Robert N. Comber

Acyclic analogues of pyrazofurin: syntheses and antiviral evaluation

Acyclic analogues of pyrazofurin, including 4-hydroxy-3(5)-[( 2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl)-1H-pyrazole-5 (3)-carboxamide (36) and 4-hydroxy-3(5)-[(2-hydroxyethoxy)methyl]-1H-pyrazole-5(3)-carboxamide (27), that possess the side chains of ganciclovir and acyclovir, respectively, were prepared by heating methyl 4-acetoxy-1-acetyl-3-bromomethyl-1H-pyrazole-5-carboxylate (15) and sodium acetate in the requisite alcohols or, for 36, with the sodium alkoxide in dry tetrahydrofuran. These analogues have no antiviral activity, except 4-hydroxy-3(5)-[(3-hydroxypropoxy)methyl]-1H-pyrazole-5(3)-carboxamide (28), which exhibited slight activity against human cytomegalovirus.

Homologated aza analogs of arabinose as antimycobacterial agents

A series of hydrolytically-stable aza analogs of arabinofuranose was prepared and evaluated against Mycobacterium tuberculosis and M. avium. The compounds were designed to mimic the putative arabinose donor involved in biogenesis of the essential cell wall polysaccharide, arabinogalactan. Though most compounds displayed little activity in cell culture, one compound showed significant activity in infected macrophage models.

Syntheses of phosphonate analogues of dideoxyadenosine (DDA)-, dideoxycytidine (DDC)-, dideoxyinosine (DDI)-, and deoxythymidine (DDT)-5'-monophosphates

Abstract Phosphonate derivatives of ddA, ddC, ddI and ddT (5f, 5e, 5c, and 5a) were prepared by condensing the 5′-aldehydes with diphenyl triphenylphosphoranylidenemethylphosphonate, reducing the resultant olefins and hydrolyzing the phosphonate phenyl esters, sequentially, with base and then C. atrox phosphodiesterase.

α-(1 → 2)-, α-(1 → 3)-, and α-(1 → 6)-Linked thioglycosidic disaccharides: syntheses and anti-HIV testing of thiokojibiose octaacetate, thionigerose, and thioisomaltose

The syntheses of several alpha-linked thioglycosidic disaccharides are described, including thiokojibiose octaacetate (1), thionigerose (2), and thioisomaltose (3). The title compounds were synthesized by coupling 2,3,4,6-tetra-O-acetyl-1.5-acetyl-1-thio-alpha-D-glucopyranose (4) with either 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethylsulfonyl-beta-D-manno pyr anose (7), 1,2:5,6-di-O-isopropylidene-3-O-trifluoromethylsulfonyl-alpha-D-++ +allofuranose (15), or methyl 2,3,4-tri-O-acetyl-6-deoxy-6-iodo-alpha-D-glucopyranoside (17), respectively. Thiokojibiose octaacetate in turn was converted to 3,4,6-tri-O-acetyl-2-S-(2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl)-2 -thio-alpha-D-glucopyranosyl bromide (9), which was used to obtain several related disaccharides and one trisaccharide. All of the compounds, including thiomaltose and thiotrehalose, which were resynthesized by known methods, were tested for their anti-HIV activity in either CEM or MT-2 cells. Anti-HIV activity was noted only with thiokojibiose octaacetate and its 1-thio analogue (14), which had IC50 values of 51 and 48 micrograms/mL in CEM cells, respectively.

Phosphate Modified Analogues of 5′-O-Phosphorylated 2′,3′-Dideoxynucleosides: Synthesis and Anti-HIV Activity

Abstract Phosphonate analogues of 5′-O-phosphoryl-2′,3′-dideoxyribofuranosyl adenine, cytosine, hypoxanthine and thymine were synthesized. The hypoxanthine and thymine analogues were inactive against HIV induced cyopathy in the CEM-4 T-cell lines. The 2′,3′-ddC and 2′,3′-ddA analogues were marginally active.