Elsevier

Tetrahedron

Volume 66, Issue 4, 23 January 2010, Pages 789-843
Tetrahedron

Tetrahedron report number 898
Recent advances in the synthesis of fluorinated nucleosides

https://doi.org/10.1016/j.tet.2009.11.001Get rights and content

Introduction

Fluorine is one of the most abundant elements on earth. However, it occurs extremely rarely in biological compounds. Due to the specific properties of fluorine atom(s), including small steric size, high electronegativity, carbon–fluorine bond strength and sensitivity of 19F NMR spectroscopy along with large 19F–1H coupling constants, etc., the introduction of fluorine atom(s) into many biologically active molecules can bring about remarkable and profound changes in their physical, chemical and biological properties.1, 2, 3 For example, research has clearly demonstrated the important effects of fluorine substitution on the inter- and intramolecular forces, which affect binding of ligands, and thus introduce receptor subtype selectivity, at cholinergic and adrenergic receptors.4, 5, 6 Fluorine substitution can also have a profound effect on drug disposition, in terms of distribution, drug clearance, route(s) and extent of drug metabolism.7 In the past several decades, the noteworthy increase in the utilization of fluorine-containing chemicals, e.g., fluorinated materials, fluorinated amino acids, fluorinated sugars, fluorinated steroids and fluorinated nucleosides, has unambiguously illustrated the significant impact that fluorine has made on all aspects of modern life.

Known to be deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) subunits, nucleosides play key roles in neurotransmission8 and regulation of cardiovascular activity9 and as signalling molecules,10 in addition to their role as intermediates for many essential cellular biosynthetic pathways. Consisting of both a base moiety and a sugar moiety, nucleosides are usually classified into two major subtypes, i.e., N-nucleosides and C-nucleosides. N-nucleosides feature a bond between the anomeric carbon of the sugar moiety and the nitrogen of the base moiety whereas C-nucleosides have a bond between the anomeric moiety and the carbon of the base moiety. Further, the nucleosides in which carbon, sulfur, phosphorus and nitrogen substitutes for the sugar ring oxygen are commonly defined as carbocyclic nucleosides,11, 12, 13, 14, 15 thionucleosides,16 phosphanucleosides17 and azanucleosides,18 respectively. Nucleosides and nucleoside analogues have achieved considerable success in the fight against viral infection.19 During the last several decades, some highly biologically active nucleosides and nucleoside analogues have been synthesized, studied and used. For example, 5-iodo-2′-deoxyuridine (IDU) was licenced as the first nucleoside antiviral, and the first antiviral chemotherapeutic agent for use in humans.20 The 2′,3′-dideoxynucleosides (ddNs) have thus far proved to be the most effective therapeutic agents against the human immunodeficiency virus (HIV)21 and hepatitis B virus (HBV).22, 23 3′-Azido-2′,3′-dideoxythymidine (AZT),24 2′,3′-dideoxyinosine (ddI)25 and 2′,3′-dideoxycytidine (ddC)26 have also been approved for the treatment of acquired immune deficiency syndrome (AIDS).

Fluorinated nucleosides, containing fluorine atom(s) or fluorine-containing groups in the sugar moiety or in the base moiety of nucleosides, have drawn increasing attention, due to the introduction of the fluorine atom(s) into some nucleosides resulting in a great improvement in the bioactivity and stability of the corresponding compounds. Perhaps the best known of the fluorinated nucleosides are FMAU,27, 28 FIAC,28 FLT,29, 30 F-ddC,31 SFDC32 and gemcitabine (Fig. 1),33, 34 all of which have high antiherpes activities, as well as antitumour activities in some cases. Especially noteworthy is gemcitabine, which has been approved by the FDA for the treatment of inoperable pancreatic cancer and of 5-fluorouracil-resistant pancreatic cancer.35, 36 Moreover, gemcitabine in combination with cisplatin,37 paclitaxel38, 39, 40 and carboplatin41, 42 was indicated for the first-line treatment of patients with inoperable, locally advanced (stage IIIA or IIIB), or metastatic (stage IV) non-small cell lung cancer, patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated, and patients with advanced ovarian cancer that has relapsed at least six months after completion of platinum-based therapy, respectively. For all these reasons, fluorinated nucleosides have been the subject of intense synthetic activity. However, to the best of our knowledge, none of the formerly published reviews have systematically addressed the synthesis of fluorinated nucleosides, although many aspects of the chemistry of fluorinated nucleosides have been reviewed.43, 44, 45, 46, 47, 48 This review mainly concentrates on the synthesis of fluorinated nucleosides that contain a fluorinated glycone moiety, and it does not cover a large group of nucleosides fluorinated at the nucleobase. In this review, most of the bases are the five naturally occurring nucleic acid bases, uracil (U), thymine (T), cytosine (C), adenine (A), and guanine (G) (Fig. 2).

Section snippets

1′-Monofluorinated nucleosides

A large number of fluoronucleoside analogues have been synthesized, and almost all of the hydrogens attached to carbons have been chemically replaced by fluorine atoms. However, the replacement of fluorine atoms at the 1′-position was seldom studied, because one might speculate that 1′-fluoronucleosides would be too unstable to be synthesized. Recently, Shuto and co-workers reported the first synthesis of 1′-fluoronucleosides (Scheme 1).49 In their synthesis, electrophilic fluorination of the

Difluorinated nucleosides

The gem-difluoromethylene (CF2) group has been suggested by Blackburn as an isopolar and isosteric substituent for oxygen.267 Analogues of di- and triphosphates in which the CF2 groups have replaced the pyrophosphate oxygen have been used as substrates in enzymatic reactions.268, 269, 270, 271 Thus, the CF2 group was extensively used to modify not only nucleotides, but also nucleoside analogues. For example, important work on 2,2-difluoro-2-deoxyriboses and the corresponding nucleosides has

Trifluoromethylated nucleosides

Many advantages could be expected from the presence of a CF3 group on the sugar moiety of nucleosides, including increasing lipophilicity320 and improved chemical and/or enzymatic stability.321, 322 In addition, the trifluoromethyl group can enhance the therapeutic properties of bioactive compounds.323, 324, 325 It should also be noted that Bansal has proposed that replacement of the methyl group in the fucose residue with the more hydrophobic trifluoromethyl group might provide an artificial

Monofluorinated or gem-difluorinated cyclopropane nucleosides

Kim et al. designed and synthesized some fluorocyclopropanoid nucleosides (±)-941 in 2001.341 As the important step of their synthetic route, introduction of fluorine and a double bond for the installation of the cyclopropyl group was actualized by an HWE reaction of the aldehyde 935 with triethyl 2-fluoro-2-phosphonoacetate using n-BuLi in THF (Scheme 140). After the resultant ester 936 was reduced with DIBAL-H, the obtained allylic alcohol 937 was subjected to ZnI2-catalytic cyclopropanation

18F-containing nucleosides

Positron emission tomography (PET) is a non-invasive imaging technology, which provides a unique window on the physiology and function of living organisms with the highest sensitivity and resolution.373, 374, 375 To date, PET plays an important role in drug discovery by validating the mechanism of drug localization, establishing the transport efficiency of a drug to the target, addressing the drug occupancy of the saturable receptor sites and determining the half life of occupancy of the drug.

Conclusions

In this review, we have systematically presented the recent advances in the synthesis of fluorinated nucleosides and it is evident that tremendous progress has been made in the past few years. Clearly, two main tactics have been employed for the synthesis of fluorinated nucleosides. One startegy has featured the installation of fluorine atom(s) into pre-modified precursor compounds before the introduction of nucleic bases. Alternatively, the second strategy has involved the regio- or

Acknowledgements

We express our sincerest thanks to our former and current colleagues who have contributed to the synthesis of fluorinated nucleosides at the Shanghai Institute of Organic Chemistry. We also gratefully acknowledge the financial support of our research in this area by the National Natural Science Foundation of China and Shanghai Municipal Scientific Committee.

Xiao-Long Qiu was born in Zizhong, Sichuan, China, in 1977. He received his BS degree from Southwest China Normal University (Southwest University) in 2000. After that, he pursued his Ph.D. degree at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (CAS) under the supervision of Professor Feng-Ling Qing and received his Ph.D. degree in 2005. His Ph.D. thesis focused on the synthesis of fluorinated amino acids and fluorinated nucleosides. Then, he joined the Biological

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    Xiao-Long Qiu was born in Zizhong, Sichuan, China, in 1977. He received his BS degree from Southwest China Normal University (Southwest University) in 2000. After that, he pursued his Ph.D. degree at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (CAS) under the supervision of Professor Feng-Ling Qing and received his Ph.D. degree in 2005. His Ph.D. thesis focused on the synthesis of fluorinated amino acids and fluorinated nucleosides. Then, he joined the Biological Chemistry Department of the University of California, Irvine as a Postdoctoral Scholar in the research group of Professor Wen-Hwa Lee. He has received the Liu Yonglin Award of the CAS (2005) and the Multidisciplinary-Postdoctoral Award (Breast Cancer Research Project) of the US Army Medical Research and Materials Command (2006–2009). His research interests mainly focus on the validation of small molecules disrupting protein–protein interactions for cancer treatment. He is a co-founder of Helix&Bond Pharmaceutical Inc., Shanghai, China.

    Xiu-Hua Xu was born in 1981 in Sheyang county, Jiangsu province of China. He received his BS degree from Nankai University in 2003. After that, he conducted his Ph.D. degree at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences under the supervision of Professor Feng-Ling Qing and received his Ph.D. degree in 2008. His current research interests are concerned with fluorinated nucleosides and sugars.

    Feng-Ling Qing received his Ph.D. in 1990 from the Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences under the supervision of Professor Chang-Ming Hu. He was promoted to an Associate Professor at the SIOC in 1992. From 1992 to 1995, he was a postdoctoral fellow at Wyeth Research (Pearl River, New York). He returned to the SIOC in 1995 and became a full Professor in 1997. From 1999 to the present time, he has been departmental head of the Key Laboratory of Organofluorine Chemistry of the SIOC. Since 2001, he has been CheungKong Professor at Donghua University. He is currently a member of the Editorial Board of Journal of Fluorine Chemistry. His research interests include the synthesis and applications of fluorine-containing building blocks, fluorinated bioactive compounds, and fluorinated functional polymers.

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