Studies on antitumor agents. VI. Syntheses and antitumor activities of acyl derivatives of 2'-deoxy-5-trifluoromethyluridine.

Yamashita, Jun‐ichi; Takeda, Setsuo; Matsumoto, Hiroshi; Terada, T.; Unemi, Norio; Yasumoto, M.

doi:10.1248/cpb.35.2090

Cited by 8 publications

(10 citation statements)

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“…Of the 34 compounds tested, 20 achieved an ILS of 50% or more in the SI80a screen. While these compounds displayed activities comparable to or greater than that obtained with cisplatin, they were from 2.5 to potency were cis-[Pt(NH3)2(7V7-pyridine)Cl]Cl (1), cis-[Pt(NH3)2(7V7-4-chloropyridine)Cl]Cl (7), cis-[Pt(NH3)2-(M3-cytosine)Cl]Cl (10), cis-[Pt(NH3)2(7V7-4-methylpyridine)Cl]Cl (11), cis-[Pt(NH3)2(/V7-4-bromopyridine)-C1]C1 (13), and c¿s-[Pt(NH3)2(iV7-2,-deoxyguanosine)Cl]Cl (23). In a few cases, relatively minor structural changes were found to produce inactivity in this series.…”

Section: Resultsmentioning

confidence: 96%

“…cis-[Pt(NH3)2(N3-cytosine)Cl]Cl (10) -2379 ci's-[Pt(NH3)2(7V3-l-Me-cytosine)Cl]Cl (16) -2365 cis-[Pt(NH3)2(iV3-5-Me-cytosine)Cl]Cl (17) -2358 cis-[Pt(NH3)2(7V9-DHPT)Cl] (N03) (18) -2234 cis-[Pt(NH3)2(M3-cytidine)Cl] (N03) (19) -2358 cis-[Pt(NH3)2(7V7-guanosine)Cl] (N03) (20) -2290 cis-[Pt(NH3)2(7V3-2'-deoxycytidine)Cl]Cl (21) -2357 cis-[Pt(NH3)2(JV3-ara-C)Cl] (N03) (22) -2355 cis-[Pt(NH3)2(N7-2'-deoxyguanosine)Cl]Cl (23) -2280…”

Section: Resultsmentioning

confidence: 99%

“…One member of the series, cis-[Pt(NH3)2(Ar3-cytosine)-C1]C1 (10), was chosen for X-ray crystallographic studies in an attempt to determine which of the two potential binding sites on the cytosine ligand, N1 or N3, is attached to platinum. As illustrated in Figure 1, the results of these studies show that the metal is bound to the N3 site.…”

Section: Resultsmentioning

confidence: 99%

“…Of the 16 platinum-triamine complexes that were tested in the L1210 leukemia screen, 4 [Pt(NH3)2(7V3-cytosine)Cl]Cl (10), were also screened and found active vs P388 leukemia. While all of the platinum-triamine complexes were less active and less potent than cisplatin in these screens, the best combination of activity and potency was observed with the pyridine (1), 4-bromopyridine (13), and 4-methylpiperidine (24) analogues.…”

Section: Resultsmentioning

confidence: 99%

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Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor) Cl]+

Hollis¹,

Amundsen²,

Stern³

1989

J. Med. Chem.

242

168

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A series of 32 cationic platinum(II) complexes of the form cis-[PtA2(Am)Cl]+, where A is a monodentate (NH3 or i-PrNH2) or A2 is a bidentate (ethylenediamine or 1,2-diaminocyclohexane) amine and Am is either a heterocyclic amine based on a pyridine, pyrimidine, purine, piperidine, or a saturated amine (RNH2) ligand, was prepared and screened against in vivo murine tumor models. Each compound was tested against Sarcoma 180 ascites (S180a) in mice, with 20 members of the series showing activity (ILS greater than 50%). Antitumor activity also was demonstrated in 4 of 16 compounds tested in the L1210 murine leukemia model (ILS greater than 25%) and in 3 of 3 tested in the P388 murine leukemia model (ILS greater than 30%). The most active and potent analogues of the series were obtained when A was NH3 and Am was N1-pyridine, N1-4-methylpyridine, N1-4-bromopyridine, N1-4-chloropyridine, N3-cytosine, or N7-2'-deoxyguanosine. Complexes containing chelating and saturated amine ligands (A), as well as two trans isomers of active cis analogues (trans-[Pt(NH3)2(Am)Cl]+, where Am = N1-pyridine or N1-4-methylpyridine), were inactive in the S180a screen. All complexes were characterized by means of elemental analysis, HPLC, and 195Pt NMR spectroscopy, and the structure of one analogue, cis-[Pt(NH3)2(N3-cytosine)Cl](NO3), was determined by using single-crystal X-ray diffraction methods. While members of this series of compounds demonstrate antitumor activity in vivo, these new agents are not classical analogues of cisplatin (i.e. cis-[PtA2X2] complexes), as they contain three nitrogen donors and only one leaving group. The results of these studies suggest that further work should be conducted to better define the limits of the structure-activity relationships among platinum(II) complexes.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor) Cl]+

Hollis¹,

Amundsen²,

Stern³

1989

J. Med. Chem.

242

168

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“…Several acyl‐ and O ‐alkylderivatives of TFT had significantly higher growth inhibition rates and therapeutic indices compared to TFT and might therefore be more useful than the parental compound, particularly 3′‐ O ‐benzyl‐TFT. ( 25,26 ) Although these derivatives slowly release the drug in body fluids in order to achieve effective concentrations over an extended period of time, they might also affect healthy tissue thereby increasing the systemic side‐effects. Due to increased TK levels often observed in solid tumors, ( 27 ) these agents may be an alternative for TFT.…”

mentioning

confidence: 99%

Therapeutic potential of the dual‐targeted TAS‐102 formulation in the treatment of gastrointestinal malignancies

et al. 2007

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Current treatment modalities for cancer combine cytotoxic drugs against DNA and novel targeted drugs affecting signal transduction pathways, which are required for growth progression and metastasizing tumors. Classical chemotherapeutic regimens for gastro-intestinal tumors include antimetabolites based on 5-fluorouracil (5FU), the platinum analog oxaliplatin and the topoisomerase inhibitor irinotecan. The thymidine analog trifluorothymidine (TFT) has been shown to bypass resistance pathways for 5FU derivatives (S-1, UFT, Xeloda) in model systems, while concurrent application with a thymidine phosphorylase inhibitor (TPI) increases the bioavailability of TFT, thereby potentiating the in vivo efficacy of TFT. The formulation TAS-102 is given orally in a 1.0:0.5 molar ratio (TFT:TPI). The formulation is dual-targeted due to the cytotoxic effect of TFT, which is enhanced by TPI, while TPI also exerts antiangiogenic effects by inhibiting thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor. Evidence is accumulating from in vitro and in vivo preclinical studies that these properties favor further combinations with other cytotoxic agents currently being used in the treatment of gastro-intestinal tumors. Also treatment with targeted agents will synergistically down-regulate signal transduction pathways responsible for growth and progression of tumors. In this review, we summarize the available information on ( T AS-102 is a promising novel combination drug, which combines several attractive features. One component is the antiangiogenic effect, which is also intended to enhance its cytotoxic effect. TAS-102 contains the cytotoxic pyrimidine analog 5-trifluoro-2′-deoxythymidine (TFT; trifluridine; 5-trifluromethyl-2′-deoxyuridine; CF 3 dUrd; FTD; F 3 TDR; F 3 Thd) and the potent thymidine phosphorylase (TP) inhibitor (TPI), and is currently evaluated in phase I studies as an oral formulation in a molar ratio of 1.0:0.5 (Fig. 1).The thymidine analog trifluorothymidine was synthesized originally by Heidelberger et al.(1) in 1964, who had already shown that TFT can be phosphorylated by thymidine kinase to its active monophosphate form in uninfected tissues mediating cytotoxicity. TFT has also been evaluated for its antitumor effects and was at least as effective against adenocarcinoma cells as compared to 5-fluoro-2′-deoxyuridine (FdUrd).(3) Based on these pharmacological data, a clinical study on TFT was carried out to evaluate its efficacy in patients with breast and colon carcinomas.(4) Some of the administration schedules have been reported to produce a reduction of tumor size (eight out of 23 breast cancer and one out of six colon cancer). However, these clinical studies were unfortunately discontinued, because of a poor pharmacokinetic profile and side-effects. TFT was also investigated as an antiviral agent and is registered as Viroptic, (5) for use against herpes simplex virus (HSV) infections. The drug was previously approved by the Food and Drug Administration (FDA) in 1980 fo...

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ChemInform Abstract: Studies on Antitumor Agents. Part 6. Syntheses and Antitumor Activities of Acyl Derivatives of 2′‐Deoxy‐5‐trifluoromethyluridine.

et al. 1987

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Studies on antitumor agents. VI. Syntheses and antitumor activities of acyl derivatives of 2'-deoxy-5-trifluoromethyluridine.

Cited by 8 publications

References 1 publication

Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor) Cl]+

Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor) Cl]+

Therapeutic potential of the dual‐targeted TAS‐102 formulation in the treatment of gastrointestinal malignancies

ChemInform Abstract: Studies on Antitumor Agents. Part 6. Syntheses and Antitumor Activities of Acyl Derivatives of 2′‐Deoxy‐5‐trifluoromethyluridine.

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