Isophosphoramide mustard analogues as prodrugs for anticancer gene-directed enzyme-prodrug therapy (GDEPT).

Abstract

Two types of prodrugs, benzyl analogues of isophosphoramide mustard (iPAM), activated by cytochrome P450, and acylthioethyl analogues, activated by esterases, were designed. In contrast to iPAM that hydrolyse rapidly, the examined compounds are stable in phosphate-buffered saline and Tris buffer. Benzyl analogues of iPAM are poor substrates for cytochrome P450, are not cytotoxic and posses no antitumour activity. Acylthioethyl analogues of iPAM are good substrates for pig liver esterase, are cytotoxic and exert antitumour activity against L1210 leukaemia in mice. The observed correlation for iPAM analogues between their susceptibility to hydrolysis and cytotoxicity and antitumour activity suggests possible application of these compounds as the prodrugs in gene-directed enzyme-prodrug therapy.

Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy

“…However, Mitsunobu conditions between IPM and 10-BH3 led to a poor yield of the desired product 14c-BH3 (5%) while a large amount of starting material 10-BH3 (76%) has been recovered. To circumvent this problem, we turned our attention on a two-step one-pot reaction, previously described by Misiura et al [53] for a 4-substituted benzyl alcohol, and involving the phosphorylation of 10-BH3 using phosphorus oxychloride in the presence of TEA, to yield the dichlorophosphate intermediate, which subsequently was treated, without isolation, with two equivalents of 2-chloroethylamine hydrochloride followed by another base addition. This sequence successfully afforded compound 14c-BH3 in moderate yield (48%).…”

“…The rapid kinetics of reduction of the imidazole prodrugs 15a-c and the high reactivity of the corresponding mustards, gave rapidly rise to the disappearance of the first signals at 11-12 ppm and the formation of a variety of by-products. In order to clearly assign the signal at 11-12 ppm to the corresponding mustard anions, reduction experiments were performed with the lower reduction-sensitivity 4-nitrobenzyl analogs 27a-c already described in the literature [53,59,60] (synthesis in supporting data). Indeed for compound 27c, a maximum of 40% of reduction was observed in the presence of 3 equivalents of sodium dithionite compared with more than 95% for compound 15c, both giving rise to the same signal at a chemical shift of 11.2 ppm.…”

Synthesis of 5-Fluorouracil Derivatives as Possible Mutual Prodrugs with Meloxicam and Ibuprofen for Targeting Cancer Tissues

“…The reaction mixture was stirred for 3.5 hours letting it warm up gradually to 10 o C, quenched with saturated ammonium chloride solution and the chloroform layer was extracted with distilled water (2 × 20 ml), the chloroform layer was dried over anhydrous sodium sulphate and filtered and the chloroform was evaporated under vacuum to give compound Ia as oily material, the percent yield is (98.60%). Synthesis of compound Ib: (11,12) To a stirred solution of compound Ia (1.33 gm, 5.589 mmol) in freshly distilled acetonitrile (20 ml) at −20 o C, a suspension of sodium 5-fluoro-6-oxo-1,6-dihydropyrimidin-2-olate (0.85 gm, 5.589 mmol) in freshly distilled acetonitrile (20 ml) was added drop wise, then the reaction mixture was stirred over night at room temperature. The mixture was filtered and the solvent of the filtrate was evaporated under vacuum to give compound Ib as oily material with percent yield (34.53%).…”

“…The mixture was filtered and the solvent of the filtrate was evaporated under vacuum to give compound Ib as oily material with percent yield (34.53%). Synthesis of compound I: (11,12) To a stirred solution of compound Ib (0.64 gm, 1.93 mmol) in dry chloroform (20 ml) at −20 o C, a suspension of (4-hydroxy-2-methyl-N-(5-methyl -1, 3thiazoiyl) benzo1, 2 thiazine -3-carboxamide-1,1-dioxide) (0.678 gm, 1.93 mmol) in dry chloroform (20 ml) and dry pyridine (2 ml) was added drop wise, then the reaction mixture was stirred over night at room temperature. The reaction mixture was filtered and the yellow precipitate was collected and recrystalized from ethanolpetroleum ether to give pale yellow powder of compound I, with percent yield (38.14%), melting point (221 o C dec.).…”

“…The IR data and CHN analysis were listed in tables 1 and 2 respectively. Synthesis of compound II: (11,12) To a stirred solution of compound Ib (0.529 gm, 1.595 mmol) in dry chloroform (20 ml) at −20 o C, a suspension of sodium (S)-2-(4-isobutylphenyl)propanoate (0.364 gm, 1.595 mmol) in dry chloroform (20 ml) was added drop wise, then the reaction mixture was stirred over night at room temperature. The reaction mixture extracted with distilled water (2 ×20 ml), the chloroform layer was dried with anhydrous sodium sulphate and filtered, the chloroform was evaporated under vacuum to yield an oily compound, and the oil residue was triturated several times with petroleum spirit.…”