Biomedical subjects
Publications and source records attributed to E E Swayze.
As mimetics of neamine, several 4-heterocyclic 2-deoxystreptamine derivatives were chemically synthesized for RNA recognition. Conversion of 4-methylthiomethyl-5,6-di-O-acetyl-diazido-2-deoxystreptamine to the 4-chloromethyl derivative followed by reactions with different nuclophilic reagents gave the 4-heterocyclic 2-deoxystreptamine derivatives in satisfactory yields.
A synthetic library motif has been developed to create linear, nitrogen-linked compounds as screening libraries to target structured RNA for drug discovery. Scaffolds were created in situ from suitably protected bifunctional compounds linked together either by acyl or amine links. Acyl links were created from amino acids, which also introduce one degree of functionality. Amine links from the amino acid nitrogen were created from an N-protected amino alcohol via Fukuyama Mitsunobu alkylation. Each amine site can then be used for introducing functionality or extending the scaffold. This synthetic scheme can be used to create a wide variety of modified-backbone PNA in situ, as shown by the synthesis of a PNA-type monomer. The synthesis steps have been enabled on a 96-well parallel-array synthesizer for high-throughput synthesis. The present study represents a versatile synthetic approach to a wide variety of potential RNA-binding molecules.
A series of imidazo[4,5-d]isothiazole nucleosides related to the antibiotic nebularine and the highly cytotoxic 6-methyl-9-beta-D-ribofuranosylpurine have been synthesized from the corresponding heterocycles. The sodium salt glycosylation of the imidazo[4,5-d]isothiazoles proceeded smoothly, giving mixtures of N-4 and N-6 regioisomers in generally good yields. The protected derivatives were deblocked using standard conditions to afford the desired imidazo[4,5-d]-isothiazole nucleosides, usually as crystalline solids. None of the new nucleosides or heterocycles displayed selective activity against human cytomegalovirus (HCMV) or herpes simplex virus type 1 (HSV-1). The N-6 glycosylated imidazo[4,5-d]isothiazoles were completely inactive up to the highest concentration tested. The N-6 glycosylated imidazo[4,5-d]isothiazoles also were inactive in antiproliferative and cytotoxicity assays, except for 3-methyl-6-beta-D-ribofuranosylimidazo[4,5-d]isothiazole (15a) and 5-(benzylthio)-6-(2-deoxy-beta-D-ribofuranosyl)imidazo[4,5-d]isothiaz ole (5e), which showed moderate inhibition of L1210 cell growth. However, the heterocycles and several of the N-4 glycosylated derivatives were toxic to HFF, KB and L1210 cells; compounds with 5-benzylthio substituents were the most cytotoxic agents in this series.
We previously described the synthesis and in vitro antiviral activity of an acyclic thiosangivamycin analog (Gupta et al., 1989a). In order to extend these initial studies, a new, multi-gram synthesis of 4-amino-7-[(2-hydroxy- ethoxy)methyl]pyrrolo]2,3-d]pyrimidine-5-thiocarboxamide (compound 229) was achieved in 5 steps from the known 5-amino-2-bromo-3,4-dicyanopyrrole in good overall yield. In plaque reduction assays with HCMV, compound 229 had an IC50 of 7 microM; in yield reduction assays the IC90 was 25 microM. The compound was less active against MCMV, HSV-1, HSV-2, and least active against VZV. Concentrations of compound 229 up to 32 microM did not affect the growth of KB cells for incubation periods up to 72 h. At 100 microM, a prolongation in population doubling time from 21 h (untreated) to 35 h was noted. This inhibition, however, was reversible upon removal of the compound suggesting the inhibition was cytostatic rather than cytotoxic. Flow cytometric studies with compound 229 in HFF cells revealed an accumulation of cells in S phase and a concurrent loss of cells in G2/M phase, suggesting an early S phase blockage. We conclude there is adequate separation between antiviral activity and cytotoxicity to merit further work with this class of pyrrolopyrimidines.
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A combinatorial library motif has been developed based on orthogonally protected aminodiol scaffolds. Amine functionality was derivatized by commercially available electrophiles including carboxylic acids, sulfonyl chlorides, isocyanates, and aldehydes. A hydroxyl moiety was converted to a carbamate linkage, allowing a variety of amines to be incorporated. The scaffold was anchored to TentaGel at the second hydroxyl via a succinyl linker, which was hydrolyzed by mild aqueous basic conditions. The method was used to make a library of about 17,000 different members in mixtures of 5 per sample.
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