A class of substituted 1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]
benzopyrans (
tricyclic pyrones; TPs) was synthesized from a one-pot condensation reaction of 6-substituted 4-hydroxy-2-pyrones and cyclohexenecarboxaldehydes. The reaction involves a 6pi-electrocyclic ring closing process, and stereo- and regioselectivities were examined. C3-Pyridyl-containing TPs may represent a novel synthetic class of microtubule de-stabilizing anti-
cancer drugs that inhibit macromolecule synthesis,
tubulin polymerization, and the proliferation of a spectrum of wild-type and multi-
drug resistant tumor cell lines in vitro. A linear skeleton with a N-containing aromatic ring attached at C3 of the top A-ring, a central
pyran B-ring and a six-membered bottom C-ring with no alkylation at C7 are required for the antitumor activities of the lead compounds, a 3-pyridyl
benzopyran (code name H10) and its 2-pyridyl regioisomer (code name H19). In addition to interacting with the
colchicine-binding site to inhibit
tubulin polymerization and increase the mitotic index, these TP analogs also block the cellular transport of
nucleosides to inhibit
DNA synthesis more effectively than other
antimitotic agents. The anticancer potential of TPs in vivo is suggested by the fact that i.p.
injections of H10 decrease the growth of solid
tumors in mice inoculated with lung or ovarian
carcinomas. A drug-delivery system involving
nanogels was studied. We incorporated the anticancer compound, 6-hydroxymethyl-1,4-anthracenedione (code name AQ10) into
PEG-PEI nanogel, and found that AQ10-encapsulated
nanogel PEG-PEI is significantly more effective in altering the growth of Pan 02 (
pancreatic cancer) cells compared to AQ10 or
nanogel PEG-PEI alone. Since AQ10 is insoluble in water,
PEG-PEI encapsulation represents a way to solubilize and deliver this as well as other poorly soluble compounds.