text: Dideoxynucleosides are analogues of nucleoside where the sugar ring lacks both 2´ and 3´-hydroxyl groups. Three years after the synthesis of zidovudine, Jerome Horwitz and his colleagues in Chicago prepared another dideoxynucleoside now known as zalcitabine (ddC). Zalcitabine is a synthetic pyrimidine nucleoside analogue, structurally related to deoxycytidine, in which the 3´-hydroxyl group of the ribose sugar moiety is substituted with hydrogen. Zalcitabine was approved by the FDA for the treatment
  of HIV-1 in June 1992.
  2´,3´-dideoxyinosine or didanosine is converted into dideoxyadenosine in vivo. Its development has a long history. In 1964 dideoxyadenosine, the corresponding adenosine analogue of zalcitabine was synthesised. Dideoxyadenosine caused kidney damage so didanosine was prepared from dideoxyadenosine by enzymatic oxidation (see table 1). It was found to be active against HIV without causing kidney damage. Didanosine was approved by the FDA for the treatment
  of HIV-1 in October 1991.
  Zalcitabine and didanosine are both obligate chain terminators, that have been developed for anti-HIV treatment. Unfortunately, both drugs lack selectivity and therefore cause side-effects.
  Further modification of the dideoxy framework led to the development of  2´,3´-didehydro-3´-deoxythymidine (stavudine, d4T). Activity of stavudine was shown to be similar to that of zidovudine, although their phosphorylation patterns differ; the
  affinity for zidovudine to thymidine kinase (the enzyme responsible for the first phosphorylation) is similar to that of thymidine, whereas the affinity<br /> for stavudine is 700-fold weaker.
  2,3-dideoxy-3'-thiacytidine (lamivudine, 3TC) was discovered by  Bernard Belleau. The history
  of lamivudine can be traced back to the mid-1970s while  Bernard Belleau was investigating sugar derivatives. Lamivudine was developed as the sulfur analogue of zalcitabine (see table 2). It was initially synthesized as a racemic mixture (BCH-189) and analysis showed that both positive and negative enantiomers of BCH-189 (2,3-dideoxy-3-thiacytidine) had in vitro activity against HIV. Lamivudine is the negative enantiomer and is a pyrimidine nucleoside analogue. The 3 carbon of the ribose ring of 2'-deoxycytidine has been replaced by a sulfur atom because it had greater anti-HIV activity and is less toxic than the positive enantiomer.
  Next in line was 2,3-dideoxy-5-fluoro-3'-thiacytidine (Emtricitabine, FTC) which is
  a structural homologue of lamivudine. The structural difference is the 5-fluoro-modification of the base moiety of lamivudine. It is similar in many ways to lamivudine and is active against both HIV-1 and hepatitis B virus (HBV).