C) and gemcitabine (Takenuki et al, 1988). DMDC and gemcitabine are metabolized to mono-, di-, and triphosphate forms by deoxycytidine kinase after incorporation into cells.…”

Section: Introductionmentioning

confidence: 99%

“…DMDC and gemcitabine are metabolized to mono-, di-, and triphosphate forms by deoxycytidine kinase after incorporation into cells. DMDC triphosphate inhibits DNA synthesis (Takenuki et al, 1988;Ono et al, 1996) and DMDC diphosphate inhibits ribonucleotide reductase as a mechanismbased inhibitor (Baker et al, 1991). DMDC showed broad anticancer activities in murine leukemia and solid tumors and in human xenograft models such as lung cancer, melanoma, colon cancer, and pancreas cancers (Yamagami et al, 1991;Miwa et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…DMDC showed broad anticancer activities in murine leukemia and solid tumors and in human xenograft models such as lung cancer, melanoma, colon cancer, and pancreas cancers (Yamagami et al, 1991;Miwa et al, 1998). DMDC is reported to be resistant against cytidine (Cyd) deaminase from mouse kidney which metabolizes DMDC to the inactive form 2'-deoxy-2'-methylidineuridine (DMDU) although ara-C was highly deaminated by this enzyme (Takenuki et al, 1988). In addition, DMDC was highly effective in tumors with high levels of Cyd deaminase.…”

Section: Introductionmentioning

confidence: 99%

“…In the first clinical trial, neither once a week (200 to 450 mg/m 2 ) nor daily for 5 days (30 or 40 mg/m 2 ) intravenous administration revealed tumor suppression (Gemma et al, 1996). Various dose regimens of oral administration such as oncedaily for 1 week every 3 weeks, once-daily for 10 days every 4 weeks, and once-daily for 2 weeks every 4 weeks have been evaluated in Phase I trials (van der Gaast et al, 1998a and1998b;Masuda et al, 2000). The dose-limiting toxicities of DMDC observed in these studies were grade 3 leucopenia, neutropenia, and thrombocytopenia.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Dose Regimen on the Toxicity of 2'-Deoxy-2'-Methylidenecytidine (Dmdc) in Monkeys

Shindoh

Kawashima²,

Shishido³

et al. 2007

J. Toxicol. Sci.

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-2'-Deoxy-2'-methylidenecytidine (DMDC) is a potential anticancer deoxycytidine analog of cytosine arabinoside. Using monkeys, we conducted a 4-week toxicity study with toxicokinetics of DMDC at 1, 3, and 10 mg/kg/day and a dose-regimen study of three different schedules of once-daily administration (5 mg/kg/day) for 1 week every 2 weeks, 2 weeks every 4 weeks, and 3 weeks every 4 weeks. Deaths, myelosuppression, intestinal toxicity, and swelling of palm and sole skin were observed by oral DMDC treatment at 10 mg/kg/day in 4-week repeated toxicity study; however, no skin disorders have been reported in humans. No notable changes were observed at 1 and 3 mg/kg/day. The curves of dose vs. AUC and the AUC at MTD in monkey are similar to those in humans. In the dose-regimen study, all the toxicities were reversible but more severe toxicity was observed with the longer administration periods. One-week interruption showed sufficient recovery of decreased WBC in dosing regimens of 1-week-on/1-week-off and 2-weeks-on/2-weeks-off. A 2-week recovery period was almost sufficient for the recovery of decreased RBC, HCT, and skin disorders in the 2-weeks-on/2-weeks-off regimen. Therefore, once-daily for 2 weeks every 4 weeks was concluded to be the optimal dose regimen. In summary, myelosuppression, intestinal toxicity, and skin disorders were observed in DMDC treatment in monkeys, the relationship between AUC and toxicity in monkeys was close to that in humans, and in preclinical studies, it is advantageous to investigate optimal dose regimens using the appropriate species.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Dose Regimen on the Toxicity of 2'-Deoxy-2'-Methylidenecytidine (Dmdc) in Monkeys

Shindoh

Kawashima²,

Shishido³

et al. 2007

J. Toxicol. Sci.

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An Efficient Method for the Preparation of 1′α-Branched-Chain Sugar Pyrimidine Ribonucleosides from Uridine: The First Conversion of a Natural Nucleoside into 1′-Substituted Ribonucleosides

Kodama¹,

Shuto²,

Nomura³

et al. 2001

Chem. Eur. J.

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The 1'alpha-phenylselenouridine derivative 13 was successfully synthesized by enolization of the 3',5'-O-TIPDS-2'-ketouridine 8, and was subjected to a radical reaction with a vinylsilyl tether--an efficient procedure for preparing 1'alpha-branched-chain sugar pyrimidine nucleosides. Successive treatment of 8 with LiHMDS and PhSeCl in THF at < -70 degrees C gave the desired 1'-phenylseleno products in 85% yield as an anomeric mixture of the 1'alpha-product 11 and the 1'beta-product 12 (11/12= 2.5:1). Highly stereoselective reduction at the 2'-carbonyl of the 1'alpha-product 11 occurred from the beta-face by using NaBH4/CeCl3 in MeOH, and subsequent introduction of a dimethylvinylsilyl tether at the 2'-hydroxyl gave the radical reaction substrate 14. The photochemical radical atom-transfer reaction of 14 by using a high-pressure mercury lamp proceeded effectively in benzene to give the exo-cyclized PhSe-transferred product 18, in which (PhSe)2 proved to be essential as an additive for radical atom-transfer cyclization reactions. Subsequent phenylseleno-group elimination of 18 gave the sugar-protected 1'alpha-vinyluridine. With this procedure, 1'alpha-vinyluridine (22) and -cytidine (25), designed to be potential antitumor agents, were successfully synthesized. This study is the first example of functionalization at the anomeric 1'-position of a nucleoside by starting from a natural nucleoside to produce a ribo-type 1'-modified nucleoside.

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Methanesulfonic‐Acid‐Catalysed Ring Opening and Glycosylation of 1,2‐(Acetylcyclopropane)‐Annulated D‐Lyxofuranose

Wang

Zhang

et al. 2014

Eur J Org Chem

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Nucleosides and nucleotides. 83. Design, synthesis, and antineoplastic activity of 2'-deoxy-2'-methylidenecytidine

Cited by 74 publications

References 0 publications

Effect of Dose Regimen on the Toxicity of 2'-Deoxy-2'-Methylidenecytidine (Dmdc) in Monkeys

Effect of Dose Regimen on the Toxicity of 2'-Deoxy-2'-Methylidenecytidine (Dmdc) in Monkeys

An Efficient Method for the Preparation of 1′α-Branched-Chain Sugar Pyrimidine Ribonucleosides from Uridine: The First Conversion of a Natural Nucleoside into 1′-Substituted Ribonucleosides

Methanesulfonic‐Acid‐Catalysed Ring Opening and Glycosylation of 1,2‐(Acetylcyclopropane)‐Annulated D‐Lyxofuranose

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