Azathioprine is an important drug used in the therapy of autoimmune disorders and in preventing graft rejection. Its molecule is composed of two main moieties: mercaptopurine and imidazole derivative. It is an immunosuppressive agent whose biological activity results from its in vivo mercaptolysis mediated by a nucleophilic attack on the C(5i) atom of imidazole ring of the azathioprine molecule. Solvation model SM5.4 with the PM3 Hamiltonian have been applied to model the reaction of azathioprine with cysteine. The employed quantum mechanical method shed new light on the mechanism of the reaction of azathioprine with cysteine in aqueous solution. The obtained results indicated that the first step in the reaction most likely involves the nucleophilic attack of the COO(-) of cysteine on the C(5i) atom of the imidazole ring of azathioprine, followed by a subsequent intramolecular attack of the SH group of the cysteine residue. It was shown that biogenic thiols such as glutathione or cysteine facilitate the first and crucial step of azathioprine metabolism, due to the presence of COO(-), SH, and NH(3)(+) groups in their molecules.
Mercaptopurine (6-MP), thioguanine (6-TG), and azathioprine (AZA) are purine antimetabolites introduced as anticancer or immunosuppressive drugs decades ago. Methylated AZA, called MAZA, is among the investigational drugs. The present study compares MAZA to the widely recognized drugs AZA, 6-MP, and 6-TG with respect to the ability of being transported across cell membranes. The obtained octanol/water phases partition coefficients and results of quantum chemical calculations predict the following sequence of hydrophobicity: MAZA > AZA > 6-TG > 6-MP.
The structure of the final degradation product formed in papaverine solutions in either water or chloroform was found to be a 2, 3, 9, 10-tetramethoxy-12-oxo-12H-indolo [2, 1-a] isoquinolinylium salt (a dibenzo [b, g] pyrrocolonium derivative). Its formation from papaverine oxidation products that is papaverinol, papaveraldine, and papaverine-N-oxide chloroform solutions under the influence of UV light, was investigated and possible reaction pathways are discussed.
It was shown previously that the papaverine oxidation products 6a,12a-diazadibenzo-[a,g]fluorenylium derivative (ligand 1) and 2,3,9,10-tetramethoxy-12-oxo-12H-indolo[2,1-a]isoquinolinium chloride (ligand 2) bind to guanine-quadruplexes (G4) of single stranded G-rich 3'-overhangs of mammalian telomeric DNA. Here we show the biological activity of ligand 1. This compound exhibit antiproliferative activity in MCF-7 cells (IC(50) for ligand 1 = 14.16 +/- 0.01 microM, 24 h, 1.158 +/- 0.056 microM, 72 h. PCNA levels were not altered after treatment of MCF-7 cells with concentrations of ligand 1 which, however, led to alterations in the cell cycle. 5 and 10 microM of the ligand 1 arrested cells in the G0/G1 phase of the cell cycle and this led to a decrease of cells in the S phase. Intracellular accumulation of ligand 1 was observed even after a cell passage and medium exchange in fluorescence microscopy while low concentrations of ligand 1 (0.001 to 0.1 microM) inhibited telomerase activity as shown by TRAP assay.
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