Base-Paired and Base-Stacked Structures of the Anti-HIV Drug Lamivudine: A Nucleoside DNA-Mimicry with Unprecedented Topology

We have prepared a DNA-mimicry of nucleosides in which
the anti-HIV
drug lamivudine (β-l-2′,3′-dideoxy-3′-thiacytidine,
3TC) self-assembles into a base-paired and helically base-stacked
hexagonal structure. Face-to-face and face-to-tail stacked 3TC3TC
dimers base-paired through two hydrogen bonds between neutral cytosines
by either N–H···O or N–H···N
atoms give rise to a right-handed DNA-mimicry of lamivudine with an
unusual highly symmetric hexagonal lattice and topology. In addition,
a base-paired and base-stacked supramolecular architecture of lamivudine
hemihydrochloride hemihydrate was also obtained as a result of our
crystal screenings. This structure is formed through partially face-to-face
stacked lamivudine pairs held together by protonated and neutral fragments.
However, no helical stacking occurs in this structure in which lamivudine
also adopts unusual conformations as the C1′-endo and C1′-exo sugar puckers and cytosine orientations
intermediate between the anti and syn conformations. As a conclusion drawn from the nucleoside duplex,
the hexagonal DNA-mimicry of lamivudine reveals that such double-stranded
helices can be assembled without counterions and organic solvents
but with higher crystallographic symmetry instead, because only water
crystallizes together with lamivudine in this structure.