Maurizio Botta

6-Alkyl- and 5,6-Dialkyl-2-methoxy-4(3H)-pyrimidinones in the Transformations of Pyrimidines. Conversion into 2-Substituted Amino- and 4-Chloro-Pyrimidine-Derivatives

Abstract 6-Alkyl- and 5,6-dialkyl-2-methoxy-4(3H)-pyrimidinones are transformed into the 2-alkyl(and 2-aryl)amino-derivatives, in good yield, by reaction with the corresponding amines. Treatment with SOCl2 -DMF gives 6-alkyl- and 5,6-dialkyl-2-methoxy-4-chloro pyrimidines.

6-alkyl and 5,6-dialkyl-2-methoxy-4(3H)- pyrimidinones in the transformations of pyrimidines—2: Synthesis and conversion into alkyluracils and 2-alkoxy-4(3H)-pyrimidinones

Abstract The synthesis of 6-alkyl and 5,6-dialkyl-2-methoxy- 4 ( 3H )-pyrimidinones 3 is described. Their versatility to be transformed into 6-alkyl and 5,6-dialkyluracils 4 ( a-h ), 6-alkyl and 5,6-dialkyl-3-methyluracils 7 ( a , e , f ) and 6-alkyl and 5,6-dialkyl-2-alkoxy-4(3H)-pyrimidinones 5 ( a-i ) is also shown.

6-alkyl-2-hethoxy-4-(3h)-pyrimidinones in the transformation of pyrimidines: regiospecific preparation, antitumor and antimicrobial activity of 4-O-acylated pyrimidine derivatives. New agents for selective acylation of amines

Abstract A high yielding synthesis of 4- O -acylated pyrlmldines is presented. These products are selective reagents for amine acylatlon. The antitumor and antimicrobial activity of compounds 1 and 2c is also reported.

Synthesis of 4-arylcoumarins from Coutarea hexandra

Abstract The structures assigned to the 5,7-dimethoxy-4-arylcoumarins isolated from Coutarea hexandra have been confirmed by synthesis, via Pechmann condensation of phloroglucinol and an ethyl benzoylacetate derivative, the hydroxy groups of which were protected either by benzylation or by methylenedioxy group formation.

The role of acid catalysis in the genesis of amber

Abstract Analysis of the hydrocarbon fraction from baltic amber is described. Transformations which have occurred in resins during the formation of amber are discussed on the grounds of acid-catalysed reactions undergone by 7,13-abietadiene and sclareol.

6-alkyl- and 5,6-dialkyl-2-methoxy-4(3H)-pyrimidinones in the transformations of pyrimidines. Regiospecific 1-N-acylation of pyrimidines.

Abstract Transformation of 6- and 5,6-dialkyl-2-methoxy-4(3H)-pyrimidinones (1a and 1b) into 1- N -acylated-pyrimidine derivatives 3( a - f ) under Friedel-Craft like conditions is presented. In different acylation conditions 4-O-acylated-pyrimidines (5a and 5b) are also obtained. Compounds (3c) and (3f) can be directly converted into 1- N -acyl-protected-isouridine analogues (8a and 8b).

Acid catalyzed rearrangements in bicyclo [3.3.1] nonanes. 2-Substituted-6-(1,3-dioxolan-2-yl)-cyclooctanones from 1-substituted-2-hydroxy-9,9-(ethylenedioxy)-bicyclo[3.3.1]-nonanes

Abstract Treatment of endo-2 or exo-2-hydroxy-1-substituted ketals 1a–d with p-toluensulfonic acid in dry benzene results in a reversible C9 bridge cleavage and affords equilibrium mixtures where 2-substituted-6-(1,3-dioxolan-2-yl)cyclooctanones 6a–d are present as main products. Yields in 6a–d are present as the steric hindrance of the substituents at C1 in the substrate increases as well. Deuterium exchange experiments are in favour of an intramolecular 1,3-hydride shift from C2 to C9.

Studies related to cephalosporins. 61. Bromination of 3-exomethylene in cepham derivatives

Abstract The methyl 3-methylene-7-phthalimidocepham-4-carnoxylate 3, the corresponding (R)-oxide 2 and the 1,1-dioxide 1 add bromine affording stereoisomeric mixtures of dibromoderivatives. These results are at variance with previous reports regarding 3-exomethylene sulfides and sulfoxides. The stereochemistry of the dibromoderivatives was unambiguously determined via X ray crystallography of 5a, following 1H-NMR correlations. The single dibromo derivatives as well as the isomeric mixtures, can be dehydrobrominated to afford 3-bromomethyl cephem derivatives (7,8,9) in very good yields.

Chapter 11. Application of Molecular Modelling to Speed-up the Lead Discovery Process

By transforming many life-threatening diseases to almost negligible problems, drug discovery has improved life expectancy and our quality-of-life in general. However, in recent years, the flat trend of new drugs reaching the market, coupled with the increase of costs of this long process has led the pharmaceutical sector to a ‘crisis’. For this reason, research and development has turned to cutting-edge technology to reduce time and expense. In this chapter, we will discuss how the impressive improvements in both structure- and ligand-based molecular modelling approaches can help to drive and speed up drug discovery, making important contributions at all levels of the process.

CHAPTER 17:Allosteric Inhibition of Abl Kinase

Since the mechanism of allosteric regulation was postulated for the first time in 1965 by Monod, Wyman and Changeux, 50 years have passed. From that moment our vision and understanding of the ligand–protein interaction process have been completely changed. Proteins started to be considered to be not fixed biological entities but flexible structures endowed with an activity which could be finely tuned by interaction with other proteins or new small molecules able to bind pockets different from the catalytic sites. In this chapter an in-depth description of one of the most studied allosteric modulation mechanisms will be provided. Abelson murine-leukemia viral-oncogene homolog-1 (c-Abl) protein kinase represents a noteworthy example of how a small post-translational modification (myristoylation of the N-terminal region of the protein sequence) can drive a mechanism of complex domain rearrangements, determining the activation state of the enzyme. Many efforts have been devoted, by scientists all around the world, to studying the molecular basis for the autoinhibition mechanism of c-Abl, and its derived oncogenic fusion protein breakpoint cluster region–Abl (Bcr–Abl), leading to the identification of the first allosteric inhibitor GNF-5, currently undergoing a Phase I clinical trial for the treatment of chronic myelogenous leukemia (CML).