Development of 5-fluorouracil-dichloroacetate mutual prodrugs as anticancer agents.

5-Fluorouracil (5-FU) is one of the most widely applied chemotherapeutic agents with a broad spectrum of activity. However, despite this versatile activity, its use poses many limitations. Herein, novel derivatives of 5-FU and dichloroacetic acid have been designed and synthesized as a new type of codrugs, also known as mutual prodrugs, to overcome the drawbacks of 5-FU and enhance its therapeutic efficiency. The stability of the obtained compounds has been tested at various pH values using different analytical techniques, namely HPLC and potentiometry. The antiproliferative activity of the new 5-FU derivatives was assessed in vitro on SK-MEL-28 and WM793 human melanoma cell lines in 2D culture as well as on A549 human lung carcinoma, MDA-MB-231 breast adenocarcinoma, LL24 normal lung tissue, and HMF normal breast tissue as a multicellular 3D spheroid model cultured in standard (static) conditions and with the use of microfluidic systems, which to a great extent resembles the in vivo environment. In all cases, new mutual prodrugs showed a higher cytotoxic activity toward cancer models and lower to normal cell models than the parent 5-FU itself.

New insight into nucleo α-amino acids - Synthesis and SAR studies on cytotoxic activity of ß-pyrimidine alanines.

Three series of the ß-pyrimidine alanines, including willardiine - a naturally occurring amino acid, were prepared from the l-serine-derived sulfamidates. Compounds 3b, 4a and 4b demonstrated antiproliferative activity toward the studied cancer cell lines, albeit the effect of these compounds on human brain astrocytoma MOG-G-CCM cells was more significant than on human neuroblastoma SK-N-AS cells. The cytosine analog of willardiine, compound 4b, reduced viability of MOG-G-CCM cells with EC50 = 36 ± 2 µM, more effectively than AMPA antagonist GYKI 52466. Willardiine showed possible capability of affecting invasiveness of glioblastoma U251 MG cells with no effect on their viability and morphology. Compound 3d, the ethyl ester of willardiine, featured activity toward binding domain hHS1S2I of the GluR2 receptor. Docking analysis revealed that the location mode of compound 3d at the S1S2 domain of hGluR2 (PDB ID: 3R7X) might differ from that of willardiine.

Potential bioisosteres of ß-uracilalanines derived from 1H-1,2,3-triazole-C-carboxylic acids.

The 1H-1,2,3-triazole-originated derivatives of willardiine were obtained by: (i) construction of the 1H-1,2,3-triazole ring in 1,3-dipolar cycloaddition of the uracil-derived azides and the carboxylate-bearing alkynes or α-acylphosphorus ylide, or (ii) N-alkylation of the uracil derivative with the 1H-1,2,3-triazole-4-carboxylate-derived mesylate. The latter method offered: (i) reproducible results, (ii) a significant reduction of amounts of auxiliary materials, (iii) reduction in wastes and (iv) reduction in a number of manual operations required for obtaining the reaction product. Compound 6a exhibited significant binding affinity to hHS1S2I ligand-binding domain of GluR2 receptor (EC50 = 2.90 µM) and decreased viability of human astrocytoma MOG-G-CCM cells in higher extent than known AMPA antagonist GYKI 52466.

Synthesis of novel aza-analogues of tiazofurin with 2-[5,5-bis(hydroxymethyl)pyrrolidin-2-yl] framework as sugar mimic.

The novel aza-analogues of tiazofurin (TZF) with 2-[5,5-bis(hydroxymethyl)pyrrolidin-2-yl] moiety, as sugar mimic, were synthesized from O,O-cyclohexylidene derivative of 4,4-bis(hydroxymethyl)-4-nitrobutanal in multi-gram scale. The synthetic route consisted of three stages: (i) the synthesis of corresponding derivative of 5,5-bis(hydroxymethyl)pyrrolidine-2-carbonitrile, (ii) the construction of ethyl thiazole-2-carboxylate part by the conversion of the pyrrolidine-2-carbonitrile into the N-trifluoroacetyl derivative followed by cyclocondensation with L-cysteine ethyl ester and then by dehydrogenation, and (iii) the final transformation of the ethyl thiazole-4-carboxylate into the aza-analogues of TZF. The TZF aza-analogues were evaluated for their antiviral activities in cell-culture-based assays.

Complexation of metal ions in Langmuir films formed with two amphiphilic dioxadithia crown ethers.

The two new crown ethers presented in this study were synthesized in order to investigate two important features of ionophores, namely metal cation complexation and interfacial properties, and the way in which they interrelate. The two derivatives were conceived as analogs of membrane phospholipids with respect to their amphiphilicity and geometry. They contain a hydrophilic 1,1'-dioxo-3,3'-dithio-14-crown ether headgroup and bear two myristoyl or stearoyl lateral chains. The length of the myristoyl and stearoyl derivatives in an extended conformation is comparable with the thickness of the individual leaflets of cell membranes. The membrane-related and complexation properties of the two crown ether derivatives were studied in monomolecular films spread on pure water and on aqueous solutions of mono-, di-, and trivalent metal salts. The properties of the monolayers are described quantitatively using thermodynamic models. The compression isotherms of the monolayers formed on different subphases show a clear-cut differentiation of the monovalent and di- or trivalent cations with both ligands. This differentiation was interpreted in terms of conformational changes occurring in the crown ether derivatives upon complexation. Molecular modeling indicates that the mono- and divalent cations are coordinated differently by the ligands, yielding complexes with different conformations. The differences of the conformations of the mono- and di- or trivalent cation complexes may be important from the point of view of the interactions with lipid membranes and the biological activity of these potential ionophores.