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A series of aza-5[H]-phenanthridin-6-ones were synthesized and evaluated as inhibitors of poly ADP-ribose polymerase-1 (PARP-1). Inhibitory potency of the unsubstituted aza-5[H]-phenanthridin-6-ones (i.e., benzonaphthyridones) was dependent on the position of the nitrogen atom within the core structure. The A ring nitrogen analogues (7-, 8-, and 10-aza-5[H]-phenanthridin-6-ones) were an order of magnitude less potent than C ring nitrogen analogues (1-, 2-, 3-, and 4-aza-5[H]-phenanthridin-6-ones). Preliminary stroke results from 1- and 2-aza-5[H]-phenanthridin-6-one prompted structure-activity relationships to be established for several 2- and 3-substituted 1-aza-5[H]-phenanthridin-6-ones. The 2-substituted 1-aza-5[H]-phenanthridin-6-ones were designed to improve the solubility and pharmacokinetic profiles for this series of PARP-1 inhibitors. Most importantly, three compounds from this series demonstrated statistically significant protective effects in rat models of stroke and heart ischemia.

The intestinal permeability and transport of 10 neolignans isolated from MYRISTICA FRAGRANS were studied by using the Caco-2 cell monolayer model. The 10 neolignans were measured by HPLC. Transport parameters and permeability coefficients were then calculated and compared with those of the model compounds, propranolol and atenolol. Among the 10 neolignans, the 8- O-4'-type neolignans demonstrated high permeability while the benzofuran-type neolignans were of poor to moderate permeability. Among them, eight neolignans were transported mainly VIA passive diffusion. These findings indicate that the 8- O-4'-type neolignans are well-absorbed compounds and can be used as oral leading compounds in drug discovery.

The bidirectional intestinal permeability of the active constituents from the roots of Saposhnikovia divaricata, including four coumarins, anomalin (1), 5-methoxy-7-(3,3-dimethylallyloxy)coumarin (2), decursin (3), and decursinol angelate (4), as well as four chromones, cimifugin (5), prim-O-glucosylcimifugin (6), 3'- O-angeloylhamaudol (7), and sec-O-glucosylhamaudol (8), was studied by using the Caco-2 cell monolayer. These compounds were assayed by HPLC, and their transport parameters, including apparent permeability coefficients (P(app)), were then calculated. The bidirectional P(app) values of the compounds were compared with those of the markers, propranolol and atenolol. Compounds 1-5 and 7 were assigned to well-absorbed compounds, while 6 and 8 were assigned to moderately absorbed compounds. The transport of 1-7 increased linearly as a function of time up to 180 min and concentration within the test range of 10-200 µM, thus their passive diffusion mechanism was proposed. The results provided some useful information for predicting the intestinal absorption in vivo of these compounds.