Synthesis of 3,4-Dihydropyrimidin(thio)one Containing Scaffold: Biginelli-like Reactions.

The interest in 3,4-dihydropyrimidine-2(1H)-(thio)ones is increasing every day, mainly due to their paramount biological relevance. The Biginelli reaction is the classical approach to reaching these scaffolds, although the product diversity suffers from some limitations. In order to overcome these restrictions, two main approaches have been devised. The first one involves the modification of the conventional components of the Biginelli reaction and the second one refers to the postmodification of the Biginelli products. Both strategies have been extensively revised in this manuscript. Regarding the first one, initially, the modification of one of the components was covered. Although examples of modifications of the three of them were described, by far the modification of the keto ester counterpart was the most popular approach, and a wide variety of different enolizable carbonylic compounds were used; moreover, changes in two or the three components were also described, broadening the substitution of the final dihydropyrimidines. Together with these modifications, the use of Biginelli adducts as a starting point for further modification was also a very useful strategy to decorate the final heterocyclic structure.

11PS04 is a new chemical entity identified by microRNA-based biosensing with promising therapeutic potential against cancer stem cells.

Phenotypic drug discovery must take advantage of the large amount of clinical data currently available. In this sense, the impact of microRNAs (miRs) on human disease and clinical therapeutic responses is becoming increasingly well documented. Accordingly, it might be possible to use miR-based signatures as phenotypic read-outs of pathological status, for example in cancer. Here, we propose to use the information accumulating regarding the biology of miRs from clinical research in the preclinical arena, adapting it to the use of miR biosensors in the earliest steps of drug screening. Thus, we have used an amperometric dual magnetosensor capable of monitoring a miR-21/miR-205 signature to screen for new drugs that restore these miRs to non-tumorigenic levels in cell models of breast cancer and glioblastoma. In this way we have been able to identify a new chemical entity, 11PS04 ((3aR,7aS)-2-(3-propoxyphenyl)-7,7a-dihydro-3aH-pyrano[3,4-d]oxazol-6(4H)-one), the therapeutic potential of which was suggested in mechanistic assays of disease models, including 3D cell culture (oncospheres) and xenografts. These assays highlighted the potential of this compound to attack cancer stem cells, reducing the growth of breast and glioblastoma tumors in vivo. These data demonstrate the enhanced chain of translatability of this strategy, opening up new perspectives for drug-discovery pipelines and highlighting the potential of miR-based electro-analytical sensors as efficient tools in modern drug discovery.

Isolation and first total synthesis of PM050489 and PM060184, two new marine anticancer compounds.

Microtubules continue to be one of the most successful anticancer drug targets and a favorite hit for many naturally occurring molecules. While two of the most successful representative agents in clinical use, the taxanes and the vinca alkaloids, come from terrestrial sources, the sea has also proven to be a rich source of new tubulin-binding molecules. We describe herein the first isolation, structural elucidation and total synthesis of two totally new polyketides isolated from the Madagascan sponge Lithoplocamia lithistoides . Both PM050489 and PM060184 show antimitotic properties in human tumor cells lines at subnanomolar concentrations and display a distinct inhibition mechanism on microtubules. The development of an efficient synthetic procedure has solved the supply problem and, following pharmaceutical development, has allowed PM060184 to start clinical studies as a promising new drug for cancer treatment.

Synthesis, characterization and immunochemical evaluation of cephalosporin antigenic determinants.

Lack of knowledge of the exact chemical structure of cephalosporin antigenic determinants has hindered clinical interpretation of adverse reactions to these drugs and delayed understanding of the mechanisms involved in the specific recognition and binding of IgE molecules to these antigenic determinants. We further resolve the relationship between structure and activity of proposed antigenic chemicals, including the rational design and synthesis of these haptenic structures. Comparative RAST inhibition studies of the synthesized molecules revealed that they were recognized by IgE antibodies induced by cephalosporin antibiotics. Thus, these data indicate that recognition is mainly directed to the acyl side chain and to the beta-lactam fragment that remains linked to the carrier protein in the cephalosporin conjugation course.

Dendrimers as carrier protein mimetics for IgE antibody recognition. Synthesis and characterization of densely penicilloylated dendrimers.

The synthesis of benzylpenicilloyl-containing dendrimers has been achieved by a convenient procedure involving quantitative functionalization of the terminal amino groups of the three Starbust PAMAM generations used (G(n); n = 0, 1, 2). All these densely penicilloylated dendrimers (G(n)P) exhibit similar, simple NMR spectroscopic data suggesting highly symmetric structures and a monodisperse nature, and the results obtained from MALDI-TOF-MS demonstrate their exact chemical composition. The use of PAMAM dendrimers has allowed us to synthesize, for the first time, carrier benzylpenicilloyl conjugates (G(n)P) of precisely defined chemical structure. The attempts to synthesize G(2)P show that forced experimental conditions are not always useful for the functionalization of the dendrimer, especially in introducing bulky groups. The initial results with sera from patients with different RAST levels were positive and thus suggestive that inhibition occurs, so recognition exists; we can therefore conclude that the hapten-carrier (dendrimer) conjugates studied mimic recognition with natural hapten-carrier (protein) conjugates.