Purine derivatives with heterocyclic moieties and related analogs as new antitumor agents.

AIM: Identification of new antiproliferative compounds. METHODOLOGY: Four series of compounds were synthesized by the Mitsunobu reaction. Their antiproliferative activity was studied against several cancer cells and a noncancerous fibroblast cell line. Their apoptotic activity was analyzed using a caspase 3/7 fluorescence assay. RESULTS & CONCLUSION: 9-alkylated-6-halogenated and 2,6-dihalogenated purines show remarkable inhibition of tumor cell proliferation, with the dichloro derivatives being the most potent of all the series. The most promising compound, tetrahydroquinoline 4c, exhibits significant antiproliferative activity against the cancer cells tested, while displaying a 19-fold lower potency against noncancerous fibroblasts, a key feature that indicates potential selectivity against cancer cells. This compound produces a high percentage of apoptosis (58%) after 24 h treatment in human breast cancer MCF-7 cells.

Quinazolinones, Quinazolinthiones, and Quinazolinimines as Nitric Oxide Synthase Inhibitors: Synthetic Study and Biological Evaluation.

The synthesis of different compounds with a quinazolinone, quinazolinthione, or quinazolinimine skeleton and their in vitro biological evaluation as inhibitors of inducible and neuronal nitric oxide synthase (iNOS and nNOS) isoforms are described. These derivatives were obtained from substituted 2-aminobenzylamines, using diverse cyclization procedures. Furthermore, the diamines were synthesized by two routes: A conventional pathway and an efficient one-pot synthesis in a continuous-flow hydrogenator. The structures of these heterocycles were confirmed by (1) H and (13) C nuclear magnetic resonance and high-resolution mass spectroscopy data. The structure-activity relationships of the target molecules are discussed in terms of the effects of both the R radical and the X heteroatom in the 2-position. In general, the assayed compounds behave as better iNOS than nNOS inhibitors, with the quinazolinone 11e being the most active inhibitor of all tested compounds and the most iNOS/nNOS selective one.

New coumarin-based fluorescent melatonin ligands. Design, synthesis and pharmacological characterization.

The design and synthesis of a series of new fluorescent coumarin-containing melatonin analogues is presented. The combination of high-binding affinities for human melatonergic receptors (h-MT1R and h-MT2R) and fluorescent properties, derived from the inclusion of melatonin pharmacophoric elements in the coumarin scaffold, yielded suitable candidates for the development of MT1R and MT2R fluorescent probes for imaging in biological media.

Derivatization of (quinolin-8-yl)phosphinimidic amides via ortho-lithiation revisited.

5The direct ortho-lithiation of N-H containing (quinolin-8-yl)phosphinimidic amides by reaction with 1 equiv. of n-BuLi described by Wang and co-workers has been re-examined. The multinuclear magnetic resonance ((1)H, (2)H, (7)Li, (13)C, (15)N and (31)P) study of the species formed in the monolithiation of N-(tert-butyl)-P,P-diphenyl-N'-(quinolin-8-yl)phosphinimidic amide 5 with n-BuLi in THF showed that proton abstraction occurred exclusively and quantitatively at the NH. The combination of the NMR results with a DFT study made it possible to describe the structure of the N-lithiated species 9 as a dimer consisting of an eight-membered ring showing two lithium ions triply coordinated to nitrogen atoms corresponding to the deprotonated amine and aminoquinoline moieties of different monomers. The formation of a polymer featuring the same coordination mode couldn't be excluded. In addition, optimized conditions for the efficient derivatization of 5 via ortho-lithiation were realised. The reaction of 5 with 2.4 equiv. of t-BuLi in THF in the temperature range of -80 °C to 25 °C for 3 h afforded a N,C(ortho)-dilithiated species that was trapped with a series of electrophiles leading to new functionalized ortho derivatives of 5 in good yields.

Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential.

Herein we present a new family of melatonin-based compounds, in which the acetamido group of melatonin has been bioisosterically replaced by a series of reversed amides and azoles, such as oxazole, 1,2,4-oxadiazole, and 1,3,4-oxadiazole, as well as other related five-membered heterocycles, namely, 1,3,4-oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and an 1,3,4-thiadiazole. New compounds were fully characterized at melatonin receptors (MT1R and MT2R), and results were rationalized by superimposition studies of their structures to the bioactive conformation of melatonin. We also found that several of these melatonin-based compounds promoted differentiation of rat neural stem cells to a neuronal phenotype in vitro, in some cases to a higher extent than melatonin. This unique profile constitutes the starting point for further pharmacological studies to assess the mechanistic pathways and the relevance of neurogenesis induced by melatonin-related structures.