Cytotoxic and Antitumoral Activity of N-(9H-purin-6-yl) Benzamide Derivatives and Related Water-soluble Prodrugs.

BACKGROUND: The development of small molecules as cancer treatments is still of both interest and importance. OBJECTIVE: Having synthesized and identified the initial cytotoxic activity of a series of chemically related N-(9H-purin-6-yl) benzamide derivatives, we continued their evaluation on cancer cell models. We also synthesized water-soluble prodrugs of the main compound and performed in vivo experiments. METHOD: We used organic chemistry to obtain compounds of interest and prodrugs. The biological evaluation included MTT assays, synergy experiments, proliferation assays by CFSE, cell cycle distribution and in vivo antitumoral activity. RESULTS: Our results show activities on cancer cell lines ranging from 3-39 µM for the best compounds, with both induction of apoptosis and decrease in cell proliferation. Two compounds evaluated in vivo showed weak antitumoral activity. In addition, the lead compound and its prodrug had a synergistic activity with the nucleoside analogue fludarabine in vitro and in vivo. CONCLUSION: Our work allowed us to gain better knowledge on the activity of N-(9H-purin-6-yl) benzamide derivatives and showed new examples of water-soluble prodrugs. More research is warranted to decipher the molecular mechanisms of the molecules.

2-(Substituted amino)-8-azachromones from 4,6-Diaryl-2-pyridones: A Synthetic Strategy toward Compounds of Broad Structural Diversity.

3-Acetoacetyl-4,6-diaryl-2-pyridones are synthesized in three steps from chalcones and then condense with carbon disulfide to afford 8-azachromones containing a methylthio group at C2. This leaving group offers an entry point for the insertion of more complex moieties via nucleophilic substitution. For this purpose, N-nucleophiles are explored according to their positions in the Mayr's nucleophilicity scale (N parameter), and three main classes are distinguished depending on whether the substitution takes place from their neutral forms, from their deprotonated anionic forms, or under nucleophilic catalysis. A broad range of primary and secondary amines may be inserted by this method, including enantiomerically pure amino acids, enabling us to explore structural diversity.

Hydroarylation of unsaturated carbon-carbon bonds in cross-conjugated enynones under the action of superacid CF3SO3H or acidic zeolite HUSY. Reaction mechanism and DFT study on cationic intermediate species.

Reactions of cross-conjugated enynones,1,5-diarylpent-1-en-4-yn-3-ones, with arenes in the system TfOH-pyridine or under the action of acidic zeolite HUSY lead regioselectively to products of hydroarylation of the acetylene bond only,1,1,5-triarylpent-1,4-dien-3-ones, in yields up to 98%. These dienones add one more arene molecule to the double carbon-carbon bond in neat TfOH forming 1,1,5,5-tetraarylpent-1-en-3-ones in high yields. Cationic reaction intermediates have been studied by means of DFT calculations to elucidate plausible reaction mechanisms.

Transformations of Conjugated Enynones in the Superacid CF3SO3H. Synthesis of Butadienyl Triflates, Indanones, and Indenes.

Conjugated 1,5-diarylpent-2-en-4-yn-1-ones add the superacid CF3SO3H to the acetylenic bond with formation of the corresponding butadienyl triflates. Under superacidic reaction conditions, these triflates are transformed into indanone or indene derivatives depending on which substituents on the aromatic ring are conjugated with the butadiene fragment. In a less acidic system (10% vol pyridine in CF3SO3H) only the formation of butadienyl triflates takes place. Cationic reaction intermediates were studied by means of NMR and DFT calculations.

A Versatile Organocatalytic Approach for the Synthesis of Enantioenriched gem-Difluorinated Compounds.

The combination of a practical and highly enantioselective organocatalytic reaction, which allows the stereoselective introduction of a benzodithiol group, with a fluorination step, gives a new and effective strategy for the stereoselective synthesis of difluorinated building blocks. The benzodithiol group is a versatile and chameleonic group that can be further functionalized before fluorination, giving customized and tailored useful synthetic strategies. As an example of the application of this facile strategy, the effective enantioselective synthesis of difluoroarundic acid is described.

A practical and stereoselective organocatalytic alkylation of aldehydes with benzodithiolylium tetrafluoroborate.

Recently, the direct substitution of allylic, benzylic, and tertiary alcohols has been achieved via SN 1-type reactions with catalytic amounts of Brønsted or Lewis acids. When a new stereogenic center is formed most of these transformations produce the desired product as a racemate, as these reactions proceed through carbenium ions. The arsenal of activation modes available in organocatalysis can be used to set up suitable reaction conditions in which chiral nucleophiles (enamine catalysis) or chiral electrophiles (iminium catalysis, chiral counterion catalysis) can easily be generated. Recently, we have used stabilized carbenium ions, directly available or obtained from the corresponding alcohols, in new organocatalytic stereoselective SN 1-type reactions. The commercially available carbenium ion benzodithiolylium tetrafluoroborate can be used for the straightforward organocatalytic stereoselective alkylation of aldehydes. In this account we will illustrate the application of this methodology in the total synthesis of natural products and the preparation of valuable starting materials.