2-Thiouracil

2-Thiouracil is a thiolated uracil derivative that is a known antihyperthyroid agent.

Immunohistochemistry of aberrant neuronal development induced by 6-propyl-2-thiouracil in rats.[Pubmed:27553673]

Toxicol Lett. 2016 Nov 2;261:59-71.

6-Propyl-2-Thiouracil (PTU)-induced hypothyroidism disrupts neuronal/glial development. This study sought to identify the sensitive immunohistochemical parameters of developmental neurotoxicity (DNT) following PTU-exposure, as well as their responses in a 28-day toxicity study in adults. In the developmental exposure study, pregnant rats were treated with 0, 1, 3, and 10ppm PTU in drinking water from gestational day 6 to postnatal day (PND) 21 and pups were examined on PNDs 21 and 77. In the adult-stage exposure study, 5-week-old male rats were treated with 0, 0.1 and 10mg PTU/kg by oral gavage for 28 days. In the developmental exposure study on PND 21, there were fewer GFAP(+), PAX6(+), and DCX(+) cells in the subgranular zone (SGZ) of the hippocampal dentate gyrus at >/=3 or 10ppm. Regarding synaptic plasticity-related molecules, there were fewer EPHA4(+) and ARC(+) cells in the dentate granule cell layer. Regarding GABAergic interneuron subpopulations, there were more RELN(+), CALB2(+), and SST(+) cells and fewer PVALB(+) cells in the dentate hilus. There were also differences in the numbers of RELN(+), PVALB(+), CALB2(+), and NPY(+) cells in the cerebral cortex, and RELN(+), PVALB(+), and SST(+) cells in the cerebellar cortex. Most of these changes were sustained until PND 77. Following adult-stage exposure (10mg/kg), there were fewer SGZ DCX(+) cells, but more RELN(+) and SST(+) cells in the dentate hilus. Results suggest that GABAergic interneuron populations in cortical tissues, hippocampal neurogenesis, and synaptic plasticity are sensitive to PTU-induced DNT during development. In contrast, only hippocampal neurogenesis was sensitive to adult-stage exposure.

Intersystem Crossing Pathways in the Noncanonical Nucleobase 2-Thiouracil: A Time-Dependent Picture.[Pubmed:27167106]

J Phys Chem Lett. 2016 Jun 2;7(11):1978-83.

The deactivation mechanism after ultraviolet irradiation of 2-Thiouracil has been investigated using nonadiabatic dynamics simulations at the MS-CASPT2 level of theory. It is found that after excitation the S2 quickly relaxes to S1, and from there intersystem crossing takes place to both T2 and T1 with a time constant of 400 fs and a triplet yield above 80%, in very good agreement with recent femtosecond experiments in solution. Both indirect S1 --> T2 --> T1 and direct S1 --> T1 pathways contribute to intersystem crossing, with the former being predominant. The results contribute to the understanding of how some noncanonical nucleobases respond to harmful ultraviolet light, which could be relevant for prospective photochemotherapeutic applications.

Eight new crystal structures of 5-(hydroxymethyl)uracil, 5-carboxyuracil and 5-carboxy-2-thiouracil: insights into the hydrogen-bonded networks and the predominant conformations of the C5-bound residues.[Pubmed:27146565]

Acta Crystallogr C Struct Chem. 2016 May 1;72(Pt 5):379-88.

In order to examine the preferred hydrogen-bonding pattern of various uracil derivatives, namely 5-(hydroxymethyl)uracil, 5-carboxyuracil and 5-carboxy-2-Thiouracil, and for a conformational study, crystallization experiments yielded eight different structures: 5-(hydroxymethyl)uracil, C5H6N2O3, (I), 5-carboxyuracil-N,N-dimethylformamide (1/1), C5H4N2O4.C3H7NO, (II), 5-carboxyuracil-dimethyl sulfoxide (1/1), C5H4N2O4.C2H6OS, (III), 5-carboxyuracil-N,N-dimethylacetamide (1/1), C5H4N2O4.C4H9NO, (IV), 5-carboxy-2-Thiouracil-N,N-dimethylformamide (1/1), C5H4N2O3S.C3H7NO, (V), 5-carboxy-2-Thiouracil-dimethyl sulfoxide (1/1), C5H4N2O3S.C2H6OS, (VI), 5-carboxy-2-Thiouracil-1,4-dioxane (2/3), 2C5H4N2O3S.3C6H12O3, (VII), and 5-carboxy-2-Thiouracil, C10H8N4O6S2, (VIII). While the six solvated structures, i.e. (II)-(VII), contain intramolecular S(6) O-H...O hydrogen-bond motifs between the carboxy and carbonyl groups, the usually favoured R2(2)(8) pattern between two carboxy groups is formed in the solvent-free structure, i.e. (VIII). Further R2(2)(8) hydrogen-bond motifs involving either two N-H...O or two N-H...S hydrogen bonds were observed in three crystal structures, namely (I), (IV) and (VIII). In all eight structures, the residue at the ring 5-position shows a coplanar arrangement with respect to the pyrimidine ring which is in agreement with a search of the Cambridge Structural Database for six-membered cyclic compounds containing a carboxy group. The search confirmed that coplanarity between the carboxy group and the cyclic residue is strongly favoured.

6-Propyl-2-thiouracil versus 6-methoxymethyl-2-thiouracil: enhancing the hydrogen-bonded synthon motif by replacement of a methylene group with an O atom.[Pubmed:27487338]

Acta Crystallogr C Struct Chem. 2016 Aug 1;72(Pt 8):634-46.

The understanding of intermolecular interactions is a key objective of crystal engineering in order to exploit the derived knowledge for the rational design of new molecular solids with tailored physical and chemical properties. The tools and theories of crystal engineering are indispensable for the rational design of (pharmaceutical) cocrystals. The results of cocrystallization experiments of the antithyroid drug 6-propyl-2-Thiouracil (PTU) with 2,4-diaminopyrimidine (DAPY), and of 6-methoxymethyl-2-Thiouracil (MOMTU) with DAPY and 2,4,6-triaminopyrimidine (TAPY), respectively, are reported. PTU and MOMTU show a high structural similarity and differ only in the replacement of a methylene group (-CH2-) with an O atom in the side chain, thus introducing an additional hydrogen-bond acceptor in MOMTU. Both molecules contain an ADA hydrogen-bonding site (A = acceptor and D = donor), while the coformers DAPY and TAPY both show complementary DAD sites and therefore should be capable of forming a mixed ADA/DAD synthon with each other, i.e. N-H...O, N-H...N and N-H...S hydrogen bonds. The experiments yielded one solvated cocrystal salt of PTU with DAPY, four different solvates of MOMTU, one ionic cocrystal of MOMTU with DAPY and one cocrystal salt of MOMTU with TAPY, namely 2,4-diaminopyrimidinium 6-propyl-2-Thiouracilate-2,4-diaminopyrimidine-N,N-dimethylacetamide-water (1/1/1/1) (the systematic name for 6-propyl-2-Thiouracilate is 6-oxo-4-propyl-2-sulfanylidene-1,2,3,6-tetrahydropyrimidin-1-ide), C4H7N4(+).C7H9N2OS(-).C4H6N4.C4H9NO.H2O, (I), 6-methoxymethyl-2-Thiouracil-N,N-dimethylformamide (1/1), C6H8N2O2S.C3H7NO, (II), 6-methoxymethyl-2-Thiouracil-N,N-dimethylacetamide (1/1), C6H8N2O2S.C4H9NO, (III), 6-methoxymethyl-2-Thiouracil-dimethyl sulfoxide (1/1), C6H8N2O2S.C2H6OS, (IV), 6-methoxymethyl-2-Thiouracil-1-methylpyrrolidin-2-one (1/1), C6H8N2O2S.C5H9NO, (V), 2,4-diaminopyrimidinium 6-methoxymethyl-2-Thiouracilate (the systematic name for 6-methoxymethyl-2-Thiouracilate is 4-methoxymethyl-6-oxo-2-sulfanylidene-1,2,3,6-tetrahydropyrimidin-1-ide), C4H7N4(+).C6H7N2O2S(-), (VI), and 2,4,6-triaminopyrimidinium 6-methoxymethyl-2-Thiouracilate-6-methoxymethyl-2-Thiouracil (1/1), C4H8N5(+).C6H7N2O2S(-).C6H8N2O2S, (VII). Whereas in (I) only an AA/DD hydrogen-bonding interaction was formed, the structures of (VI) and (VII) both display the desired ADA/DAD synthon. Conformational studies on the side chains of PTU and MOMTU also revealed a significant deviation for cocrystals (VI) and (VII), leading to the desired enhancement of the hydrogen-bond pattern within the crystal.