4 research outputs found
Controlled Synthesis of New 5âFluorocytosine Cocrystals Based on the p<i>K</i><sub>a</sub> Rule
5-Fluorocytosine (5-FC) was investigated
for the controlled synthesis
of cocrystals by applying the p<i>K</i><sub>a</sub> rule.
Five cocrystals were designed and developed with adipic, succinic,
terephtalic, benzoic, and malic acids, all exhibiting negative Îp<i>K</i><sub>a</sub> values ranging from close to zero up to roughly
â1. 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><sub>2</sub><sup>2</sup>(8) motifs and assembled via complementary
NâH¡¡¡O and NâH¡¡¡N hydrogen
bonds, respectively. However, in the cocrystal with malic acid (Îp<i>K</i><sub>a</sub> = â0.1), an intermediate supramolecular
synthon pattern between salts and cocrystals is observed. In this
crystal packing, the homodimer of 5-FC molecules held by the NâH¡¡¡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 5âFluorocytosine Cocrystals Based on the p<i>K</i><sub>a</sub> Rule
5-Fluorocytosine (5-FC) was investigated
for the controlled synthesis
of cocrystals by applying the p<i>K</i><sub>a</sub> rule.
Five cocrystals were designed and developed with adipic, succinic,
terephtalic, benzoic, and malic acids, all exhibiting negative Îp<i>K</i><sub>a</sub> values ranging from close to zero up to roughly
â1. 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><sub>2</sub><sup>2</sup>(8) motifs and assembled via complementary
NâH¡¡¡O and NâH¡¡¡N hydrogen
bonds, respectively. However, in the cocrystal with malic acid (Îp<i>K</i><sub>a</sub> = â0.1), an intermediate supramolecular
synthon pattern between salts and cocrystals is observed. In this
crystal packing, the homodimer of 5-FC molecules held by the NâH¡¡¡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 5âFluorocytosine. Toward Salt Formation
5-Fluorocytosine
(5-FC) was crystallized with complementary dicarboxylic
acids, aiming to achieve a controlled synthesis of structures based
on the Îp<i>K</i><sub>a</sub> rule proposed in the
saltâcocrystal 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><sub>a</sub> = 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>2<sub>1</sub>/<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 donorâacceptor site, leading to the constitution
of a 5-FCâacidâ5-FC heterodimer. Such a heterodimer
is observed in only one donorâacceptor 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 platinumÂ(II) complexes featuring phosphine
and chloroquine ligands with the general formula [PtClÂ(P)<sub>2</sub>(CQ)]ÂPF<sub>6</sub> (where (P)<sub>2</sub> = triphenylphosphine (PPh<sub>3</sub>) (<b>5</b>), 1,3-bisÂ(diphenylphosphine)Âpropane (dppp)
(<b>6</b>), 1,4-bisÂ(diphenylphosphine)Âbutane (dppb) (<b>7</b>), 1,1â˛-bisÂ(diphenylphosphine)Âferrocene (dppf) (<b>8</b>), and CQ = chloroquine] and their precursors of the type [PtCl<sub>2</sub>(P)<sub>2</sub>] are described. The complexes were characterized
by elemental analysis, absorption spectroscopy in the infrared and
ultravioletâvisible (UV-vis) regions, multinuclear (<sup>1</sup>H, <sup>13</sup>C, <sup>31</sup>P, <sup>15</sup>N, and <sup>195</sup>Pt) NMR spectroscopy, cyclic voltammetry, and mass spectrometry (in
the case of chloroquine complexes). The interactions of the new platinumâchloroquine
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