7-Deazapurine nucleosides

In the past three decades, pyrrolo[2,3-d]pyrimidine (7-deazapurine) nucleoside analogues, both of natural and of nonnatural21 origin, have... 

At this stage a new approach for the synthesis of 7-deazapurine nucleosides has been demonstrated leading to the synthesis of 2-deoxy-cadeguomycin. A key feature is the conversion of differentially protected 2/-deoxyribosylpyrrolo[2,3-d]pyrimidine-2,4-dione into a protected 2-aminopyrrolo[2,3-<7]pyrimidine-4-one. Efforts toward the ribo-series of intermediates has revealed some promise although issues regarding the choice of ribose protecting groups need to be sorted out. 

Imidazo[l,2-a][l,3,5]triazines have been prepared by annulation of the imidazole onto an existing triazine as well as by annulation of the triazine onto an imidazole precursor. Depending upon the desired substituent pattern, both routes allow effective preparation of variously substituted heterocycles. Research on this ring system has been minimal until recently, when several papers have focused on the synthesis of nucleoside derivatives, which can be thought of as 5-aza-7-deazapurine nucleosides. 

Ingale, S. A., Pujari, S. S., Sirivolu, V. R., Ding, P., Xiong, H., Mei, H., Seela, F. (2011). 7-Deazapurine and 8-Aza-7-deazapurine Nucleoside and Oligonucleotide Pyrene "Click" Conjugates Synthesis, Nucleobase Controlled Fluorescence Quenching,... 

Shi J, McBrayer TR, Whitaker T, Coats SJ, Zhou L, Zhang H, Detorio MA, Johns M, Bassit L, Schinazi RF, Powdrill MH, Goette M (2011) Synthesis and antiviral activity of 2 -deoxy-2 -fluoro-2 -C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5 -tri-phosphates. Bioorg Med Chem Lett 21 7094-7098... 

Except for the oxetanocin G analogue 22, carbocyclic 7-deazaguanosines do not seem to provide a fruitful source of potential antiviral agents. This obs ation agrees with others who have noted decreases in antiviral activity when carbocyclic 7-deazapurine nucleosides are compared to their purine parent systems. This correlation carries over into the cytotoxicity results in that the carbocyclic 7-deazaguanosines reported hoein showed no cytotoxicity, which is in contrast to what is often seen in the 7-deaztq)urine nucleoside series. 

Bergen et al7 synthesised C5-modified pyrimidine and C7-modified 7-deazapurine nucleoside triphosphates (86a-d). The authors reported... 

Seela et al7 reported the synthesis of 7-deazapurine (pyrrolo[2,3-djpyrimidine) 2 -deo)yrihonucleosides (88), ineluding (3-d- and p-L-enantiomers, fluoro-derivatives and 2, 3 -dideo3yrihonueleosides with well-defined stereochemistry. These eompounds have potential applications as antiviral or anticancer agents (7-deazapurine nueleosides), and the 7-deazapurine nucleoside triphosphates are used in Sanger dideoxy DNA-sequencing. 

A number of imidazo[4,5-c]pyridine nucleosides (3-deazapurine nucleosides) are of special interest because of their biological properties. 3-Deazaadenosine (655) inhibits biochemical methylations by acting as either an inhibitor or substrate of (S)-adenosylhomocysteine hydrolase <79BP1897>. Compound (655) has antiviral <78BBR(82)417> and antimalarial activities <80MI 708-01). 3-Deaz-... 

Nitration. This reagent system nitrates 1-deazapurine nucleosides. The regio-selectivity depends on existing substitution patterns. 

Two reviews on imidazopyridines are worth mentioning. The review by Lunt on the chemistry of 1- and 3-deazapurines covered them most completely up to the time of its publication (85MI5). However, the concise review of Montgomery and Secrist in the book (84CHEC(5)) contained still more information and references. In a special review on aza- and deazaanalogues of purine nucleosides, the most significant section is dedicated to 1- and 3-deazapurine nucleosides (81KG147). 

The introduction of A -glycosyl residues into IPs is a special type of N-alkylation providing new powerful medicines of these purine derivatives. The synthesis of 1-and 3-deazapurine nucleosides was reviewed in (81KG147). 

Despite the ubiquity and potential usefulness of the deazapurine nucleoside both as tools and therapies, studies on their biosynthetic pathways have been limited. 

An empirical rule that predicts the sign of the Cotton effect of glycosylated uracil, cytosine, thymine, adenine, and guanine has been developed. The rule is not restricted to pentofuranosyl residues linked to N-1 of pyrimidines and to N-9 of purines, but can be applied to cyclic and acyclic sugars linked to any position on these bases. The c.d. spectra of the double-headed nucleosides 5 -deoxy-5 -(indol-l-yl)- and 5 -deoxy-5 -(6-methylthiopurin-9-yl)-adenosine and -uridine have been reported, and 3-deazapurine nucleosides have been shown to prefer a syn conformation about the iV-glycosidic bond by comparison of their c.d. spectra with those of common nucleosides. ... 

The enzyme, purine nucleoside phosphorylase (PNP), is directly involved with blood levels of T-cells. Low levels of this enzyme will inhibit T-ceU prohferation. Drugs that inhibit the enzyme can also be expected to act against proliferation of malignant T-cells. The PNP inhibitor forodesine (36) has shown early activity against T-cell mahgnancies. Treatment of the deazapurine (32) with lithium leads to derivative 33... 

Purines show typical absorption spectra which are useful for the identification and the determination of their structure tautomeric equilibria can also be studied. By comparison of the spectra of natural and synthetic derivatives of purines, the N9 glycosylic linkage was established for nucleosides. The relatively simple spectra of purines show two main bands. Purine shows maxima around 220 nm and at 263 nm in neutral solution. Since the imidazole ring has no characteristic UV absorption, the spectra of purines and pyrimidines show similarities. Similar observations have been made for 7-deazapurines, 8-azapurines etc. In the series of adenine hypoxanthine, and xanthine (at pH 6) only one maximum is observed guanine, isoguanine, and purinc-2,6-diamine show two maxima. 

Another promising approach to 2 -deoxyribonucleosides with only a slightly modified purine which shows selective base pairing with 2 -deoxythymidinc (dT) and can be incorporated into DNA is represented by compounds of type 10. Here, position 7 of a 7-deazapurine heterocycle is substituted by an alkynyl side chain. Such nucleosides, e.g. 7-deaza-2 -deoxy-7-hex-l-ynyl-adenosine, exhibit strong fluorescence = 275 nm, = 405 nm). ... 

Another type of convertible nucleoside phosphoramidite, a derivative of (5 S)-5 -C-(5-bromo-2-penten-l-yl)-2 -deoxyribosylfuranosyl thymidine (49), has been reported. The synthesis of this phosphoramidite was stereoselective and involved a Sakurai reaction between 5 -C-thymidine aldehyde and allyltrimethylsilane. Seela has reported the synthesis of the ribosyl-phosphoramidite derivatives of 7-bromo- and 7-iodo-8-aza-7-deazapurine-2,6-diamine (50a,b) from advanced synthetic precursors and of the bromo- and iodo-derivatives at the 5-position of uracyl phosphoramidite (51a,b). He further described the effect on base-pair stability due to their incorporation into oligonucleotide duplexes. ... 

The synthesis and hybridisation properties of oligodeoxynucleotides containing 7-( 1 -propynyl)-7-deaza-2 -deoxyguanosine and 7-( 1 -propynyl)-7-deaza-2 -deoxya-denosine have been described. The suitably protected nucleosides 199a and 199b were synthesised and incorporated into oligomers. Thermal denaturation of these oligomers hybridised to RNA demonstrates an increased stability relative to 7-unsubstituted deazapurine and unmodified controls. 

Numerous syntheses have also been reported for arabinofuranosyl nucleoside analogues, prepared either conventionally from arabinofuranosyl derivatives or via 2,2-anhydro-nucleosides obtained from appropriate ribonucleosides. 5-Aza-cytosine-D-arabinoside has been synthesized and found to show similar antiviral activity to Ara-C(arabinosyl-cytosine). 7-a-, 7-<3-, 9-0 -, and 9- 3-arabino-furanosyl derivatives of 3-deazaguanine have also been prepared, but none showed any anti-tumour activity. 9-(o -D-Arabinofuranosyl)-8-aza[2- C]-adenine, 7-(/3-D-arabinofuranosyl)-pyrrolo[2,3-d]pyrimidine-4(3//)-one (15)," l-(a-D-arabinofuranosyl)- and l-(/3-D-xylofuranosyl)-4-nitropyrazole, and Ot-arabino-nucleosides of 5-fluoro-cytosine and -uracil derivatives have also been prepared. An improved synthesis of 9-(/3-D-arabinofuranosyl)-2-fluoro-adenine has been reported. The ratio of o to 3 anomers obtained by phase-transfer reaction of 2,3,5-tri-O-benzyl-D-arabinofuranosyl bromide with 6-chloro-2-thiomethyl-7-deazapurine varied with the quaternary ammonium salt used as a catalyst, although the jU-anomer predominated in every case. 2,2-Anhydro-nucleosides have been used to prepare l-j3-D-arabinofiiranosyl derivatives of 5-alkylthio-uracils, 5-ethyl-cytosine, and 5-ethyl-uracil, 8-alkylamino-purines, and 2-aralkylamino-l,4-dihydro-4-imino-pyrimidine hydrochlorides (16). ... 

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