Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer.

Herein we report the synthesis of two series of 4-phenylphthalazin-1-ones 11a-i and 4- benzylphthalazin-1-ones 16a-h as anti-lung adenocarcinoma agents with potential inhibitory activity against PARP-1. All the newly synthesized phthalazinones were evaluated for their anti-proliferative activity against A549 lung carcinoma cell line. Phthalazinones 11c-i and 16b, c showed significant cytotoxic activity against A549 cells at different concentrations (0.

Synthesis and evaluation of malonate-based inhibitors of phosphosugar-metabolizing enzymes: class II fructose-1,6-bis-phosphate aldolases, type I phosphomannose isomerase, and phosphoglucose isomerase.

In the design of inhibitors of phosphosugar metabolizing enzymes and receptors with therapeutic interest, malonate has been reported in a number of cases as a good and hydrolytically-stable surrogate of the phosphate group, since both functions are dianionic at physiological pH and of comparable size. We have investigated a series of malonate-based mimics of the best known phosphate inhibitors of class II (zinc) fructose-1,6-bis-phosphate aldolases (FBAs) (e.g.

Glycolytic and non-glycolytic functions of Mycobacterium tuberculosis fructose-1,6-bisphosphate aldolase, an essential enzyme produced by replicating and non-replicating bacilli.

The search for antituberculosis drugs active against persistent bacilli has led to our interest in metallodependent class II fructose-1,6-bisphosphate aldolase (FBA-tb), a key enzyme of gluconeogenesis absent from mammalian cells. Knock-out experiments at the fba-tb locus indicated that this gene is required for the growth of Mycobacterium tuberculosis on gluconeogenetic substrates and in glucose-containing medium. Surface labeling and enzymatic activity measurements revealed that this enzyme was exported to the cell surface of M.

Rational design, synthesis, and evaluation of new selective inhibitors of microbial class II (zinc dependent) fructose bis-phosphate aldolases.

We report the synthesis and biochemical evaluation of several selective inhibitors of class II (zinc dependent) fructose bis-phosphate aldolases (Fba). The products were designed as transition-state analogues of the catalyzed reaction, structurally related to the substrate fructose bis-phosphate (or sedoheptulose bis-phosphate) and based on an N-substituted hydroxamic acid, as a chelator of the zinc ion present in active site. The compounds synthesized were tested on class II Fbas from various pathogenic microorganisms and, by comparison, on a mammalian class I Fba.

Highly Selective Inhibitors of Class II Microbial Fructose Bis-phosphate Aldolases.

We hereby describe the rationale synthesis and biochemical evaluation of the most powerful and selective inhibitors of class II fructose bis-phosphate aldolases so far reported. These inhibitors are of potential therapeutic interest, since the class II enzyme is present exclusively in microorganisms (among which many pathogenic species) and is absent from man, plants, and animals.

Synthesis and biochemical evaluation of selective inhibitors of class II fructose bisphosphate aldolases: towards new synthetic antibiotics.

We report the synthesis and biochemical evaluation of selective inhibitors of class II (zinc-dependent) fructose bisphosphate aldolases. The most active compound is a simplified analogue of fructose bisphosphate, bearing a well-positioned metal chelating group. It is a powerful and highly selective competitive inhibitor of isolated class II aldolases.