A series of ureides active against grand mal epilepsy have been studied by using classical potential energy calculations. The series includes phenyl ethyl and diphenyl derivatives of hydantoins, succinimides, glutarimides, oxazolidine-2,4-diones, pyrimidine-2,6-diones, barbituric acids, and phenacemide. A thorough examination of the conformational possibilities did not reveal an exclusive conformation that could account for their activity. However, comparisons with diazepam and other benzodiazepines known to have the ability to competitively bind with drugs such as diphenylhydantoin at some sites show that there is a distinct conformational preference that may well account for their activity against grand mal epilepsy. The conformational studies led to the proposal of a general model for anticonvulsant activity comprising two aromatic rings or their equivalent in a favored orientation and a third region, usually a cyclic ureide, comprising a number of hydrogen-bond-forming functional groups. The specific placement of hydrogen-bonding groups in this region appears to be of less importance than the correct conformational arrangement of the hydrophobic elements.

No abstract

Breast cancers are either estrogen receptor-positive (ER) or negative (ER). ER breast cancers are clinically more aggressive and have fewer effective treatment options. Quercetin and vincristine are both active against ER breast cancers and exhibit synergism in vitro. However, the clinical use of quercetin is hampered by its low water solubility. In addition, optimal synergism can only be achieved at a particular ratio of the drugs. Therefore, the objectives of this study are to develop a liposomal formulation to solubilize quercetin, and to co-encapsulate and coordinate the release of quercetin and vincristine in their synergistic ratios to maximize anticancer activity. The optimal synergistic molar ratio of quercetin/vincristine was found to be 1 : 2 by in-vitro MTT assay. Quercetin liposomes were prepared by the film hydration method followed by extrusion, and vincristine was subsequently loaded into the core of the liposomes by remote loading with manganese sulfate and the ionophore A23187. The optimal liposome formulation co-encapsulating quercetin and vincristine comprised egg sphingomyelin/cholesterol/PEG2000 ceramide/quercetin (72.5 : 17.5 : 5 : 5 mol ratio). This formulation was physically stable, enhanced quercetin solubility 8.6 times, co-encapsulated quercetin and vincristine with efficiencies of 78.3 and 78.5%, respectively, and displayed coordinated release of both drugs to maintain the synergistic molar ratio. In-vitro MTT assays of this liposomal formulation showed significant synergism, with a combination index of 0.113 and a dose-reduction index value of 115 at ED50 for vincristine. Therefore, liposomal delivery represents a strategy to solubilize poorly soluble drugs and coordinate the release of two drugs in their synergistic ratio for optimal anticancer effect.