The mechanism of action of AZT
As suggested by its name, AZT is a structural analog of the nucleoside thymidine. The 3’ hydroxyl group of thymidine’s deoxyribose sugar is substituted with an azido group (N3). Thymidine is one of the four nucleosides used as the building blocks of DNA.
Synthesis of azidothymidine from thymidine
In the first published synthesis of AZT , the 5’ hydroxyl of thymidine was protected with a trityl group. The steric bulk of trityl chloride makes it highly selective for primary alcohols, leaving the more sterically encumbered secondary 3’ hydroxyl unmodified. The stereochemistry at the 3’ position was preserved by two sequential SN2 reactions. Activation of the 3’ hydroxyl as a mesylate (2) and hydrolysis gave inverted stereochemistry at this position. A second activation of the hydroxyl as a mesylate (3) and nucleophilic displacement with lithium azide yielded the azido substituent with conservation of thymidine’s stereochemistry (4). Deprotection of the trityl group under acidic conditions gave AZT.