Novel Hybrid Compound 4-[(E)-2-phenylethenesulfonamido]-N-hydroxybutanamide with Antimetastatic and Cytotoxic Action: Synthesis and Anticancer Screening.

BACKGROUND: One of the most promising strategies to develop multi-targeted anticancer therapeutics is to introduce to the structure of a potential drug two or more pharmacophores (functional groups or structural fragments), which have antiproliferative, proapoptotic or antimetastatic properties acting via different mechanisms. OBJECTIVE: To design, synthesize and perform screening of a novel hybrid anticancer compound. METHOD: A novel hybrid compound 4-[(E)-2-phenylethenesulfonamido]-N-hydroxybutanamide, combining butanehydroxamate and styrenesulfonamide moieties, was designed, synthesized and investigated as a potent antimetastatic and antiproliferative agent. The structure and purity of the synthesized compound were confirmed by 1H NMR, 13C NMR, LC/MS spectroscopy and elemental analysis. The compound was screened for the anticancer activity in vitro against HeLa and in vivo against Lewis lung carcinoma tumor, using an antitumor metalloenzyme inhibitor GM6001 (Ilomastat, Galardin) and Pifithrin-µ as control anticancer agents. RESULTS: It was found that the application of our compound resulted in a high fraction of apoptotic cells in the cell population, along with disruption in the cell cycle profile manifested as arrest of proliferative phases. Furthermore, changes of the morphological properties (i.e., an enhancement of adhesive properties and reduction of the nuclear-to-cytoplasm ratio) were found. The in vivo screening revealed that the compound significantly inhibited the metastasizing process that was manifested by a reduction in the number and volume of metastases. CONCLUSIONS: The obtained results demonstrate that our compound can serve as a base for further structure optimization in order to design new highly-effective antimetastatic and antitumor agents.

Synthesis and crystal structure of N-(4-chloro-phen-yl)-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidin-2-amine.

The title compound, C13H12ClN5, was synthesized by the cyclization of 1-(4,6-di-methyl-pyrimidin-2-yl)-4-phenyl-thio-semicarbazide in the presence of Ni(NO3)2. The mol-ecular structure of the compound is essentially planar. In the crystal, mol-ecules form dimers via pairs of N-H⋯N hydrogen bonds between the H atom of the exocyclic amino group and the N atom at the 4-position of the triazole ring. The resulting dimers are packed into layers which are connected by π-stacking inter-actions between the aromatic systems of the pyrimidine and benzene nuclei, and between the triazole cores.

Crystal structure of di-chlorido-{4-[(E)-(meth-oxy-imino-κN)meth-yl]-1,3-thia-zol-2-amine-κN (3)}palladium(II).

In the title compound, [PdCl2(C5H7N3OS)], the Pd(II) atom adopts a distorted square-planar coordination sphere defined by two N atoms of the bidentate ligand and two Cl atoms. The mean deviation from the coordination plane is 0.029 Å. The methyl group is not coplanar with the plane of the metallacycle [torsion angle C-O-N-C = 20.2 (4)°]. Steric repulsion between the methyl group and atoms of the metallacycle is manifested by shortened intra-molecular H⋯C contacts of 2.27, 2.38 and 2.64 Å, as compared with the sum of the van der Waals radii of 2.87 Å. The amino group participates via one H atom in the formation of an intra-molecular N-H⋯Cl hydrogen bond. In the crystal, the other H atom of the amino group links mol-ecules via bifurcated N-H⋯(Cl,O) hydrogen bonds into chains parallel to [001].

[1-(2-Oxidobenzyl-idene)-4-phenyl-thio-semicarbazidato-κO,N,S](pyridine-κN)copper(II).

In the structure of the title compound, [Cu(C(14)H(11)N(3)OS)(C(5)H(5)N)], the Cu(II) atom exhibits a slightly distorted square-planar CuN(2)OS coordination polyhedron consisting of a phenyl O, an azomethine N and a thio-amide S atom from the tridentate thio-semicarbazonate dianion, and the N atom of a pyridine mol-ecule. The thio-semicarbazonate ligand exists in the thiol tautomeric form as an E isomer. Rotational disorder of the pyridine and phenyl rings in a 1:1 ratio of the respective components is observed. An extensive network of weak N-H⋯S, C-H⋯O, C-H⋯N and C-H⋯S hydrogen-bonding inter-actions consolidates the structure.

Poly[[µ(2)-(1Z,N'E)-2-(1,3-benzothia-zol-2-ylsulfan-yl)-N'-(2-oxidobenzyl-idene-κO:O)acetohydrazidato-κO,N'](pyridine-κN)copper(II)].

In the title compound, [Cu(C(16)H(11)N(3)O(2)S(2))(C(5)H(5)N)](n), the Cu(II) atom displays a square-pyramidal CuN(2)O(3) coordination geometry with strong elongation in the vertex direction. The hydrazone mol-ecule is coordinated to the Cu(II) atom in a tridentate manner in the enolic form, creating five- and six-membered chelate metallarings. The pyridine mol-ecule completes the square-planar base of the copper coordination environment. The crystal structure displays zigzag polymeric Cu-O-Cu chains along [001]. Several weak π-π inter-actions between benzothia-zole rings were found in the same direction [centroid-centroid distances = 3.7484 (16), 3.7483 (16), 3.6731 (17) and 3.7649 (17) Å].

cis-(Pyridin-2-ylcarbonimidodithio-ato-κS,S')bis-(triphenyl-phosphane-κP)palladium(II).

The title compound, [Pd(C(6)H(4)N(2)S(2))(C(18)H(15)P)(2)], was obtained as a minor product from the reaction of trans-PdCl(2)(PPh(3))(2) with piperazine-1,4-dicarbothioic acid bis-(pyridin-2-yl)amide. The Pd(II) atom displays a slightly distorted square-planar PdP(2)S(2) geometry with a bidentately coordinated pyridin-2-ylcarbonimidodithio-ate ligand and two triphenyl-phosphine mol-ecules, coordinated in cis positions. The crystal structure features weak π-π [centroid-centroid distance =3.7327(15) Å] and C-H⋯π inter-actions and contains an almost spherically shaped void of 50.4 Å(3) per unit cell.

trans-Dichloridobis(4-methoxy-aniline-κN)palladium(II).

In the title compound, [PdCl(2)(C(7)H(9)NO)(2)], the Pd atom is situated on a crystallographic centre of inversion. The coordination environment of the Pd atom shows a slightly distorted square-planar geometry. The crystal structure exhibits weak inter-molecular Pd⋯Cl inter-actions, with Pd⋯Cl distances of 3.6912 (6) Å. A chain-like arrangement of mol-ecules realized by inter-molecular N-H⋯Cl hydrogen bonds is observed along [010].

cis-Bis[1-allyl-3-(2-pyrid-yl-κN)thio-ureato-κS]palladium(II).

Yellow plate-like shaped crystals of the title compound, [Pd(C(9)H(10)N(3)S)(2)], were obtained by ligand-exchange reaction between palladium(II) acetyl-acetonate and the corresponding organic reagent at room temperature. The Pd(II) atom shows a slightly distorted square-planar coordination geometry consisting of two ligand mol-ecules in a cis conformation that bind in their thio-lic tautomeric form. Weak inter-molecular Pd⋯H inter-actions with Pd-H distances of 3.328 (2) Šwere observed in the crystal structure. The three-dimensional network of the crystal structure is realized by weak inter-molecular C-H⋯N, N-H⋯N and C-H⋯S hydrogen bonds.