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ability to cleave nucleic acid targets, enhanced nuclease stability, cellularuptake and distribution, in vivo tissue distribution, metabolism and clearance.Although substantial progress in the medicinal chemistry of oligonucleotides hasbeen made in the past three years, it is not yet possible to reach the conclusionabout the therapeutic ability of the novel modifications. Preliminary data oneffects on nuclease stability and hybridization properties for a few modificationsand activity in vitro suggest that the next generation of oligonucleotides maydisplay substantially improved potencies and selectivity.PYRIMIDINE MODIFICATIONS (Nucleotide)A relatively large number of modified pyrimidines have been synthesizedand now incorporated into oligonucleotides and evaluated. The principle sitesof modification are C-2, C-4, C-5 and C-6 (8). These and other nucleosideanalogues have recently been thoroughly reviewed. 250C-4C-23N24N156C-5C-6Sites of Pyrimidine Modification (8)In as much as the C-2 position is involved in Watson-Crick hybridization,oligonucleotides containing C-2 alkyl modified pyrimidines have shownunattractive hybridization characters. However, an oligonucleotide containing2-thiopyrimidine(9) was found to hybridize well to DNA and, in fact even betterto RNA with a thermal melting temperature (Tm) value of 1.5 ° C/modification.In a different study, oligoribonucleotides with 2’-o-methyl-2-thiouridine (10)47Pyrimidine…..