Development of biodegradable thin films for efficient, specific and controlled delivery of capecitabine.

Cancer is the leading cause of death worldwide. Capecitabine (CP) shows severe side effects because of early metabolism in stomach that affects the normal cells and organs, particularly liver and stomach. In this scope, we report the biocompatible, nontoxic polymeric thin films loaded with anti-cancer drug, CP for target specific, sublingual delivery of CP. Chitosan (CS) and polyvinyl alcohol (PVA) were used as biodegradable polymers alongwith glutaraldehyde (GLA) cross linker. CP-loaded thin films (TFCP1-TFCP5) were fabricated by solvent casting method. The results of Fourier transform infrared spectroscopy confirmed the presence of CP and polymers (CS and PVA) with GLA which binds through hydrogen bonding, and compatibility of drug with different excipients. Thermogravemetric analysis showed that the thin films are highly stable while differential scanning calorimeter thermograms confirmed the complete miscibility/entrapment of CP within PVA/CS thin film matrix. X-ray diffraction patterns revealed the molecular ineractions between CP and polymer matrix. High degree of swelling index of thin films at pH 7.4 was observed in comparison to pH 5.5. CP release studies in acetate (pH 5.5) and phosphate buffer (pH 7.4) showed that the thin films swell and result in drug diffusion faster in phosphate buffer through diffusion governed by Higuchi's model. Cytotoxicity results displayed that CPTFs killed MCF-7 and T47D (human breast adenocarcinoma) cells more effectively as compared to CP alone. The results of adhesion assay also showed that the PVA and CS both are safe and biocompatible. TFCP1 and TFCP3 thin films efficiently induced the apoptosis as compared to CP alone. The improved ability of TFCP1 and TFCP3 to induce cytotoxicity in MCF-7 cells reflects the potential of these thin films for targeted drug delivery. The CPTFs were stable for 4 months at 4 °C/60% ± 2%RH and 25 °C/70% ± 2%RH. In conclusion, the thin film formulations showed target specific controlled and burst release properties and thus could prove to be effective for human breast cancer treatment.

Carboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents.

BACKGROUND: Tributyltin (IV) compounds are promising candidates for drug development. In the current study, we evaluated in-vitro and in-silico profile of carboxylate derivatives of tributyltin (IV) complexes. METHODS: ADMET and drug-likeliness properties were predicted using MetaPrint2D React, preADMET, SwissADME and Molsoft tools. SwissTargetPrediction predicted molecular targets for compounds. In-vitro bioactivity was evaluated by quantifying cytotoxicity against HepG2, THP-1 cell lines, isolated lymphocytes and leishmania promastigotes as well as measuring protein kinase (PK) inhibition activity. RESULTS: Results indicate partial compliance of compounds with drug-likeliness rules. Ch-409 complies with WDI and Lipinski rules. ADMET profile prediction shows strong plasma protein binding except for Ch-409, low to high GI absorption and BBB penetration (Cbrain/Cblood = 0.942-11; caco-2 cells permeability 20.13-26.75 nm/sec), potential efflux by P-glycoprotein, metabolism by CYP3A4, medium inhibition of hERG, mutagenicity and capacity to be detoxified by glutathionation and glucuronidation. Molecular targets include proteases, enzymes, membrane receptors, transporters and ion channels where Ch-409 targets membrane receptors only. Compounds are significantly (p < 0.05) cytotoxic against HepG2 cell line and leishmania as compared with normal isolated lymphocytes. Ch-459 indicates highest toxicity against leishmania (mortality 97.9 ± 3.99%; LC50 0.323 ± 0.002 µg/mL) whereas Ch-409 possesses maximum cytotoxicity against HepG2 cell line (IC50 0.08 ± 0.001 µg/mL) as well as 97.5 ± 1.98% (LC50 0.954 ± 0.158 µg/mL) mortality of leishmania promastigotes. It was observed that antileishmanial effect was reduced by 16.38%-34.38% and 15-38.2% in the presence of NaN3 and mannitol respectively. PK inhibition and reactive oxygen species production are possible mechanisms for cytotoxicity. CONCLUSIONS: Selected carboxylate derivatives of tributyltin (IV) complexes possess significant antileishmanial and cytotoxic potential. These are promising compounds for the development of antileishmanial and anticancer drugs. Graphical Abstract Carboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents.

2-(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-ylmeth-yl)isoindoline-1,3-dione.

The title compound, C(11)H(9)N(5)O(2)S, was synthesized from N-phthaloylglycine and thio-carbohydrazide by the fusion method. This is the first report of a triazole derivative of N-phthaloylglycine. The title compound exists in the thione form. The mol-ecule is non-planar, with a dihedral angle between the isoindoline ring system and the triazole ring system of 82.24 (5)°. The crystal structure is stabilized by inter-molecular hydrogen bonding linking the mol-ecules into a three-dimensional network.

2-Propyl-4H-thia-zolo[3,2-a][1,3,5]triazine-4-thione.

In the title compound, C(8)H(9)N(3)S(2), the n-propyl chain is disordered over two orientations (site-occupancy ratio = 0.522:0.478) and is roughly perpendicular to the fused thia-zolotriazine system. The angle between the fused ring and the propyl chain is 83.6 (1)° [ 82.2 (1)° for the disordered chain]. The structure is stabilized by C-H⋯N hydrogen bonds.

Ethyl 4-(3-butyrylthio-ureido)benzoate.

The title compound, C(14)H(18)N(2)O(3)S, crystallizes in the thio-amide form with an intra-molecular N-H⋯O hydrogen bond associated with the thio-urea unit. With the benzoic acid and the butyrylthio-ureido units, the mol-ecule consists of two planar building blocks connected by the common NH function adjacent to the aromatic ring. The inter-planar angle is 33.38 (3)°. Mol-ecules are connected in chains parallel to [110] by classical hydrogen bonds of the N-H⋯O type from the other NH group to the benzoate C=O of a neighboring mol-ecule.

Ethyl 4-(3-benzoyl-thio-ureido)benzoate.

The title compound, C(17)H(16)N(2)O(3)S, crystallizes in the thio-amide form with an intra-molecular N-H⋯O hydrogen bond across the thio-urea system. Mol-ecules are connected in chains parallel to [10] by hydrogen bonds from the second thio-urea N-H group to the benzoate C=O function.

N-(Benzothia-zol-2-yl)butyramide.

The title compound, C(11)H(12)N(2)OS, was synthesized from 2-amino-benzothia-zole and butanoyl chloride in anhydrous acetone. In the crystal structure, mol-ecules are linked by N-H⋯N and C-H⋯O hydrogen bonds and by C-H⋯π inter-actions.

N-(Thia-zol-2-yl)acetamide.

The title compound, C(5)H(6)N(2)OS, was synthesized from acetyl chloride and 2-amino-thia-zole in dry acetone. The asymmetric unit contains two mol-ecules. The crystal structure is stabilized by N-H⋯N and C-H⋯O hydrogen bonds.

1-(4-Acetyl-phen-yl)-3-butyrylthio-urea.

The title compound, C(13)H(16)N(2)O(2)S, crystallizes in the thio-amide form with an intra-molecular hydrogen bond of type N-H⋯O(butyr-yl). Mol-ecules are linked into chains parallel to [10] by a further hydrogen bond of type N-H⋯O(acet-yl). C-H⋯O and C-H⋯S hydrogen bonds are also present.

1-(1,3-Benzothia-zol-2-yl)-3-benzoyl-thio-urea.

The title compound, C(15)H(11)N(3)OS(2), was synthesized from benzoyl thio-cyanate and 2-amino-benzothia-zole in dry acetone. The thio-urea group is in the thio-amide form. The mol-ecules are stabilized by two inter-molecular C-H⋯S and C-H⋯O hydrogen bonds. Intra-molecular N-H⋯O hydrogen bonding results in a pseudo-S(6) planar ring with dihedral angles of 11.23 and 11.91° with the benzothiazole ring system and the phenyl ring, respectively.

catena-Poly[[tri-n-butyltin]-mu-N-(1-naphthyl)maleamato].

The crystal structure of catena-poly[[tri-n-butyltin]-mu-3-(1-naphthylaminocarbonyl)acrylato-kappa(2)O(1):O(3)], [Sn(C(4)H(9))(3)(C(14)H(10)NO(3))](n), is composed of polymeric chains wherein the metal center exhibits a distorted trigonal-bipyramidal geometry, with three n-butyl groups defining the trigonal plane [mean Sn[bond]C 2.133 (7) A] and the axial positions being occupied by the carboxylate O atoms of two different N-(1-naphthyl)maleamate ligands with inequivalent Sn[bond]O distances [2.167 (4) and 2.457 (4) A]. The N-(1-naphthyl)maleamate fragment forms an essentially planar seven-membered ring involving an intramolecular N[bond]H...O hydrogen bond.