We show that DNA containing a conformationally-locked anti analogue of O(6)-alkylguanine is a poor substrate for human O(6)-methylguanine-DNA methyltransferase (MGMT) and the alkyltransferase-like protein, Atl1. This highlights the requirement for the syn conformation and rationalises why certain O(6)-alkylguanines are poor MGMT substrates.

Natural products from medicinal plants either as pure compounds or standardized extracts, provide unlimited opportunities for new drug leads, because of the unmatched availability of chemical diversity. Due to an increasing demand for therapeutic drugs from natural products, interest particularly in edible plants has grown throughout the world. The phytochemical screening was carried out via standard procedures while the isolation and characterization was done using different solvents via thin layer and column chromatography. The bioactivity studies of the purely active compound isolated was achieved using different clinical bacterial isolates, gram negative (E. coli and Salmonella typhi) and positive (Staphylococcus aureus); the radical scavenging power of the purely active compound was assayed using 2,2-diphenyl-1-picrylhydrazyl(DPPH) and characterization using GCMS, 1HNMR, 13CNMR and FTIR was carried out to facilitate structure elucidation. The focus of this paper is on the analytical and biological methodologies, which includes the extraction, isolation, bioactivity studies, and characterization of the purely active ingredients in the stem bark of Adenanthera pavonina.

Promutagenic O 6-alkylguanine adducts in DNA are repaired in humans by O 6-methylguanine-DNA-methyltransferase (MGMT) in an irreversible reaction. Here we describe the synthesis of a phosphoramidite that allows the preparation of oligodeoxyribonucleotides (ODNs) containing a novel tricyclic thio analogue of O 6-methylguanine in which the third ring bridges the 6-thio group and C7 of a 7-deazapurine. These ODNs are very poor substrates for MGMT and poorly recognised by the alkyltransferase-like protein, Atl1. Examination of the active sites of both MGMT and Atl1 suggest large steric clashes hindering binding of the analogue. Such analogues, if mutagenic, are likely to be highly toxic.

No abstract

Phosphoramidite are the DNA building blocks. For the DNA synthesis to proceed it is necessary to block or protect all the nucleophilic centres not involved in the reaction at each step of the synthesis. The commonly used DNA protecting groups includes; dimethoxytrityl (DMT) which is used to protect the 5'-OH, benzoyl (Bz) is used to protect the exocyclic NH 2 groups of adenine and cytosine whilst isobutyryl (Ib) group is used for guanine protection. Thymine does not need protection as it has no exocyclic NH 2 groups. The phosphate group is usually protected with the cyanoethyl group, whilst the 3'-OH is protected by virtue of the connection to the controlled pore glass (CPG) solid support. Here, the 2-amino group of the nucleoside, 1 was initially protected as its dimethylformamidine derivative (using N,N-dimethylformamide) which later decomposed into the N-formylamino compound which was never been used before and was found to be suitable for the protection of the exocyclic amino group for DNA synthesis. The 5'-OH group as usual was protected with dimethoxytrityl (DMT) using dimethoxytrityl chloride following which phosphitylation gave the phosphoramidite compound 4. The chemistry involved in the conversion of the dimethylformamidine to N-formylamino compound is presented here.