Biomedical subjects

Thanasis Gimisis

Publications and source records attributed to Thanasis Gimisis.

4 recordsLinked to original sources

PubMed2006

Tautomerism in the guanyl radical.

Despite a few decades of intense study, a full description of tautomers of one-electron-oxidized guanine remains to be achieved. Here we show that two of these tautomers are produced by the protonation of an 8-haloguanine electron adduct. The rate constants for the reactions of hydrated electrons (e(aq)(-)) with a variety of 8-substituted guanine derivatives have been measured by a pulse radiolysis technique and correlated with both inductive and resonance components of the substituents. The fate of electron adducts was investigated by radiolytic methods coupled with product studies and addressed computationally by means of time-dependent DFT (TD-B3LYP/6-311G**//B1B95/6-31+G**) calculations. The reaction of e(aq)(-) with 8-haloguanosine or 8-halo-2'-deoxyguanosine produces the first observable transient species that decay unimolecularly (k = 1 x 10(5) s(-)(1) at 22 degrees C) to give the one-electron oxidized guanosine or 2'-deoxyguanosine. Theory suggests that the electron adducts of 8-bromoguanine derivatives protonated at C8 form a pi-complex, with the Br atom situated above the molecular plane, that is prompt to eject Br(-). The two short-lived intermediates, which show a substantial difference in their absorption spectra, are recognized to be the two purine tautomers (i.e., iminic 7 and aminic 3 forms). The spin density distributions of the two tautomers are quite different at the O6 and N10 positions, whereas they are very similar at the N3, C5, and C8 positions. The resonance structures of the two tautomers are discussed in some detail. B1B95/6-31+G calculations show also that the tautomerization from the iminic (7) to the aminic (3) arrangement is a water-assisted process.

Journal Article↗

PubMed2006

Binding of oxalyl derivatives of beta-d-glucopyranosylamine to muscle glycogen phosphorylase b.

Five oxalyl derivatives of beta-d-glucopyranosylamine were synthesized as potential inhibitors of glycogen phosphorylase (GP). The compounds 1-4 were competitive inhibitors of rabbit muscle GPb (with respect to alpha-d-glucose-1-phosphate) with K(i) values of 0.2-1.4 mM, while compound 5 was not effective up to a concentration of 10 mM. In order to elucidate the structural basis of their inhibition, we analysed the structures of compounds 1-4 in complex with GPb at 1.93-1.96 Angstrom resolution. The complex structures reveal that the inhibitors can be accommodated at the catalytic site at approximately the same position as alpha-d-glucose and stabilize the T-state conformation of the 280 s loop by making several favourable contacts to Asp283 and Asn284 of this loop. Comparison with the lead compound N-acetyl-beta-d-glucopyranosylamine (6) shows that the hydrogen bonding interaction of the amide nitrogen with the main-chain carbonyl oxygen of His377 is not present in these complexes. The differences observed in the K(i) values of the four analogues can be interpreted in terms of subtle conformational changes of protein residues and shifts of water molecules in the vicinity of the catalytic site, variations in van der Waals interactions, conformational entropy and desolvation effects.

Animals↗

PubMed2004

Synthesis and biological evaluation of novel 1'-branched and spironucleoside analogues.

Novel anomeric spironucleosides and 1'-cyano-2',3'-didehydro-2',3'-dideoxyuridine, a structural analogue of known anti-HIV agents, were prepared by nucleophilic addition of organolithium reagents to 1'-cyano-2'-deoxy- and 1'-cyano-2'-deoxy-2'beta-bromo-uridine derivatives, respectively. The yield and distribution of products depended on the reaction conditions, which were studied in detail. Although none of the compounds exhibited antiviral activity, two compounds displayed cytostatic activity against both murine leukemia and human T-lymphocyte cells.

Antiviral Agents↗

PubMed2002

5-Endo-trig radical cyclizations: disfavored or favored processes?

Relative kinetic data were determined for the 5-endo-trig cyclization of radical 12 compared to hydrogen abstraction from (TMS)(3)SiH in the temperature range of 344-430 K, which allows for the estimation of a rate constant of 2 x 10(4) s(-)(1) at 298 K with an activation energy of ca. 9 kcal/mol for the cyclization process. The 5-endo-trig cyclization of a variety of radicals that afford five-membered nitrogen-containing heterocycles was addressed computationally at the UB3LYP/6-31G level. The 5-endo vs 4-exo mode of cyclication and the effect of delocalization of the unpaired electron in the transition state were investigated. Because the ring formed during cyclization contains five sp(2) centers, electrocyclization via a pentadienyl-like resonance form was also considered. For comparison, similar calculations were performed for 4-penten-1-yl and related radicals. The factors that affect the activation energies of homolytic 5-endo-trig cyclization were determined. In the absence of steric or conformational effects, the endo cyclization to form the five-membered ring was strongly favored over exo cyclization to form the four-membered ring not only on thermodynamic grounds but also kinetically. When a substituent on the double bond was able to delocalize the unpaired electron in the transition state of the 4-exo path, the two modes of cyclization became kinetically comparable. These results have an important bearing on the generalization of the Baldwin-Beckwith rules, which classified the 5-endo-trig radical cyclization as a "disfavored" process.

Journal Article↗