Synthesis and antitumor activity of a series of ftorafur analogs: the effect of varying electronegativity at the 1'-position

Holshouser, Mark H.; Shipp, Annette M.; Ferguson, Paul W.

doi:10.1021/jm00380a016

Cited by 10 publications

(9 citation statements)

References 2 publications

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“…These results contrast with those obtained with the sulfur analogs 848 − 850 of the 5FU prodrug Ftorafur ( 847 ) (Chart ). The substitution of sulfur in 847 would increase the electronegativity at the position next to the N1−C2‘ bond and, possibly, increase the rate of release of 5FU from compounds 848 − 850 …”

Section: F Nucleoside Analogscontrasting

confidence: 76%

“…Furthermore, no significant difference in terms of anticancer activity against the Walker tumor model and the bone marrow toxicity existed 559 between the coadministration of BCNU and The cyclic sulfoxide 801 also had a greatly reduced activity as compared to the acyclic sulfide 791. 554 These results contrast with those obtained with the sulfur analogs 848-850 of the 5FU prodrug Ftorafur (847) 560 (Chart 22). The substitution of sulfur in 847 would increase the electronegativity at the position next to the N1-C2′ bond and, possibly, increase the rate of release of 5FU from compounds 848-850.…”

Section: F Nucleoside Analogsmentioning

confidence: 88%

“…The cyclic sulfoxide 801 also had a greatly reduced activity as compared to the acyclic sulfide 791 (Chart ). The substitution of sulfur in 847 would increase the electronegativity at the position next to the N1−C2‘ bond and, possibly, increase the rate of release of 5FU from compounds 848 − 850 …”

Section: F Nucleoside Analogsmentioning

confidence: 99%

“…In both cases, the oxidized sulfur analogs 849 and 850 were more active than the compounds 848 and 847 . However, the more active compounds 849 and 850 were also the more water soluble of the four analogs and thus the solubility factor may be of greater importance 22 Structures for VII.F …”

Section: F Nucleoside Analogsmentioning

confidence: 99%

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A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

1997

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Section: F Nucleoside Analogscontrasting

confidence: 76%

Section: F Nucleoside Analogsmentioning

confidence: 88%

Section: F Nucleoside Analogsmentioning

confidence: 99%

Section: F Nucleoside Analogsmentioning

confidence: 99%

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A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

1997

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“…2'-Deoxy uridine 3',5'-Cyclic Monophosphate Ammonium Salt (10). Compound 10 appeared in fractions 81-90 (yield 69%).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and antitumor and antiviral properties of 5-halo- and 5-(trifluoromethyl)-2'-deoxyuridine 3',5'-cyclic monophosphates and neutral triesters

Béres¹,

Sági²,

Bentrude³

et al. 1986

J. Med. Chem.

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The title diesters (11-15; halo substituents F, C1, Br, I) were prepared by DCC-induced cyclization of the precursor 5'-monophosphate or direct halogenation of the 2'-deoxyuridine 3',5'-cyclic monophosphate. Antitumor activities of 11-15 in cell systems (L1210 and Raji/O) were compared to those of the corresponding nucleosides and 5'-monophosphates. Thus, the 5-F-and 5-CF3-2'-deoxyuridines proved to be highly active derivatives [ID50 values (wg/mL) for L1210,0.002 and 0.06, respectively], with the 5'-monophosphates showing comparable potencies. The corresponding 3',5'-cyclic monophosphate diesters were 20-30 times less potent but nonetheless highly cytostatic.All derivatives including 11-15 had greatly increased IDN values for the thymidine kinase deficient (TK-) L1210and Raji cells. The 3',5'-cyclic diesters (11-15) evidently are not efficient prodrug sources of the nucleoside 5'-monophosphates in TK-cells. They also proved to be 100-to 2000-fold less efficient inhibitors of L1210 thymidylate synthetase than were the 5'-monophosphates. The 5-substituted 2'-deoxyuridines and their 5'-monophosphates were potent inhibitors of herpes simplex virus (MICN mostly 0.07-10 pg/mL) and vaccinia virus (MICN 0.07-0.2 wg/mL), with antiviral activity decreasing in the order 5-I,5Br > 5-CF3 > 5-C1> 5-F. The 3',5'-cyclic monophosphates (11-15) were for the most part 10-to 40-fold less active than the 5'-monophosphates in the virus assay systems (e.g., MICm for the 5-Br and 5-1 derivatives ranged 1-20 wg/mL). By contrast 11-15 were considerably more potent inhibitors of vaccinia virus growth (MI& 0.4-2 pg/mL). As the neutral 3',5'-cyclic methyl phosphate triesters (16-18), the 5-1 and 5-Br compounds were less potent in antiviral and cytostatic agents than the 3',5'-cyclic diesters, while the 5-iodo benzyl triester was in several cases as active as the 3',5'-cyclic diester. The title compounds (11-15) appear to require extracellular hydrolysis to the nucleoside before functioning as antitumor or antiviral agents.

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Synthesis Of Nucleosides

Vorbrüggen¹,

1999

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This chapter deals with the synthesis of nucleosides (e.g., the formation of N ‐glycosides of sugars such as D ‐ribose or 2‐deoxy‐D‐ribose with heterocyclic nitrogen bases). The methods of nucleoside synthesis have been treated in a number of reviews and monographs. It is now generally accepted that nucleosides were among the first organic compounds formed at the start of evolution in the early history of our planet earth. To support this point, guanine and adenine were heated with D ‐ribose in seawater, which contains the Lewis acid magnesium chloride as catalyst. One thus obtained the nucleosides guanosine and adenosine together with comparable yields of unnatural α‐nucleosides. The latter were gradually photoanomerized to the thermodynamically more stable compounds in overall yields of 5–6%. The furanose form of ribose reacts faster than the pyranose form. Corresponding syntheses of the pyrimidine nucleosides uridine and cytidine from uracil , cytosine and ribose are more problematic and remain an enigma. The recent conversion of glycolaldehyde‐ O ‐phosphate and formaldehyde to ribose‐2,4‐di‐ O ‐phosphate might give new insights into the prebiotic syntheses of uridine and cytidine. The evidence and hypotheses for these prebiotic conversions and the evolution of RNA, as well as the implications of an “RNA World,” have been reviewed. These RNA nucleosides are reduced in vivo as 5′‐ O ‐diphosphates by ribonucleotide reductases to the corresponding 2′‐deoxynucleosides—the building blocks of DNA such as 2′‐deoxyguanosine. The thermodynamically controlled synthesis of these four building blocks of RNA has implications for the design of efficient, high yielding, new methods for the synthesis of the naturally occurring nucleosides, nucleoside antibiotics, and modified nucleosides that may serve as antimetabolites to fight viral and parasitic diseases and cancer. The nucleoside rings in this chapter are depicted arbitrarily in the anti conformation, as occurs predominantly in the crystal and solution (based primarily on NOE‐ 1 H‐ and 13 C‐NMR measurements) forms of pyrimidine nucleosides. Only a few nucleosides, such as 6‐methyluridine, occur with the heterocyclic ring predominantly in the syn conformation. The synthesis of C ‐nucleosides has been reviewed previously and is not covered in this review.

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Synthesis and antitumor activity of a series of ftorafur analogs: the effect of varying electronegativity at the 1'-position

Cited by 10 publications

References 2 publications

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

Synthesis and antitumor and antiviral properties of 5-halo- and 5-(trifluoromethyl)-2'-deoxyuridine 3',5'-cyclic monophosphates and neutral triesters

Synthesis Of Nucleosides

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