\u201cA step further in the discovery of phthalein derivatives as Thymidylate Synthase inhibitors\u201d

Phenolphthalein (Pth) was discovered as a low micromolar inhibitor of the enzyme ThymidylateSynthase (TS), an important target for anticancer chemotherapy. In the present work, a newseries of Pth derivatives have been designed and synthesized. All the compounds have beencharacterized through NMR techniques. A set of twelve Pth derivatives has been tested againstthree TS enzymes and their bio-profiles obtained. The bio-profiling studies suggest that theinhibitory potency of the compounds has been improved of about fifty times againstLactobacillus casei TS (LcTS) and five times against humant TS (hTS) with respect to the lead.The most active compound shows an inhibition constant (Ki) of 70 nM against Escherichia coliTS (EcTS)

Theoretical study of electronic spectra and photophysics of uracil derivatives.

The changes that the UV absorption spectrum and the photophysics of uracil undergo under hydrogen substitution or deprotonation, were studied theoretically within the CS-INDO/CI scheme. First of all this method was tested on uracil. It was then used for the calculation of the electronic structure of excited states (Sn, Tn) of a large number of uracil derivatives (1-, 3- and 5-methyluracil; 1,3-, 1,5- and 3,5-dimethyluracil; 5-fluoro- and 5-chlorouracil), including some anions (1- and 3-methyluracil anion). The excited states were obtained in the singly-excited configuration interaction approximation (S-CI) and the correlation effects on (pi pi*) states were studied by including the most important doubly- and triply-excited configurations in the CI. The S-CI wavefunctions were used for the calculation of the most important electronic matrix elements for spin-orbit coupling. The photophysics of these compounds is discussed using Jablonski diagrams

CYCLIZATION REACTIONS OF 1,3-DIBROMOPROPAN-2-OL, 2,3-DIBROMOPROPAN-1-OL AND 1-BROMOMETHYLOXIRANE WITH 6-AMINO-2,3-DIHYDRO-2-THIOXO-4(1H)-PYRIMIDINONE

The cyclization reactions, carried out in strongly- or weakly-basic media, are described. Sometimes, 7-amino-2,3-dihydro-3-hydroxymethyl-5H-thiazolo[3,2-a]pyrimidin-5-one is separated out, together with 8-amino-3,4-dihydro-3-hydroxy-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, as the principal product. A mechanism of reaction, during which the cyclizating agents are changed into oxirane derivatives, is proposed. The results of single-crystal X-ray investigations on 8-amino-3,4-dihydro-3-hydroxy-7-nitroso-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one (R = 0.035 for 1013 reflections), and on 7-hydroxymethyl-6,7-dihydrothiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-9(1H)-one (R = 0.027 for 1607 reflections) are reported

Naphthofuranone derivatives as specific inhibitors of thymidylate synthases

Synthetic compounds of 1, 2 -naphthalein molecules (I) having specific inhibitory properties of the enzymatic activity of thymidylate synthases of bacterial species, their preparation, their pharmaceutical composition and use in the treatment and prophylaxis of infectious pathologies are disclosed

Dal Ligand based design di inibitori della Timidilato Sintasi all'Analisi Comparativa dei Complessi Enzima-Inibitore

.n/

NAPHTHOFURANONE DERIVATIVES AS SPECIFIC INHIBITORS OF THYMIDYLATE SYNTHASES

Synthetic compounds of 1, 2 -naphthalein molecules (I) having specific inhibitory properties of the enzymatic activity of thymidylate synthases of bacterial species, their preparation, their pharmaceutical composition and use in the treatment and prophylaxis of infectious pathologies are disclose

Separation, structural determination and biological evaluation of the thymidylate synthase inhibitor 3,3-di(4'-hydroxyphenyl)-6(7)-chloro-1-oxo-1H,3H-naphtho[1,8-cd]pyran

The chloro substituted 3,3-di-(4'-hydroxyphenyl)-1-oxo-1H,3H-naphtho[1,8-cd]pyran was synthesized in a 40/60 mixture of C-6 or C-7 substituted isomers, respectively. The two isomers were separated by hplc. The X-ray crystal structure of the mixture was obtained. Both the mixture and the single isomers were tested against Lactobacillus Casei thymidylate synthase. The X-ray analysis clearly revealed co-crystallization of the two isomeric species. The apparent Ki of the mixture was 0.8 muM, while those of the C-6 and C-7 substituted isomers were 0.42 and 0.52 muM, respectively, thus showing that the position of the chlorine in the naphthalene ring was not critical for enzymatic activity

Structure-based studies on species-specific inhibition of thymidylate synthase

Thymidylate synthase (TS) is a well-recognized target for anticancer chemotherapy. Due to its key role in the sole de novo pathway for thymidylate synthesis and, hence, DNA synthesis, it is an essential enzyme in all life forms. As such, it has been recently recognized as a valuable new target against infectious diseases. There is also a pressing need for new antimicrobial agents that are able to target strains that are drug resistant toward currently used drugs, In this context, species specificity is of crucial importance to distinguish between the invading microorganism and the human host, yet thymidylate synthase is among the most highly conserved enzymes. We combine structure-based drug design with rapid synthetic techniques and mutagenesis, in an iterative fashion, to develop novel antifolates that are not derived from the substrate and cofactor, and to understand the molecular basis for the observed species specificity. The role of structural and computational studies in the discovery of nomanalog antifolate inhibitors of bacterial TS, naphthalein and dansyl derivatives, and in the understanding of their biological activity profile, are discussed