Cytotoxic, analgesic and anti-inflammatory activity of colchicine and its C-10 sulfur containing derivatives.

10-Alkylthiocolchicines have been obtained and characterized by spectroscopic methods and their biological activities as: cytotoxic, anti-inflammatory and analgesic activities have been tested. Cytotoxic activity against SKOV-3 ovarian cell line for 10-alkylthiocolchicine analogues was reported and tested compounds showed to be more active than commonly used doxorubicin. Some of tested C-10 alkylthiolated colchicines have been found to exhibit cytotoxicity at levels comparable to that of the natural product-colchicine. 10-Methylthiocolchicine has IC50 = 8 nM and 10-ethylthiocolchicine has IC50 = 47 nM in comparison to colchicine IC50 = 37 nM. Moreover for 10-alkylthioderivatives apoptosis test, cyclin B1 and cell cycle tests were performed. 10-n-Butylthiocolchicine was tested for anti-inflammatory and analgesic activities it showed to produce analgesic rather than anti-inflammatory effect.

Antifungal, anticancer, and docking studies of colchiceine complexes with monovalent metal cation salts.

Complexes of colchiceine with monovalent cation perchlorates and iodides have been obtained and characterized by spectroscopic methods. DFT and spectroscopic studies reveal that the dihedral angle ω1-1a-12-12a , crucial for colchicine biological mechanism of action, that is, binding to tubulins depends on the diameter of the complexed metal cation. Biological tests indicated no antifungal properties of colchicine (it was active only toward A.pullulans), in contrast to its derivative-(colchiceine). Complexation of colchiceine with metal cations improved significantly the antifungal potency, even below MIC <1 µg/ml. The colchiceine complexes were more potent than colchiceine, and some of them were even more potent than the fungicidal standard IPBC. The highest potency of colchiceine complexes was noted against A. pullulans (MIC = 0.5 µg/ml). In contrast to the findings concerning antifungal potency, the anticancer studies showed complexes of colchicine more active (~IC50  = 2 nM) than those of colchiceine (~IC50  = 6 µM). MDA-MB-231 breast cancer cell lines and human lung fibroblasts CCD39Lu were also tested.

7-Deacetyl-10-alkylthiocolchicine derivatives - new compounds with potent anticancer and fungicidal activity.

A series of new semi-synthetic 7-deacetyl-10-alkylthiocolchicne derivatives with ethyl, n-propyl, i-propyl and n-butyl substituents were synthesised and characterised by spectroscopic methods, elemental analysis, DFT calculations and molecular docking simulations. All the synthesized compounds have been tested for fungicidal and anticancer activities against SKOV-3, LoVo, MCF-7, MDA-MB-231 and the lung-derived fibroblast CCD39Lu. All the new colchicine derivatives exhibit significantly higher cytotoxicity towards the SKOV-3 tumour cell line than the natural product - colchicine. The most effective cytotoxic agents were 7-deacetyl-10-n-buthylthiocolchicine and 7-deacetyl-10-i-propylthiocolchicine. Among all the compounds tested, 7-deacetyl-10-n-buthylthiocolchicine exhibited the highest fungicidal activity. Molecular modeling indicated that several mutations found in the ß-tubulin unit of the tested fungal strains are crucial for antifungal activity and selectivity of 7-deacetyl-10-n-buthylthiocolchicine. The obtained results may be useful for the development of selective colchicine derivatives as effective fungicidal and/or anticancer drugs.

Quantum-chemical, NMR, FT IR, and ESI MS studies of complexes of colchicine with Zn(II).

Colchicine is a tropolone alkaloid from Colchicinum autumnale. It shows antifibrotic, antimitotic, and anti-inflammatory activities, and is used to treat gout and Mediterranean fever. In this work, complexes of colchicine with zinc(II) nitrate were synthesized and investigated using DFT, 1H and 13C NMR, FT IR, and ESI MS. The counterpoise-corrected and uncorrected interaction energies of these complexes were calculated. We also calculated their 1H, 13C NMR, and IR spectra and compared them with the corresponding experimentally obtained data. According to the ESI MS mass spectra, colchicine forms stable complexes with zinc(II) nitrate that have various stoichiometries: 2:1, 1:1:1, and 2:1:1 with respect to colchichine, Zn(II), and nitrate ion. All of the complexes were investigated using the quantum theory of atoms in molecules (QTAIM). The calculated and the measured spectra showed differences before and after the complexation process. Calculated electron densities and bond critical points indicated the presence of bonds between the ligands and the central cation in the investigated complexes that satisfied the quantum theory of atoms in molecules. Graphical Abstract DFT, NMR, FT IR, ESI MS, QTAIM and puckering studies of complexes of colchicine with Zn(II).

Mass Spectrometric Study of Colchicine and its Synthetic Derivatives 10-Alkylthiocolchicines.

The mass spectra behaviour of five 10-alkylthiocolchicine derivatives has been studied using electron ionization and MALDI-TOF MS techniques. Fragmentation patterns of colchicines derivatives after EI have been investigated, as well as mass spectra after collision-induced dissociation (CID) MALDI have been used to gain structural information. To the best of our knowledge, this is the first time that the MALDI MS/MS data for colchicine and its alkylthio derivatives have been described. It has been shown also that the data derived from mass spectra can be used for identification/quantitative determination of natural and modified alkaloids of colchicine group. The detailed fragmentation pathways proposed here could be helpful for the characterization of other colchicines of these type. The utility of different ionization techniques for analysis of compounds of this class has been evaluated. Due to the cytotoxic activity towards tumour cell lines, 10-alkylthiocolchicines may be considered as the active ingredients of anticancer agents. If these compounds find use in medical treatment, their distribution in organism and their metabolism will have to be monitored by spectroscopic or spectrometric methods. The characteristic fragment ions may be used by Selected Reaction Monitoring method for determination of colchicine analogues.

Study of Reactive Melt Processing Behavior of Externally Plasticized Cellulose Acetate in Presence of Isocyanate.

Two types of externally plasticized cellulose acetate (CA) were chemically modified using 4,4'-methylene diphenyl diisocyanate (MDI) as crosslinking agent. Crosslinking was performed in the molten state by means of melt mixing in an internal mixer. The viscoelastic properties of the non-crosslinked, externally plasticized CA show typical temperature dependence, similar to conventional thermoplastics. A strong increase in storage modulus is observed with increasing crosslink density indicating that the crosslinked compounds exhibit predominately elastic response. The complex viscosity also increases considerably with increasing crosslink density and does not reach the typical Newtonian plateau at low radial frequencies any more. The viscoelastic properties correlate well with the data recorded online during reactive melt processing in the internal mixer. In comparison to the non-crosslinked CA, the crosslinked compounds show higher glass transition temperature, higher VICAT softening temperatures, improved thermal stability and lower plasticizer evaporation at evaluated temperatures.