A contrathermodynamic sequence selectivity (5′-deoxyadenosine > 5′-deoxyguanosine) for UVirradiation-induced strand damage in duplex DNA containing 5-bromo-2′-deoxyuridine was reported several years ago (Saito, I.; Sugiyama, H. J. Am. Chem. Soc. 1990, 112, 6720.). In contrast, much smaller sequence selectivity was observed for similar duplexes containing 5-iodo-2′-deoxyuridine. We investigated the mechanism of UV-irradiation-induced cleavage of duplex DNA containing 5-bromo-2′-deoxyuridine (1, BrdU) and 5-iodo-2′-deoxyuridine (2, IdU) under anaerobic conditions using a variety of structural probes. The preference for UV-induced cleavage in 5′-dABrdU sequences is a confluence of at least three factors, photoinduced forward electron transfer, charge recombination, and electron migration within the DNA duplex. Our results also indicate that UV-irradiation of duplexes (32 nucleotides long) containing 5-iodo-2′-deoxyuridine results in strand scission involving initial photoinduced single electron transfer. The selectivity for 5′-dAIdU sequences is smaller than that in the analogous 5-bromo-2′-deoxyuridine duplexes and may be the result of faster dehalogenation of the initially formed 5-halopyrimidine radical anion and/or competitive direct carbon-iodine bond homolysis.5-Bromo-2′-deoxyuridine (1, BrdU) and 5-iodo-2′-deoxyuridine (2, IdU) exhibit a number of interesting and potentially useful chemical properties. 1 For instance, incorporation of these molecules in nucleic acids sensitizes the biopolymers to γ-radiolysis. 2 In addition, the 5-halopyrimidine nucleosides' sensitivity to UV-irradiation has been exploited in the application of these molecules as structural probes of protein-nucleic acid interactions and nucleic acid structure. 3,4 The enhancement of DNA damage caused by UV-irradiation of duplexes containing 1 and 2 has received considerable attention. 5-8 Approximately 10 years ago Saito and Sugiyama reported that UV-induced strand damage in duplex DNA containing 1 was highly dependent on the identity of the nucleotide bonded to the 5′-phosphate of 5-bromo-2′-deoxyuridine. 5 In contrast to previous studies, it was observed that UV-irradiated duplexes containing the sequence 5′-dABrdU exhibited significantly greater amounts of alkali-labile lesion formation than analogous molecules containing either a 2′-deoxyguanosine (dG) or 2′-deoxycytidine (dC) in place of the adjacent 2′-deoxyadenosine (dA). 9 These researchers postulated a novel mechanism involving initial photoinduced single electron transfer (PSET) from a 2′-deoxyadenosine bonded to the 5′-phosphate of 1 (Scheme 1). Preferential damage observed in 5′-dABrdU (3) sequences via PSET compared to those containing a 2′-deoxyguanosine nucleotide bonded to the 5′-phosphate of the halopyrimidine was surprising, given that electron transfer from deoxyguanosine is more favorable thermodynamically. 10 We now wish to report on studies that support this proposal, and demonstrate that the origin of this unexpected sequence selectivity for DNA damage in biopolymers ...

No abstract

No abstract

Tris(triisopropylsilyl)silane (iPr 3 Si) 3 SiH has been synthesized and studied by X-ray and neutron diffraction. It possesses an unusual structure in which the four silicon atoms are nearly coplanar, ∠Si-Si-Si ) 118.41(5)°. The Si-H distance is found to have a normal value of 1.506(2) Å. Thermal and room-temperature photochemical decomposition of (iPr 3 -Si) 3 SiH leads to the elimination of iPr 3 SiH and the generation of bis(triisopropylsilyl)silylene, [(iPr 3 Si) 2 Si:]. Reactions of (iPr 3 Si) 2 Si: include precedented insertions into H-Si bonds and addition to the π-bonds of olefins, alkynes, and dienes. Despite theoretical predictions of a triplet ground state for [(iPr 3 Si) 2 Si:], stereospecific addition to cis-and trans-2-butene was observed.

Chronic hepatitis C (CHC) is a major liver disease caused by the hepatitis C virus. The current standard of care for CHC can achieve cure rates above 95%; however, the drugs in current use are administered for a period of 8–16 weeks. A combination of safe and effective drugs with a shorter treatment period is highly desirable. We report synthesis and biological evaluation of a series of 2′,3′- and 2′,4′-substituted guanosine nucleotide analogues. Their triphosphates exhibited potent inhibition of the HCV NS5B polymerase with IC50 as low as 0.13 μM. In the HCV replicon assay, the phosphoramidate prodrugs of these analogues demonstrated excellent activity with EC50 values as low as 5 nM. A lead compound AL-611 showed high levels of the nucleoside 5′-triphosphate in vitro in primary human hepatocytes and in vivo in dog liver following oral administration.