1-(3-Cyano-2,3-dideoxy-.beta.-D-erythro-pentofuranosyl)thymine (cyanothymidine): synthesis and antiviral evaluation against human immunodeficiency virus

Greengrass, C. W.; Hoople, David W. T.; Street, S. D. A.; Hamilton, Fiona; Marriott, M. S.; Bordner, Jon; Dalgleish, Angus; Mitsuya, Hiroaki; Broder, Samuel

doi:10.1021/jm00123a019

Cited by 24 publications

(2 citation statements)

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“…Although many thymidine and uridine derivatives have been prepared as possible anti-HIV agents, and several have been or are currently being tested, the pursuit of such analogues would be improved by development of useful stereochemical guidelines. For example, 3'-cyano-3'-deoxythymidine (CN-ddT) was synthesized and evaluated as a potential anti-HIV drug (6) because the 3'-cyano group was reasoned to be electronically and sterically similar to hydroxy and azido groups, thus making the molecule similar overall to AZT; however, the compound is ineffective. Thus more sophisticated stereochemical analysis is required.…”

mentioning

confidence: 99%

Structure of the anti-human immunodeficiency virus agent 3'-fluoro-3'-deoxythymidine and electronic charge calculations for 3'-deoxythymidines.

Camerman

Mastropaolo²,

Camerman³

1990

Proc. Natl. Acad. Sci. U.S.A.

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The crystal and molecular structures of the anti-human immunodeficiency virus agent 3'-fluoro-3'-deoxythymidine have been determined by x-ray diffraction and stereochemical comparisons with thymidine have been made. Atomic charge distributions have been calculated by the complete neglect of differential overlap method for thymidine and antiretrovirally active and inactive C3'-substituted analogues. The structural and electronic results suggest that antiviral activity in these analogues may be correlated with the presence of an electronegative atom attached to C3'.

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mentioning

confidence: 99%

Structure of the anti-human immunodeficiency virus agent 3'-fluoro-3'-deoxythymidine and electronic charge calculations for 3'-deoxythymidines.

Camerman

Mastropaolo²,

Camerman³

1990

Proc. Natl. Acad. Sci. U.S.A.

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“…Many were inactive, but a few blocked the replication of HIV in human T cells. 14,16,17,22, 147 An unsaturated form of ddT called 2',3'-didehydro-2',3'-dideoxythymidine, is about as active as AZT on a molar basis.16,17 Unlike AZT, it does not affect the activity of thymidylate k i n a~e ; l~~ whether it induces bone marrow toxicity remains undetermined. The dose-limiting toxicity is peripheral neuropathy.…”

Section: Biochemical Pharmacology Of Other Antiretroviral Dideoxymentioning

confidence: 99%

Clinical applications of 3′‐azido‐2′,3′‐ dideoxythymidine (AZT) and related dideoxynucleosides

Broder

1990

Medicinal Research Reviews

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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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1-(3-Cyano-2,3-dideoxy-.beta.-D-erythro-pentofuranosyl)thymine (cyanothymidine): synthesis and antiviral evaluation against human immunodeficiency virus

Cited by 24 publications

References 0 publications

Structure of the anti-human immunodeficiency virus agent 3'-fluoro-3'-deoxythymidine and electronic charge calculations for 3'-deoxythymidines.

Structure of the anti-human immunodeficiency virus agent 3'-fluoro-3'-deoxythymidine and electronic charge calculations for 3'-deoxythymidines.

Clinical applications of 3′‐azido‐2′,3′‐ dideoxythymidine (AZT) and related dideoxynucleosides

Synthesis Of Nucleosides

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