Discovery of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (EP128265, MPI-0441138) as a potent inducer of apoptosis with high in vivo activity.

Using a live cell, high-throughput caspase-3 activator assay, we have identified a novel series of 4-anilinoquinazolines as inducers of apoptosis. In this report, we discuss the discovery of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine, compound 2b (EP128265, MPI-0441138) as a highly active inducer of apoptosis (EC50 for caspase activation of 2 nM) and as a potent inhibitor of cell proliferation (GI50 of 2 nM) in T47D cells. Compound 2b inhibited tubulin polymerization, was effective in cells overexpressing ABC transporter Pgp-1, and was efficacious in the MX-1 human breast and PC-3 prostate cancer mouse models. In contrast to the SAR of 4-anilinoquinazolines as EGFR kinase inhibitors, the methyl group on the nitrogen linker was essential for the apoptosis-inducing activity of 4-anilinoquinazolines and substitution in the 6- and 7-positions of the quinazoline core structure decreased potency.

Cytotoxic xanthones from Psorospermum molluscum from the Madagascar rain forest.

Two new cytotoxic xanthones were isolated from extracts of the Madagascar rain forest plant Psorospermum cf. molluscum using bioassay-guided fractionation with the Escherichia coli SOS chromotest. The structures of the new dihydrofuranoxanthones, designated 3',4'-deoxy-4'-chloropsoroxanthin-(3',5'-diol) ( 1) and psoroxanthin ( 4), were determined on the basis of 2D-NMR, MS, and UV spectroscopic data and are structurally related to the psorospermins, a known class of plant antitumor agents. A new hydroxyprenylated xanthone ( 5) is also described. Xanthones 1 and 4 showed selective in vitro cytotoxicity against ABAE cells (bovine endothelial cell line).