Aceclofenac is a popular analgesic, antipyretic, and nonsteroidal anti-inflammatory drug (NSAID) used for prolonged treatment (at least three months) in musculoskeletal disorders. It is characterized by several limitations such as poor water solubility and low oral bioavailability. The main side-effect of aceclofenac, as well as all NSAIDs, is the gastrotoxicity; among other adverse effects, there is the risk of bleeding since aceclofenac reversibly inhibits platelet aggregation. With the aim to reduce these drawbacks, we have designed, synthesized, and characterized, both in vitro and in vivo, an orally administrable pro-drug of aceclofenac (ACEgal). ACEgal was obtained by conjugating carboxyl group with the 6-OH group of d-galactose; its structure was confirmed by X-ray powder diffractometry. The pro-drug was shown to be stable at 37 °C in simulated gastric fluid (SGF-without pepsin, pH = 1.2) and moderately stable in phosphate buffered saline (PBS, pH = 7.4). However, it hydrolyzed in human serum with a half-life ( t) of 36 min, producing aceclofenac. Furthermore, if compared to its parent drug, ACEgal was four-times more soluble in SGF. To predict human intestinal absorption, cell permeability in a Caco-2 model of aceclofenac and ACEgal was determined. Anti-inflammatory, analgesic, and ulcerogenic activities have been investigated in vivo. In addition, oxidative stress parameters (thiobarbituric acid reactive substances, TBARS, and glutathione, GSH) and platelet antiaggregatory activity both of parent drug and pro-drug were evaluated. Results clearly showed that the conjugation of aceclofenac to a galactose molecule improves physicochemical, toxicological (at gastric and blood level), and pharmacological profile of aceclofenac itself without changing intestinal permeability and antiplatelet activity (in spite the new sugar moiety).

The therapy of human cancer is one of the more pursued goals by medicinal chemistry research. Most of the compounds clinically used as a treatment owe their efficacy to their cytotoxic interaction (direct or indirect) with nuclear DNA. This interaction results in the inhibition of DNA synthesis and the degradation of nucleic strands. Ellipticine is a naturally occurring 6H-pyrido[4,3-b]carbazole alkaloid endowed with antitumor activity, and several ellipticine derivatives have been used in clinical trials. We previously reported some 1,4-dimethyl-9H-carbazole derivatives structurally related to ellipticine. The purpose of our research was to transform the pyridocarbazole in a prodrug so that it would have more penetration in the tumor cells and block their replication. Our prodrug is slowly hydrolyzed in human plasma in the corresponding acid. From these preliminary results, we deduce that our compound can block cellular replication. Our hypothesis is that the antitumoral activity is probably related to the induction of damage to DNA, without cellular lysis in the short term.

Synthesis and Antiproliferative Activity of 3-Aryl-2-[1H(2H)-benzotriazol--1(2)-yl]acrylonitriles Variously Substituted. Part 4.-Two new series of benzotriazolyl acrylonitriles like (VI) and (XII) are prepared by condensation of benzotriazoles (I) and (VII) with chloroacetonitrile (II). The N-alkylated products are obtained as mixtures of isomers. In the first series, the effect of electron-releasing or electron-withdrawing groups associated with the increase of lipophilicity and steric hindrance on antiproliferative activity is investigated, while in the second series, the influence of substituents at the phenyl moiety, found active against M. tuberculosis, are examined. The syntheses are accomplished by Knoevenagel condensation of the intermediates with appropriate aldehydes, e.g. (V). The most cytotoxic compounds are evaluated against a panel of human cell lines derived from hematological and solid tumors. Compound (VI) is more potent than 6-mercaptopurine on all cell lines, but less potent than etoposide. Compounds (XI) and (XII) display moderate activity against some resistant strains of Mycobacterium. -(CARTA*, A.; PALOMBA, M.; BOATTO, G.; BUSONERA, B.; MURREDDU, M.; LODDO, R.; Farmaco 59 (2004) 8, 637-644; Dip. Farm.

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