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′-<i>endo</i> and C1′-<i>exo</i> sugar puckers and cytosine orientations intermediate between the <i>anti</i> and <i>syn</i> 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

The Continuum in 5‑Fluorocytosine. Toward Salt Formation

5-Fluorocytosine (5-FC) was crystallized with complementary dicarboxylic acids, aiming to achieve a controlled synthesis of structures based on the Δp<i>K</i>_a rule proposed in the salt–cocrystal continuum study and to provide structural information helpful in the comprehension of its supramolecularity. Although 5-FC tends to be basic, p<i>K</i>_a = 3.26, only three salts are reported. In this way, new 5-FC salts were obtained, the fumaric, maleic and oxalic ones, all crystallizing in the monoclinic space group <i>P</i>2₁/<i>c</i>. In the 5-FC oxalate and fumarate cases, the acid molecules are placed on an inversion center in a fashion that each half molecule exhibits one terminal donor–acceptor site, leading to the constitution of a 5-FC–acid–5-FC heterodimer. Such a heterodimer is observed in only one donor–acceptor site of the maleate of 5-FC, whose acid molecule exhibits a closed chain architecture. Infrared and Raman spectra recorded for the three compounds complement the salt characterization on the basis of the extent of proton transfer. Thermal analysis evidence that the salt formation decreases the melting point of the new compounds, ranking this molecule as a coformer candidate to improve the physical properties of other drugs