On the stability of Pt(IV) pro-drugs with haloacetato ligands in the axial positions.

The design of Pt(IV) pro-drugs as anticancer agents is predicated on the assumption that they will not undergo substitution reactions before entering the cancer cell. Attempts to improve the cytotoxic properties of Pt(IV) pro-drugs included the use of haloacetato axial ligands. Herein, we demonstrate that Pt(IV) complexes with trifluoroacetato (TFA) or dichloroacetato (DCA) ligands can be unstable under biologically relevant conditions and readily undergo hydrolysis, which results in the loss of the axial TFA or DCA ligands. The half-lives for Pt(IV) complexes with two TFA or DCA ligands at pH 7 and 37 °C range from 6 to 800 min, which is short relative to the duration of cytotoxicity experiments that last 24-96 h. However, complexes with two monochloroacetato (MCA) or acetato axial ligands are stable under biologically relevant conditions. The loss of the axial ligands depends primarily on the electron-withdrawing strength of the axial ligands, but also upon the nature of the equatorial ligands. We were unable to find obvious correlations between the structures of the Pt(IV) complexes and the rates of decay of the parent compounds. The X-ray crystal structures of the bis-DCA and bis-MCA Pt(IV) derivatives of oxaliplatin did not reveal any significant structural differences that could explain the observed differences in stability.

Novel acylethanolamide derivatives that modulate body weight through enhancement of hypothalamic pro-opiomelanocortin (POMC) and/or decreased neuropeptide Y (NPY).

Newly synthesized acylethanolamide derivatives oleoyl-L-valinolamide (1), oleoyl-D-valinolamide (2), elaidoyl-L-valinolamide (3), elaidoyl-D-valinolamide (4) stearoyl-L-valinolamide (5), and palmitoyl-L-valinolamide (6) were investigated in mice as antiobesity compounds. Compounds 1, 2, 5, 6 significantly decreased body weight by 6.57% following eight injections of 1 mg/kg i.p. during 39 days, while 3 and 4 showed no such activity. Receptor binding indicated that no compound activated CB1, CB2, PPARα, or TRPV1 receptors. Hypothalamic RT-PCR showed that mRNA expression of the anorexigenic genes POMC and CART was up-regulated by 1, 2, 5 and 1, 2, respectively, while that of the orexigenic genes NPY and CaMKK2 was down-regulated by the respective compounds 1, 5, 6 and 1, 2, 5. Oleoyl-L-valinolamide enhances anorectic pathways and lead to decreased glucose levels, enhanced locomotor activity, and improved cognition. Effects of oleoyl-L-valinolamide on weight were dose-dependent, and it could be given orally. 1, 2, 4, 5 down-regulated FAAH mRNA expression.