Synthesis of Imidazo[4,5‐b]quinoxaline Ribonucleosides as Linear Dimensional Analogs of Antiviral Polyhalogenated Benzimidazole Ribonucleosides

We have recently found that 2,5,6‐trichloro‐1‐(β‐D‐ribofuranosyl)benzimidazole (TCRB) and the corresponding 2‐bromo analog have better in vitro activities against HCMV than the clinically used agents ganciclovir and foscarnet. These benzimidazole nucleosides act by a unique mechanism, however, their biological target has not been completely identified. As an approach to probing the target, we have designed imidazo[4,5‐b]quinoxaline nucleosides as linear dimensional analogs of the benzimidazole nucleosides to study the spatial limitation of the binding site in the target enzyme. A convenient route was developed for the synthesis of 2‐substituted 6,7‐dichloroimidazo[4,5‐b]quinoxalines involving a reaction of 2,3,6,7‐tetrachloroquinoxaline with ammonia followed by a ring annulation as the key step. This furnished the versatile heterocycle 6,7‐dichloroimidazo[4,5‐b]quinoxalin‐2‐one. Ribosylation of 2‐substituted imidazo[4,5‐b]quinoxalines was influenced by the functional group at the 2‐position and the 2‐one compound was found to smoothly undergo ribosylation. The 2‐one group of the nucleoside was converted into specifically selected 2‐substituted compounds. Evaluation of the compounds for activity against two herpesviruses and for cytotoxicity showed they were less active and/or more cytotoxic than TCRB. We conclude therefore, that the binding pocket on the protein target of TCRB will tolerate some electronic and size changes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112195/1/199800071_ftp.pd

Synthesis of a pyrido[1,2-a]purine nucleoside by a novel ring cleavage-annulation reaction of 3-[beta]-D-ribofuranosylimidazo-[4,5-d]--triazin-4-one

Treatment of 7-(2,3,5-tris--(t-butyldimethylsilyl)-[beta]--ribofuranosyl)imidazo[4,5-]-v-triazin-4-one (1) with MnO2 in hot pyridine furnished 7-(2,3,5-tris--(t-butyldimethylsilyl)-[beta]--ribofuranosyl)pyrido[1,2-a]-purine (4). Treatment of 4 with tetra--butylammonium fluoride furnished the free nucleoside 5.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29091/1/0000126.pd

A novel and efficient synthesis of the naturally occurring nucleoside doridosine

1-Methylisoguanosine was synthesized by a one-pot reaction involving a condensation of 5-amino-1-([beta]--ribofuranosyl)imidazole-4-carboxamide (1) with methyl isothiocyanate, treatment of the resulting thiourea derivative with DCC furnished 5-(3-methyl-1-ureido)-1-([beta]--ribofuranosyl)imidazole-4-carbonitrile (4) which was then annulated with ethanolic ammonia to furnish doridosine in a 68% yield from 1.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25938/1/0000501.pd

The synthesis and chemistry of certain anthelmintic benzimidazoles

A basis for interest in the benzimidazole ring system as a nucleus from which to develop potential chemotherapeutic agents was established in the 1950s when it was found that 5,6-dimethyl-l-([alpha]-D-ribofuranosyl)benzimidazole (I) was an integral part of the structure of vitamin B12. As a result of these interests and extensive studies, one health related arena that has benefited greatly has been the treatment of parasitic diseases. The discovery of thiabendazole in 1961 further spurred chemists around the world to design and synthesize several thousand benzimidazoles for screening for anthelmintic activity but less than twenty of them have reached commercial use. Much of this work has been done by pharmaceutical companies and is only reported in the patent literature. In this paper, Leroy Townsend and Dean Wise review the development of some of the synthetic methods that have been critical to the preparation of the benzimidazoles of anthelmintic importance. Only a few molecules that demonstrate the processes are discussed here, but numerous reviews of the synthesis and chemistry of other benzimidazoles are available1-3.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28637/1/0000451.pd

A novel method for the synthesis of 6,7-unsubstituted pyrrolo[3,2-]pyrimidines

The synthesis of 2,4-dimethoxypyrrolo[3,2-]pyrimidine () is described. This facile, 3-step synthesis involves the bromination of 2,4-dimethoxy-6-methyl-5-nitropyrimidine (), and the subsequent conversion of compound into compound .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24161/1/0000419.pd

A novel approach towards the synthesis of the 3,4,5-trihydro-1,3-diazepin-5-ol ring structure

A catalytic reduction of the nitrile portion of the trimethylsilyl cyanohydrin to a primary amine has produced an situ annulation to generate the 3,4,5-trihydro-1,3-diazepin-5-ol ring. This ring substructure has demonstrated important biological significant.3Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25459/1/0000909.pd

A further investigation of the stannic chloride-catalyzed condensation reaction of 1-hexene and 1,2,3,5-tetra-O-acyl-[beta]--ribofuranoses

The reaction of 1-hexene with either 1-O-acetyl-2,3,5-tri-O-benzoyl-[beta]--ribofuranose (5b) or 1,2,3,5-tetra-O-acetyl-[beta]--ribofuranose (5a) in the presence of stannic chloride leads to the formation of a complex mixture of products. By a combination of 1H-n.m.r. and mass spectroscopy, the products were shown to be anomeric and diastereomeric mixtures of the 8,9,11-tri-O-acyl-protected derivatives of 7,10-anhydro-1,2,3,4,5,6-hexadeoxy--allo(altro)-undec-4-enitol (1) and 7,10-anhydro-5-chloro-1,2,3,4,5,6-hexadeoxy--allo(altro)-undecitol (2). The [alpha] anomer of 1 was the predominant anomer, whereas the [alpha] and [beta] anomers of 2 were present in approximately equal amounts. It was found that 2 was not formed when trimethylsilyl trifluoromethanesulfonate was used as the catalyst instead of stannic chloride. The acyl-protected sugar 3,6-anhydro-2-deoxy--allo(altro)-heptose (3), prepared by ozonolysis of 1, reacted with tert-butoxycarbonylmethyltriphenylphosphorane to give tert-butyl trans-5,8-anhydro-6,7,9-tri-O-acetyl-2,3,4-trideoxy--allo(altro)-non-2-enanate (4). The basicity of the ylide was sufficient to cause anomerization and resulted in an [alpha],[beta] ratio of 5:1 in the product, 4.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25238/1/0000680.pd

A total synthesis of the naturally occurring pyrrolo[2,3-]pyrimidine nucleoside, mycalisine A

The first total synthesis of mycalisine A, a pyrrolo[2,3-]pyrimidine nucleoside, was accomplished by a multi-step synthesis from toyocamycin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27618/1/0000662.pd

Specificity of adenine binding to lima bean lectin

The interactions between lima bean lectin (LBL) and adenine were examined using a series of synthetic purine analogs. Binding was sensitive to modification at most positions of the purine ring, suggesting a high degree of specificity for adenine binding. Methylation ofthe 6 NH2-group to MeNH-, Me2N- and Me3N+-analogs progressively decreased the binding affinity. Compounds lacking the 6 NH2-group were not bound. Methylation of adenine at N1, N3 or N7 also inhibited binding, indicating specific interactions with these ring nitrogens. In contrast to the previous report that N9-substituted adenines, nucleosides and nucleotides were not bound [Roberts, D. D. and Goldstein, I. J. (1983) J. Biol. Chem. 258, 13820], 9-methyl- and 9-benzyl-substituted adenines were bound to LBL with high affinity. Substitutions at C-2 and C-8 were tolerated and, in some cases, increased the affinity of binding to LBL. Heterotropic interactions between the adenine and 1,8-anilinonaphthalenesulphonate binding sites were also sensitive to modification of the purine ring. 2-Methylthioadenine and 4-aminopyrazolo[3,4-d]pyrimidine showed increased allosteric interaction with 1,8-anilinonaphthalenesulphonate binding, whereas several adenine analogs with a 9-p-nitrobenzyl substituent appeared to be negative effectors of 1,8-anilinonaphthalenesulphonate binding.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26427/1/0000515.pd

Pyrrolopyrimidine nucleosides 19. A total synthesis of the nucleoside antibiotic cadeguomycin [2-amino-7-([beta]-d-ribofuranosyl)-pyrrolo[2,3-]pyrimidin-4-one-5-carboxylic acid]

A total synthesis of 2-amino-7-([beta]-D-ribofuranosyl)pyrrolo[2,3-]pyrimidin-4-one-5-carboxylic acid has been accomplished and confirms the previous structural assignment for the nucleoside antibiotic cadeguomycin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25460/1/0000910.pd