Dipartimento Farmaco-Chimico, Università di Messina, Via SS Annunziata, 98168 Messina, Italy, Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125 Catania, Italy, and Laboratorio de Sintesis Asimetrica, Departamento de Quimica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza, CSIC, E-50009 Zaragoza, Aragon, Spain, Pedro Merino: pmerino@unizar.es

Chemical Synthesis of Heterocyclic−Sugar Nucleoside Analogues

Recent advances in the synthesis of fluorinated nucleosides

The synthesis of modified nucleic acids has been the subject of much study ever since the structure of DNA was elucidated by Watson and Crick at Cambridge and Wilkins and Franklin at King's College over half a century ago. This review describes recent developments in the synthesis and application of these artificial nucleic acids, predominantly the phosphoramidites which allow for easy inclusion into oligonucleotides, and is divided into three separate sections. Firstly, modifications to the base portion will be discussed followed secondly by modifications to the sugar portion. Finally, changes in the type of nucleic acid linker will be discussed in the third section. Peptide Nucleic Acids (PNAs) are not discussed in this review as they represent a separate and large area of nucleic acid mimics.

Recent highlights in modified oligonucleotide chemistry

The structures and relative stabilities of the complexes between Cu2+ and uracil, 2-thiouracil, 4-thiouracil, and 2,4-dithiouracil were investigated by B3LYP/6-311+G(2df,2p)//B3LYP/6-31G* DFT calculations. In those systems in which both types of basic centers, that is, a carbonyl and a thiocarbonyl group, are present, association of Cu2+ with the oxygen atom is systematically favored, in contrast to what was found for the corresponding Cu+ complexes. This can be understood by considering that association of Cu2+ is immediately followed by oxidation of the base, which accumulates the negative charge at the oxygen atoms. Similarly, for 2,4-dithiouracil the most basic site for Cu+ attachment is the sulfur atom at the 4-position, while for association of Cu2+ it is sulfur at the 2-position. In contrast, differences between uracil-Cu+ and uracil-Cu2+ complexes are very small, and in both cases the oxygen atom at the 4-position is the most basic. Cu2+ binding energies are about 4 and 1.2 times larger than Cu+ binding energies and proton affinities, respectively. Uracil- and thiouracil-Cu2+ complexes are thermodynamically unstable but kinetically stable with respect to their dissociation into uracil*+ + Cu+ or thiouracil*+ + Cu+. The Cu2+ binding energies vary with the difference between the second ionization potential of the metal and the first ionization potential of the base. regardless of the reference acid (H+, Cu+, Cu2+) the basicity trend is 2,4-dithiouracil > 4-thiouracil > 2-thiouracil > uracil.

Association of Cu2+ with Uracil and Its Thio Derivatives: A Theoretical Study

Nucleoside analogues have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compounds, including gemcitabine and cytarabine, are the go-to option in first-line treatments. However, these materials do have limitations and the development of next generation compounds remains a topic of significant interest and necessity. Herein, we discuss recent advances in the chemical synthesis and biological evaluation of nucleoside analogues as potential anticancer agents. Focus is paid to 4′-heteroatom substitution of the furanose oxygen, 2′-, 3′-, 4′- and 5′-position ring modifications and the development of new prodrug strategies for these materials.

https://www.mdpi.com/1420-3049/25/9/2050/pdf

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

Three types of 4-thiofuranoid glycal with different 3,5-O-silyl protecting groups were prepared and their electrophilic glycosidation was investigated. The 3,5-bis-O-(tert-butyldimethylsilyl)-4-thiofuranoid glycal (5) was obtained through mesylation of 2-deoxy-4-thio-D-erythro-pentofuranose (4) and subsequent base-promoted elimination, while thermal elimination of sulfoxide derivatives was suitable for the preparation of 3,5-O-(tetraisopropyldisiloxane-1,3-diyl) (9) and 3,5-O-(di-tert-butylsilylene) (11) 4-thioglycals. The glycosidation reactions of these 4-thioglycals were carried out, in the presence of either PhSeCl or NIS, by using silylated derivatives of uracil, thymine, cytosine, and N(6)-benzoyladenine. Among the three 4-thioglycals, 11 was found to be an excellent glycosyl donor, forming the desired beta-anomer exclusively irrespective of the nucleobase employed.

Stereoselective synthesis of the β-anomer of 4'-thionucleosides based on electrophilic glycosidation to 4-thiofuranoid glycals

Novel stereoselective entry to 2'-beta-carbon-substituted 2'-deoxy-4'-thionucleosides from 4-thiofuranoid glycals.

Novel Stereoselective Entry to 2′-β-Carbon-Substituted 2′-Deoxy-4′-thionucleosides from 4-Thiofuranoid Glycals.

/pdf/stereoselective-synthesis-of-the-b-anomer-of-4-56duob7f3b.pdf

Stereoselective Synthesis of the β-Anomer of 4′-Thionucleosides Based on Electrophilic Glycosidation to 4-Thiofuranoid Glycals.

The 4-thiofuranoid glycal 6 was converted into 1-chlorinated derivative 7 through LDA lithiation. When 7 was treated with LTMP, successful C-2 lithiation occurred, and subsequent treatment of the lithiated species with MeI gave 8. Dechlorination of 8 with Na/liq.NH3 yielded the 2-methyl glycal 9. Glycosidation of 9 with silylated thymine was mediated with PhSeCl as an electrophile, and gave the beta-isomer 10 stereoselectively. Removal of the 2'-phenylselenenyl group of 10 was effected with tributyltin radical, and subsequent deprotection furnished the target 2'-beta-methyl 4'-thiothymidine (11). In a similar manner, the corresponding cytosine analogue 12 could also be synthesized.

Noriaki Shiina

Papers

Stereoselective synthesis of the β-anomer of 4'-thionucleosides based on electrophilic glycosidation to 4-thiofuranoid glycals

Novel stereoselective entry to 2'-beta-carbon-substituted 2'-deoxy-4'-thionucleosides from 4-thiofuranoid glycals.

Novel Stereoselective Entry to 2′-β-Carbon-Substituted 2′-Deoxy-4′-thionucleosides from 4-Thiofuranoid Glycals.

Stereoselective Synthesis of the β-Anomer of 4′-Thionucleosides Based on Electrophilic Glycosidation to 4-Thiofuranoid Glycals.

Stereoselective synthesis of 2′-ß-carbon-substituted 2′-deoxy-4′-thioribonucleosides from 4-thiofuranoid glycal