Controlled Synthesis of New 5‑Fluorocytosine Cocrystals Based on the p<i>K</i>_a Rule

5-Fluorocytosine (5-FC) was investigated for the controlled synthesis of cocrystals by applying the p<i>K</i>_a rule. Five cocrystals were designed and developed with adipic, succinic, terephtalic, benzoic, and malic acids, all exhibiting negative Δp<i>K</i>_a values ranging from close to zero up to roughly −1. The synthesized cocrystals were analyzed by single crystal X-ray diffraction, and the observed supramolecular synthons were compared to the reported structures containing 5-FC. In the first four cocrystals, the intermolecular interactions between adjacent 5-FC molecules form two different homodimers showing <i>R</i>₂²(8) motifs and assembled via complementary N–H···O and N–H···N hydrogen bonds, respectively. However, in the cocrystal with malic acid (Δp<i>K</i>_a = −0.1), an intermediate supramolecular synthon pattern between salts and cocrystals is observed. In this crystal packing, the homodimer of 5-FC molecules held by the N–H···O interactions is preserved, but a new heterodimer is formed between 5-FC and the acid molecule, such as the ones observed for 5-FC salts. These differences were analyzed using UNI Force Field Calculations to establish the intermolecular potentials of the synthons. As an application, we synthesized a cocrystal of 5-FC with 5-fluorouracil. This can be considered the first step toward the application of 5-FC for the design of new tailor-made drugs

Controlled Synthesis of New 5‑Fluorocytosine Cocrystals Based on the p<i>K</i>_a Rule

5-Fluorocytosine (5-FC) was investigated for the controlled synthesis of cocrystals by applying the p<i>K</i>_a rule. Five cocrystals were designed and developed with adipic, succinic, terephtalic, benzoic, and malic acids, all exhibiting negative Δp<i>K</i>_a values ranging from close to zero up to roughly −1. The synthesized cocrystals were analyzed by single crystal X-ray diffraction, and the observed supramolecular synthons were compared to the reported structures containing 5-FC. In the first four cocrystals, the intermolecular interactions between adjacent 5-FC molecules form two different homodimers showing <i>R</i>₂²(8) motifs and assembled via complementary N–H···O and N–H···N hydrogen bonds, respectively. However, in the cocrystal with malic acid (Δp<i>K</i>_a = −0.1), an intermediate supramolecular synthon pattern between salts and cocrystals is observed. In this crystal packing, the homodimer of 5-FC molecules held by the N–H···O interactions is preserved, but a new heterodimer is formed between 5-FC and the acid molecule, such as the ones observed for 5-FC salts. These differences were analyzed using UNI Force Field Calculations to establish the intermolecular potentials of the synthons. As an application, we synthesized a cocrystal of 5-FC with 5-fluorouracil. This can be considered the first step toward the application of 5-FC for the design of new tailor-made drugs

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

Chiral Platinum(II) Complexes Featuring Phosphine and Chloroquine Ligands as Cytotoxic and Monofunctional DNA-Binding Agents

Chiral molecules in nature are involved in many biological events; their selectivity and specificity make them of great interest for understanding the behavior of bioactive molecules, by providing information about the chiral discrimination. Inspired by these conformational properties, we present the design and synthesis of novel chiral platinum­(II) complexes featuring phosphine and chloroquine ligands with the general formula [PtCl­(P)₂(CQ)]­PF₆ (where (P)₂ = triphenylphosphine (PPh₃) (<b>5</b>), 1,3-bis­(diphenylphosphine)­propane (dppp) (<b>6</b>), 1,4-bis­(diphenylphosphine)­butane (dppb) (<b>7</b>), 1,1′-bis­(diphenylphosphine)­ferrocene (dppf) (<b>8</b>), and CQ = chloroquine] and their precursors of the type [PtCl₂(P)₂] are described. The complexes were characterized by elemental analysis, absorption spectroscopy in the infrared and ultraviolet–visible (UV-vis) regions, multinuclear (¹H, ¹³C, ³¹P, ¹⁵N, and ¹⁹⁵Pt) NMR spectroscopy, cyclic voltammetry, and mass spectrometry (in the case of chloroquine complexes). The interactions of the new platinum–chloroquine complexes with both albumin (BSA), using fluorescence spectroscopy, and DNA, by four widely reported methods were also evaluated. These experiments showed that these Pt-CQ complexes interact strongly with DNA and have high affinities for BSA, in contrast to CQ and CQDP (chloroquine diphosphate), which interact weakly with these biomolecules. Additional assays were performed in order to investigate the cytotoxicity of the platinum complexes against two healthy cell lines (mouse fibroblasts (L929) and the Chinese hamster lung (V79-4)) and four tumor cell lines (human breast (MDA-MB-231 and MCF-7), human lung (A549), and human prostate (DU-145)). The results suggest that the Pt-CQ complexes are generally more cytotoxic than the free CQ, showing that they are promising as anticancer drugs