Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kα/mTOR inhibitors.

PI3Kα/mTOR ATP-competitive inhibitors are considered as one of the promising molecularly targeted cancer therapeutics. Based on lead compound A from the literature, two similar series of 2-substituted-4-morpholino-pyrido[3,2-d]pyrimidine and pyrido[2,3-d]pyrimidine analogs were designed and synthesized as PI3Kα/mTOR dual inhibitors. Interestingly, most of the series gave excellent inhibition for both enzymes with IC50 values ranging from single to double digit nM. Unlike many PI3Kα/mTOR dual inhibitors, our compounds displayed selectivity for PI3Kα. Based on its potent enzyme inhibitory activity, selectivity for PI3Kα and good therapeutic index in 2D cell culture viability assays, compound 4h was chosen to be evaluated in 3D culture for its IC50 against MCF7 breast cancer cells as well as for docking studies with both enzymes.

A spiroligomer α-helix mimic that binds HDM2, penetrates human cells and stabilizes HDM2 in cell culture.

We demonstrate functionalized spiroligomers that mimic the HDM2-bound conformation of the p53 activation domain. Spiroligomers are stereochemically defined, functionalized, spirocyclic monomers coupled through pairs of amide bonds to create spiro-ladder oligomers. Two series of spiroligomers were synthesized, one of structural analogs and one of stereochemical analogs, from which we identified compound 1, that binds HDM2 with a Kd value of 400 nM. The spiroligomer 1 penetrates human liver cancer cells through passive diffusion and in a dose-dependent and time-dependent manner increases the levels of HDM2 more than 30-fold in Huh7 cells in which the p53/HDM2 negative feed-back loop is inoperative. This is a biological effect that is not seen with the HDM2 ligand nutlin-3a. We propose that compound 1 modulates the levels of HDM2 by stabilizing it to proteolysis, allowing it to accumulate in the absence of a p53/HDM2 feedback loop.

Ethanol alters the expressions of c-Fos and myelin basic protein in differentiating oligodendrocytes.

Myelination occurs in the central nervous system of the human fetus, adolescents, and young adults. Ethanol interferes with myelination in part by altering the composition of the myelin sheath. Here we show that ethanol also affected the expression of the transcription factor c-Fos in differentiating oligodendrocytes (OLGs). Central glial-4 OLG progenitors were induced to differentiate in the absence and presence of 100 mM ethanol, and ethanol-caused changes in the levels of c-Fos and myelin basic protein (MBP) were determined by Western blot analysis at selected developmental stages. The relatively high c-Fos level in progenitors did not immediately decrease to a low level at the onset of differentiation but displayed a downregulation at a later developmental stage. Ethanol delayed the developmental c-Fos downregulation maintaining c-Fos at a 45% higher level at 2 days of differentiation (DoD). Ethanol also decreased the rate of the burst of MBP expression that occurred between 1 and 2 DoD, reducing the MBP level by 47% at 2 DoD. The ethanol-caused delays of c-Fos downregulation and MBP upregulation were both blocked by the protein kinase C (PKC) inhibitor bisindolylmaleimide I (BIM). Likewise, treatment of OLGs with a low 5-nM concentration of the PKC activator by 12-O-tetradecanoylphorbol-13-acetate mimicked the ethanol effects on the expression of both proteins, effects that were also counteracted by BIM. The results indicate that ethanol-caused delays of the stage-specific c-Fos downregulation and the inhibition of MBP expression both occur through a PKC-mediated mechanism. The ethanol-caused delay in c-Fos downregulation may disrupt normal timing for expression of genes involved in OLG differentiation, and the inhibited MBP expression may alter the myelin sheath composition.