T. Sudhakar Rao

A novel synthesis of S6-cyanoethyl-2′-deoxy-6-thioguanosine and its incorporation into triple helix forming oligonucleotides☆

Abstract A simple and expeditious synthesis of S 6 -cyanoethyl-2′-deoxy-6-thioguanosine from 2′-deoxyguanosine has been accomplished in good yield and incorporated into several triple helix forming oligonucleotides using the solid-phase phosphoramidite chemistry.

A total synthesis of 2'-deoxy-9-deazaguanosine (9-deaza-dG) and its incorporation into triple helix forming oligodeoxyribonucleotides with antiparallel motif

Abstract A simple synthesis of 2-amino-7-(2-deoxy-β-D- erythro -pentofuranosyl)pyrrolo-[3,2- d ]pyrimidin-4(3 H )-one (9-deaza-dG) has been achieved and it has been incorporated into triplex forming oligonucleotides using the solid-support, phosphoramidite chemistry. 9-Deaza-dG is effective in preventing the formation of G-tetrads in G-rich oligonucleotides.

Synthesis of Certain Acyclic Nucleoside Analogs of 1,2,4-Triazolo[3,4-f][1,2,4]triazine and Pyrimido[5,4-d]pyrimidine

Abstract Synthesis of 2-penten-1-yl (8a) and ganciclovir analog (8b) of 1,2,4-triazolo[3,4-f][1,2,4]triazine was accomplished by the ring annulation of the corresponding hydrazides (6a and 6b), which in turn was obtained by the dehydrative coupling of 4 with 5a or 5b. Base catalysed ring expansion of N9-alkylpurine-6-carbonitriles (10a 10c 10e) provided the acyclic analogs of 4-aminopyrimido-[5,4-d]pyrimidines (13a 13d 13e). Debenzylation of 13e afforded the ganciclovir analog (13f) of 4-amino-8-(β-D-ribofuranosylamino)-pyrimido[5,4-d]pyrimidine. However, compound 10b did not undergo the expected rearrangement but resulted in the formation of the methyl formimidate derivative (12).

Synthesis of Triple Helix Forming Oligonucleotides Containing 2′-Deoxyformycin A

Abstract N7-Benzoyl-2′-deoxyformycin A (5) was prepared from formycin A and incorporated into the triple helix forming oligonucleotide PRE2ap at CG inversion sites. The modified oligonucleotide containing three substitutions of 2′-deoxyformycin A displayed a 10-fold increase in binding affinity as compared to its unmodified counterpart. This provided a method to accommodate CG inversion sites within target sites for antiparallel triple helix formation.

Incorporation of 2′-Deoxy-9-deazaguanosine and 2′-Deoxy-7-deaza-6-thioguanosine into G-Rich Oligodeoxyribonucleotides

Abstract The preparation of suitably protected monomeric phosphoramidite building blocks of 2′-deoxy-9-deazaguanosine (8) and 2′-deoxy-7-deaza-6-thioguanosine (12) and their incorporation into G-rich Oligodeoxyribonucleotides are described.

Total synthesis of 2′-deoxy-2′-arafluoro-tubercidin, -toyocamycin, -sangivamycin and certain related nucleosides

A total synthesis of novel nucleosides 2′-deoxy-2′-arafluoro-tubercidin 12, -toyocamycin 23, -sangivamycin 24 and -thiosangivamycin 25 has been accomplished for the first time starting from 4-chloropyrrolo[2,3-d]pyrimidine 4, and 2-bromo-5-(ethoxymethyleneamino)pyrrole-3,4-dicarbonitrile 16. The sodium-salt glycosylation of secondary amines 4 and 16 with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide 5 gave the major β-nucleosides 6 and 17 along with minor amounts of α-anomers 7 and 18. Ammonolysis of compound 6 gave the tubercidin analogue 12. The annulation of epimers 17 and 18 furnished the bromotoyocamycin 21 and its α-anomer 22, respectively. Compound 21 was converted into analogues of toyocamycin 23, sangivamycin 24 and thiosangivamycin 25. Similar functional-group manipulation of substrates 7 and 22 provided the α-anomers of compounds 12, 23, 24 and 25. Among the nucleosides tested, the sangivamycin 24 and thiosangivamycin 25 analogues have shown some interesting anti-(human cytomegalovirus) activity and it was observed that compound 25 is more active than compound 24, but less potent than 9-(1,3-dihydroxypropan-2-yloxymethyl)guanine in vitro.

Synergistic Effect of 5-Nitro-2′-deoxyuridine with Ganciclovir Against Human Cytomegalovirus In Vitro

Abstract In this paper we describe a practical synthesis of 5-nitro-2′-deoxyuridine (4) and 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-nitrouracil (11). These compounds were then evaluated for their ability to inhibit the growth of human cytomegalovirus (HCMV, strain AD169) in MRC-5 cells using a plaque reduction assay. Compound 11 was unable to inhibit the growth of HCMV at the highest concentration tested (100 μg/mL). However, compound 4 (5-NO2-dU) exhibited marginal activity against HCMV in vitro in a dose-dependent manner with a 50% inhibitory concentrations (IC50) of 1 to 5 μg/mL. Combinations of 5-NO2-dU with ganciclovir synergistically inhibited HCMV induced cell killing in culture.

Synthesis of Triple Helix Forming Oligonucleotides with a Stretched Phosphodiester Backbone

Abstract Total synthesis of novel DMT-phosphoramidites of thymidine (11 and 15) and 2′-deoxyguanosine (8 and 20) have been accomplished. The utility of these modified building blocks in the preparation of triple helix forming oligodeoxyribonucleotides with a stretched phosphodiester backbone has been evaluated. It was found that the oligonucleotides with extended backbones were unable to enhance the binding to duplex targets containing CG or TA base pairs.

Synthesis of triple helix forming oligonucleotides with a stretched phosphodiester backbone

Abstract Total syntheses of novel DMT-phosphoramidites of thymidine ( 11 and 15 ) and 2′-deoxyguanosine ( 8 and 20 ), and their utility in the preparation of triple helix forming oligodeoxyribonucleotides with a stretched phosphodiester backbone are described.

Inhibition of Tumor Necrosis Factor Alpha (TNFα) Expression and Function In Vitro by Modified Antisense Oligonucleotides

Abstract Antisense oligonucleotides containing C-5 hexynyl/propynyl modified pyrimidines were synthesized using solid phase phosphoramidite chemistry. These modified oligonucleotides were found to have significant inhibitory activity against TNFα production in vitro.