Synthesis of 4'-Ethynyl-2'-deoxy-4'-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2013 Jun 25

PMID 23795238

Citations 4

Authors

Kazuhiro Haraguchi

Hisashi Shimada

Keiogo Kimura

Genta Akutsu

Hiromichi Tanaka

Hiroshi Abe

Takayuki Hamasaki

Masanori Baba

Elizabeth A Gullen

Ginger E Dutschman

Yung-Chi Cheng

Jan Balzarini

Affiliations

Soon will be listed here.

Abstract

The synthesis of 4'-ethynyl-2'-deoxy-4'-thioribonucleosides was carried out utilizing an electrophilic glycosidation in which 4-ethynyl-4-thiofuranoid glycal served as a glycosyl donor. Electrophilic glycosidation between and the silylated nucleobases (-acetylcytosine, -benzoyladenine and -acetyl--diphenylcarbamoylguanine) was carried out in the presence of -iodosuccinimide (NIS) leading to the exclusive formation of the desired β-anomers and . Anti-HIV studies demonstrated that these 4'-thio nucleosides were less cytotoxic to T-lymphocyte (i.e. MT-4 cells) than the corresponding 4'-ethynyl derivatives of 2'-deoxycytidine (), 2'-deoxyadenosine () and 2'-deoxyguanosine (). Comparison of the selectivity indices (SI) was made between 4'-thionucleosides ( and ) and the corresponding 4'-oxygen analogues by using the reported CC and EC values. In the case of cytosine and adenine nucleosides, comparable SI values were obtained: (545) and (458); (>230) and (1,630). In contrast, 4'-ethynyl-2'-deoxy-4'-thioguanosine was found to possess a SI value of >18,200, which is twenty times better than that of (933).

Citing Articles

Synthesis of Nucleoside Analogs Containing Sulfur or Selenium Replacements of the Ribose Ring Oxygen or Carbon.

Benckendorff C, Sunde-Brown P, Ni Cheallaigh A, Miller G J Org Chem. 2024; 89(23):16977-16989.

PMID: 39572188 PMC: 11629386. DOI: 10.1021/acs.joc.4c02409.

Discovery of a Novel Template, 7-Substituted 7-Deaza-4'-Thioadenosine Derivatives as Multi-Kinase Inhibitors.

Mashelkar K, Byun W, Ko H, Sung K, Tripathi S, An S Pharmaceuticals (Basel). 2021; 14(12).

PMID: 34959689 PMC: 8708872. DOI: 10.3390/ph14121290.

Advance of structural modification of nucleosides scaffold.

Lin X, Liang C, Zou L, Yin Y, Wang J, Chen D Eur J Med Chem. 2021; 214:113233.

PMID: 33550179 PMC: 7995807. DOI: 10.1016/j.ejmech.2021.113233.

Recent Advances in the Chemical Synthesis and Evaluation of Anticancer Nucleoside Analogues.

Guinan M, Benckendorff C, Smith M, Miller G Molecules. 2020; 25(9).

PMID: 32354007 PMC: 7248840. DOI: 10.3390/molecules25092050.

References

Dong S, Paquette L . Stereoselective synthesis of conformationally constrained 2'-deoxy-4'-thia beta-anomeric spirocyclic nucleosides featuring either hydroxyl configuration at C5'. J Org Chem. 2005; 70(5):1580-96. DOI: 10.1021/jo048071u. View

Jeong L, Lee H, Jacobson K, Kim H, Shin D, Lee J . Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-uronamides as highly potent and selective agonists at the human A3 adenosine receptor. J Med Chem. 2006; 49(1):273-81. DOI: 10.1021/jm050595e. View

Pauwels R, Balzarini J, Baba M, Snoeck R, Schols D, Herdewijn P . Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods. 1988; 20(4):309-21. DOI: 10.1016/0166-0934(88)90134-6. View

Jayakanthan K, Johnston B, Pinto B . Stereoselective synthesis of 4'-selenonucleosides using the Pummerer glycosylation reaction. Carbohydr Res. 2008; 343(10-11):1790-800. DOI: 10.1016/j.carres.2008.02.014. View

Baba M, De Clercq E, Tanaka H, Ubasawa M, Takashima H, Sekiya K . Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase. Proc Natl Acad Sci U S A. 1991; 88(6):2356-60. PMC: 51230. DOI: 10.1073/pnas.88.6.2356. View

Haraguchi K, Takahashi H, Shiina N, Horii C, Yoshimura Y, Nishikawa A . Stereoselective synthesis of the beta-anomer of 4'-thionucleosides based on electrophilic glycosidation to 4-thiofuranoid glycals. J Org Chem. 2002; 67(17):5919-27. DOI: 10.1021/jo020037x. View

Kodama E, Kohgo S, Kitano K, Machida H, Gatanaga H, Shigeta S . 4'-Ethynyl nucleoside analogs: potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro. Antimicrob Agents Chemother. 2001; 45(5):1539-46. PMC: 90502. DOI: 10.1128/AAC.45.5.1539-1546.2001. View

Gunaga P, Kim H, Lee H, Tosh D, Ryu J, Choi S . Stereoselective functionalization of the 1'-position of 4'-thionucleosides. Org Lett. 2006; 8(19):4267-70. DOI: 10.1021/ol061548z. View

Haraguchi K, Shimada H, Tanaka H, Hamasaki T, Baba M, Gullen E . Synthesis and anti-HIV activity of 4'-substituted 4'-thiothymidines: a new entry based on nucleophilic substitution of the 4'-acetoxy group. J Med Chem. 2008; 51(6):1885-93. DOI: 10.1021/jm070824s. View

10.

Ohrui H, Kohgo S, Kitano K, Sakata S, Kodama E, Yoshimura K . Syntheses of 4'-C-ethynyl-beta-D-arabino- and 4'-C-ethynyl-2'-deoxy-beta-D-ribo-pentofuranosylpyrimidines and -purines and evaluation of their anti-HIV activity. J Med Chem. 2000; 43(23):4516-25. DOI: 10.1021/jm000209n. View

11.

Ichikawa E, Kato K . Sugar-modified nucleosides in past 10 years, a review. Curr Med Chem. 2001; 8(4):385-423. DOI: 10.2174/0929867013373471. View

12.

Hayakawa H, Kohgo S, Kitano K, Ashida N, Kodama E, Mitsuya H . Potential of 4'-C-substituted nucleosides for the treatment of HIV-1. Antivir Chem Chemother. 2004; 15(4):169-87. DOI: 10.1177/095632020401500401. View