Circadian and chemotherapy-related changes in urinary modified nucleosides excretion in patients with metastatic colorectal cancer

Urinary levels of modified nucleosides reflect nucleic acids turnover and can serve as non-invasive biomarkers for monitoring tumour circadian dynamics, and treatment responses in patients with metastatic colorectal cancer. In 39 patients, median overnight urinary excretion of LC-HRMS determinations of pseudouridine, was ~ tenfold as large as those of 1-methylguanosine, 1-methyladenosine, or 4-acetylcytidine, and ~ 100-fold as large as those of adenosine and cytidine. An increase in any nucleoside excretion after chemotherapy anticipated plasma carcinoembryonic antigen progression 1–2 months later and was associated with poor survival. Ten fractionated urines were collected over 2-days in 29 patients. The median value of the rhythm-adjusted mean of urinary nucleoside excretion varied from 64.3 for pseudouridine down to 0.61 for cytidine. The rhythm amplitudes relative to the 24-h mean of 6 nucleoside excretions were associated with rest duration, supporting a tight link between nucleosides turnover and the rest-activity rhythm. Moreover, the amplitude of the 1-methylguanosine rhythm was correlated with the rest-activity dichotomy index, a significant predictor of survival outcome in prior studies. In conclusion, urinary excretion dynamics of modified nucleosides appeared useful for the characterization of the circadian control of cellular proliferation and for tracking early responses to treatments in colorectal cancer patients

Breakthroughs in medicinal chemistry: New targets and mechanisms, new drugs, new hopes-6

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...]

The addition of halogens and interhalogens on palladacyclopentadienyl complexes bearing quinolyl-thioether as spectator ligands. A kinetic and computational study

We have studied the oxidative addition of halogens (I2 and Br2) and interhalogens (ICl and IBr) on complexes of the type [Pd(thioquinoline)C4(COOMe)4], (thioquinoline = 8-(methylthio)quinoline, 8-(t-butylthioquinoline, 2-methyl-8 (methylthio)quinoline, 2-methyl-8-(t-butylthio)quinoline). The expected palladium(thioquinoline)-r-butadienyl derivatives have been obtained by the stoichiometric addition of I2 and Br2 to a solution of the starting palladacyclopentadienyl complexes. The bromine in excess induces the extrusion of the di-bromo-(E, E)-r-butadiene and the formation of the thioquinoline palladium(II) di-bromide species. The kinetics and mechanism of these reactions have been determined. Except for one case which was analyzed in detail by a computational study, the oxidative addition of the interhalogens ICl and IBr yields the species that is less predictable from the thermodynamic point of view. In general the computational approach justifies the reaction progress and allows an interpretative clue suggesting a kinetically governed path to the reaction products. Finally, the solid state structures of two reaction products were resolved and reporte

Addition of halogens and interhalogens on palladacyclopentadienyl complexes stabilized by pyridyl-thioether N-S spectator ligands

We have studied from the experimental and theoretical point of view the oxidative addition of halogens (I-2 and Br-2) and interhalogens (ICl and IBr) on palladiumcyclopentadienyl complexes bearing heteroditopic pyridyl-thioether spectator ligands.Addition of I-2 or of a stoichiometric amount of Br-2 to a CDCl3 solution of the starting palladacyclo-pentadienyl complexes yields the expected palladium-sigma-butadienyl derivatives. The bromide derivative in the presence of a further excess of Br-2 gives the wanted dibromo-(E, E)-sigma-butadienyl and the pyridylthioether palladium(II) dibromide species. The rates of these reactions have been determined.When the interhalogens are used as oxidizing agents the thermodynamically hampered species is formed at first. Only in the case of the reaction of IBr is the formation of the energetically hampered derivative followed by partial isomerization to the most stable complex. The rate of isomerization and the related equilibrium constant between isomers have been measured. On the basis of the experimental evidence and the computational approach we have proposed a plausible energetic path yielding the first formed unexpected species.Finally, the solid state structures of two reaction products were resolved and reported. (C) 2016 Elsevier B.V. All rights reserved

SYNTHESIS OF CARBOCYCLIC PHOSPHONONUCLEOSIDES

International audienc

Recherche d’inhibiteurs des enzymes de réparation de l’ADN hNeil1 et hOGG1, de nouvelles cibles pertinentes pour le développement de thérapies anticancéreuses

National audienc