Functionalization of 2-Mercapto-5-methyl-1,3,4-thiadiazole: 2-(ω-Haloalkylthio) Thiadiazoles vs. Symmetrical Bis-Thiadiazoles.

A study on the functionalisation of 2-mercapto-5-methyl-1,3,4-thiadiazole has been conducted, yielding two series of products: 2-(ω-haloalkylthio)thiadiazoles and symmetrical bis-thiadiazoles, with variable chain lengths. The experimental conditions were optimised for each class of compounds by altering the base used and the reagents' proportions, leading to the development of separate protocols tailored to their specific reactivity and purification needs. The target halogenide reagents and bis-thiadiazole ligands were obtained either as single products or as mixtures easily separable by chromatography. Characterisation of the products was performed using 1D and 2D NMR spectra in solution, complemented by single crystal X-ray diffraction (XRD) for selected samples, to elucidate their structural properties.

Polydentate N,O-Ligands Possessing Unsymmetrical Urea Fragments Attached to a p-Cresol Scaffold.

In this study, three series of polydentate N,O-ligands possessing unsymmetrical urea fragments attached to a p-cresol scaffold are obtained, namely mono- and bi-substituted open-chain aromatics, synthesised using a common experiment, as well as fused aryloxazinones. Separate protocols for the preparation of each series are developed. It is found that in the case of open-chain compounds, the reaction output is strongly dependent on both bis-amine and carbamoyl chloride substituents, while oxazinones can be effectively obtained via a common protocol. The products are characterized via 1D and 2D NMR spectra in solution and using single-crystal XRD. A preliminary study on the coordination abilities of the products performed via ITC shows that there are no substantial interactions in the pH range of 5.0-8.5 in general.

Effect of Water on CO2 Adsorption on CaNaY Zeolite: Formation of Ca2+(H2O)(CO2), Ca2+(H2O)(CO2)2 and Ca2+(H2O)2(CO2) Complexes.

Efficient CO2 capture materials must possess a high adsorption capacity, suitable CO2 adsorption enthalpy and resistance to water vapor. We have recently reported that Ca2+ cations exchanged in FAU zeolite can attach up to three CO2 molecules. Here we report the effect of water on the adsorption of CO2. Formation of Ca2+(H2O)(CO2), Ca2+(H2O)(CO2)2 and Ca2+(H2O)2(CO2) mixed ligand complexes were established. The Ca2+(H2O)(CO2) species are readily formed even at ambient temperature and are characterized by ν(12CO2) and ν(13CO2) infrared bands at 2358 and 2293 cm-1, respectively. The Ca2+(H2O)(CO2)2 species are produced at low temperature and are identified by a ν(13CO2) band at 2291 cm-1. In the presence of large amounts of water, Ca2+(H2O)2(CO2) complexes were also evidenced by ν(12CO2) and ν(13CO2) bands at 2348 and 2283 cm-1, respectively. The results demonstrate that, although it has a negative effect on CO2 adsorption uptake, water in moderate amounts does not block CO2 adsorption sites.

New Heterocyclic Combretastatin A-4 Analogs: Synthesis and Biological Activity of Styryl-2(3H)-benzothiazolones.

Here, we describe the synthesis, characterization, and biological activities of a series of 26 new styryl-2(3H)-benzothiazolone analogs of combretastatin-A4 (CA-4). The cytotoxic activities of these compounds were tested in several cell lines (EA.hy926, A549, BEAS-2B, MDA-MB-231, HT-29, MCF-7, and MCF-10A), and the relations between structure and cytotoxicity are discussed. From the series, compound (Z)-3-methyl-6-(3,4,5-trimethoxystyryl)-2(3H)-benzothiazolone (26Z) exhibits the most potent cytotoxic activity (IC50 0.13 ± 0.01 µM) against EA.hy926 cells. 26Z not only inhibits vasculogenesis but also disrupts pre-existing vasculature. 26Z is a microtubule-modulating agent and inhibits a spectrum of angiogenic events in EA.hy926 cells by interfering with endothelial cell invasion, migration, and proliferation. 26Z also shows anti-proliferative activity in CA-4 resistant cells with the following IC50 values: HT-29 (0.008 ± 0.001 µM), MDA-MB-231 (1.35 ± 0.42 µM), and MCF-7 (2.42 ± 0.48 µM). Cell-cycle phase-specific experiments show that 26Z treatment results in G2/M arrest and mitotic spindle multipolarity, suggesting that drug-induced centrosome amplification could promote cell death. Some 26Z-treated adherent cells undergo aberrant cytokinesis, resulting in aneuploidy that perhaps contributes to drug-induced cell death. These data indicate that spindle multipolarity induction by 26Z has an exciting chemotherapeutic potential that merits further investigation.

Spontaneous conversion of O-tosylates of 2-(piperazin-1-yl)ethanols into chlorides during classical tosylation procedure.

A direct conversion of piperazinyl ethanols into chlorides via a classical O-tosylation protocol is observed. The acceleration of the transformation by the piperazine unit is demonstrated. It is found that the reaction goes via the corresponding O-tosylate, which converts spontaneously into chloride with different rate depending on the substrate structure. In the case of pirlindole derivative, partially aromatized chloride formation was observed upon prolongation and/or increased excess of tosyl chloride.

Synthesis, Spectroscopic Properties, Crystal Structure And Biological Evaluation of New Platinum Complexes with 5-methyl-5-(2-thiomethyl)ethyl Hydantoin.

BACKGROUND: The accidental discovery of Cisplatin's growth-inhibiting properties a few decades ago led to the resurgence of interest in metal-based chemotherapeutics. A number of well-discussed factors such as severe systemic toxicity and unfavourable physicochemical properties further limit the clinical application of the platinating agents. Great efforts have been undertaken in the development of alternative platinum derivatives with an extended antitumor spectrum and amended toxicity profile as compared to the reference drug cisplatin. The rational design of conventional platinum analogues and the re-evaluation of the empirically derived "structure- activity" relationships allowed for the synthesis of platinum complexes with great diversity in structural characteristics, biochemical stability and antitumor properties. METHODS: The new compounds have been studied by elemental analyses, IR, NMR and mass spectral analyses. The structures of the organic compound and one of the new mixed/ammine Pt(II) complexes were studied by X-ray diffraction analysis. The cytotoxic effects of the compounds were studied vs. the referent antineoplastic agent cisplatin against four human tumour cell lines using the standard MTT-dye reduction assay for cell viability. The most promising complex 3 was investigated for acute toxicity in male and female H-albino-mice models. RESULTS: A new organic compound (5-methyl-5-(2-thiomethyl)ethyl hydantoin) L bearing both S- and Ncoordinating sites and three novel platinum complexes, 1, 2 and 3 were synthesized and studied. Spectral and structural characterization concluded monodentate S-driven coordination of the ligand L to the metal center in complexes 1 and 2, whereas the same was acted as a bidentate N,S-chelator in complex 3. Ligand L crystallizes in the tetragonal space group I41/a (No 88) with one molecule per asymmetric unit. While complex 3 crystallizes in the monoclinic space group P21/c (No 14) with one molecule per asymmetric unit. In the same complex 3, the platinum ion coordinates an L ligand, a chloride ion and an ammonia molecule. In the in vitro experiments, the tested L and complexes 1 and 2 exhibited negligible cytotoxic activity in all tumor models. Accordingly, complex 3 is twice as potent as cisplatin in the HT-29 cells and is at least as active as cisplatin on the MDA-MB-231 breast cancer cell line. In the in vivo toxicity estimation of complex 3 no signs of common toxicity were observed. CONCLUSION: The Pt(II)-bidentate complex 3 exhibited significant cytotoxic potential equaling or surpassing that of the reference drug cisplatin in all the tested tumor models. Negligible anticancer activity on the screened tumor types has been shown by the ligand L and its Pt(II) and Pt(IV) complexes 1 and 2, respectively. Our study on the acute toxicity of the most active complex 3 proved it to be non-toxic in mice models.

Combretastatin A-4 analogues with benzoxazolone scaffold: Synthesis, structure and biological activity.

In order to design and synthesize a new class of heterocyclic analogues of natural combretastatin A-4 and its synthetic derivative AVE8062, the benzoxazolone ring was selected as a scaffold for a bioisosteric replacement of the ring B of both molecules. A library of 28 cis- and trans-styrylbenzoxazolones was obtained by a modified Wittig reaction under Boden's conditions. Structures of the newly synthesized compounds bearing the 3,4,5-trimethoxy-, 3,4-dimethoxy-, 3,5-dimethoxy-, and 4-methoxystyryl fragment at position 4, 5, 6 or 7 of benzoxazolone core were determined on the basis of spectral and X ray data. The in vitro cytotoxicity of styrylbenzoxazolones against different cell lines was examined. Stilbene derivative 16Z, (Z)-3-methyl-6-(3,4,5-trimethoxystyryl)-2(3H)-benzoxazolone, showed highest antiproliferative potential of the series, with IC50 of 0.25 µM against combretastatin resistant cell line HT-29, 0.19 µM against HepG2, 0.28 µM against EA.hy926 and 0.73 µM against K562 cells. Furthermore, the results of flow cytometric analysis confirmed that 16Z induced cell cycle arrest in G2/M phase in the cell lines like combretastatin A-4. This arrest is followed by an abnormal exit of cells from mitosis without cytokinesis into a pseudo G1-like multinucleate state leading to late apoptosis and cell death. Accordingly, synthetic analogue 16Z was identified as the most promising potential anticancer agent in present study, and was selected as lead compound for further detailed investigations.

3-[2-(5-tert-Butyl-1,2-oxazol-3-yl)hydrazinyl-idene]chroman-2,4-dione.

In the title compound, C(16)H(15)N(3)O(4), the dihedral angle between the chromane and isoxazole rings [r.m.s. deviations = 0.042 and 0.007 Å, respectively] is 20.33 (12)°. The mol-ecular geometry is stabilized by an intra-molecular N-H⋯O hydrogen bond. In the crystal, N-H⋯O hydrogen bonds generate chains along the c-axis direction. The crystal studied was a non-morohedral twin.

3-Carb-oxy-phenyl-boronic acid-theophylline (1/1).

The title two-component mol-ecular crystal [systematic name: 3-(dihy-droxy-boran-yl)benzoic acid-1,3-dimethyl-7H-purine-2,6-dione (1/1)], C(7)H(7)BO(4)·C(7)H(8)N(4)O(2), comprises theophylline and 3-carb-oxy-phenyl-boronic acid mol-ecules in a 1:1 molar ratio. In the crystal, mol-ecules are self-assembled by O-H⋯O and N-H⋯N hydrogen bonds, generating layers parallel to (-209). The layers are stacked through π-π [centroid-centroid distance = 3.546 (2) Å] and C-H⋯π inter-actions.

(R)-Methyl {[(2-carb-oxy-bicyclo-[2.2.2]octan-1-yl)-ammonio]-methyl}-phos-phon-ate dichloro-methane 0.25-solvate.

The carb-oxy-lic acid mol-ecule of the title compound, C(11)H(20)NO(5)P·0.25CH(2)Cl(2), exists as a zwitterion with the H atom of the phospho-nate group being transferred to the imine N atom. In the asymmetric unit, there are two crystallographically independent acid mol-ecules adopting the same absolute configuration and differing slightly in their geometrical parameters. In each mol-ecule, the imino and carboxyl groups are connected via an intra-molecular N-H⋯O hydrogen bond. Inter-molecular O-H⋯O and N-H⋯O hydrogen bonds induce the formation of layers parallel to the ab plane. The dichloro-methane solvent mol-ecule, with a site occupancy of 0.5, is located between the layers.

(4-Carbamoylphen-yl)boronic acid.

In the title compound, C(7)H(8)BNO(3), the mol-ecule lies on an inversion center leading to a statistical disorder of the B(OH)(2) and CONH(2) groups. In the crystal structure, mol-ecules are linked by N-H⋯O and O-H⋯O hydrogen bonds, forming sheets parallel to the bc plane. The B(OH)(2) and CONH(2) groups are twisted out of the mean plane of the benzene ring by 23.9 (5) and 24.6 (6)°, respectively.

Crystal structure and properties of the copper(II) complex of sodium monensin A.

The preparation and structural characterization of a new copper(II) complex of the polyether ionophorous antibiotic sodium monensin A (MonNa) are described. Sodium monensin A binds Cu(II) to produce a heterometallic complex of composition [Cu(MonNa)(2)Cl(2)].H(2)O, 1. The crystallographic data of 1 show that the complex crystallizes in monoclinic space group C2 with Cu(II) ion adopting a distorted square-planar geometry. Copper(II) coordinates two anionic sodium monensin ligands and two chloride anions producing a neutral compound. The sodium ion remains in the inner cavity of the ligand retaining its sixfold coordination with oxygen atoms. Replacement of crystallization water by acetonitrile is observed in the crystal structure of the complex 1. Copper(I) salt of the methyl ester of MonNa, 2, was identified by X-ray crystallography as a side product of the reaction of MonNa with Cu(II). Compound 2, [Me-MonNa][H-MonNa][CuCl(2)]Cl, crystallizes in monoclinic space group C2 with the same coordination pattern of the sodium cation but contains a chlorocuprate(I) counter [CuCl(2)](-), which is linear and not coordinated by sodium monensin A. The antibacterial and antioxidant properties as two independent activities of 1 were studied. Compound 1 is effective against aerobic Gram(+)-microorganisms Bacillus subtilis, Bacillus mycoides and Sarcina lutea. Complex 1 shows SOD-like activity comparable with that of the copper(II) ion.

Ammonium hydrogen (RS)-[(5-methyl-2-oxo-1,3-oxazolidin-3-yl)meth-yl]phospho-nate.

In the title compound, NH(4) (+)·C(5)H(9)NO(5)P(-), the five-membered methyl-oxazolidin-2-one unit is disordered over two positions, the major component having a site occupancy of 0.832 (9). A three-dimensional network of O-H⋯O and N-H⋯O hydrogen bonds stabilizes the crystal structure.