Structure--activity relationships of nogalamycin analogues.

Nogalamycin (1) has been modified by changes at C-10 and C-7 and in the dimethylamino group to prepare an extensive series of analogues. The chemistry involved in the modifications and structure--activity relationships among these nogalamycin analogues are discussed, as well as comparisons with previously reported compounds 1, 7-con-O-methylnogarol (2), and disnogamycin (11).

2-(Aminomethyl)chromans that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma and ischemia.

A series of 2-(aminomethyl)chromans was developed as potent inhibitors of iron-dependent lipid peroxidation. Compounds within this class are extremely effective at inhibiting lipid peroxidation with IC50's as low as 0.2 microM. Selected members were found to enhance early neurological recovery and survival in a mouse head injury model. In this assay, improvement in the 1-h post-head-injury neurological status (grip test score) by as much as 230% of control was observed. One of the most efficacious compounds (35) was evaluated in two models of cerebral ischemia where significant neuroprotection was observed. These results provide further support for the importance of cerebroprotective antioxidants for the treatment of traumatic and ischemic injury as well as additional evidence for the role of oxygen radicals in postischemic brain damage.

Novel 21-aminosteroids that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma.

A novel class of 21-aminosteroids has been developed. Compounds within this series are potent inhibitors of iron-dependent lipid peroxidation in rat brain homogenates with IC50's as low as 3 microM. Furthermore, selected members enhance early neurological recovery and survival in a mouse head injury model. Significant improvement in the 1 h post-head-injury neurological status (grip test score) by as much as 168.6% of the control has been observed. The most efficacious compound in this assay (30) showed an increase in the 1-week survival of 78.6% as compared to 27.3% for the vehicle-treated mice in the head-injury model. Based on its biological profile, 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha- methylpregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate (30) was selected for further evaluation and is currently entering phase I clinical trials for the treatment of head and spinal trauma.

Metronidazole phosphate--a water-soluble prodrug for parenteral solutions of metronidazole.

To develop a parenteral solution of relatively water-insoluble metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol), its phosphate ester was synthesized via two routes. One route utilized 2-cyanoethyl phosphate and the other utilized pyrophosphoryl tetrachloride. The first method used dicyclohexylcarbodiimide as a coupling agent and the cyanoethyl group was removed under mild alkaline conditions. The second method was a one-step procedure in which free acid of metronidazole phosphate was isolated as a crystalline solid. The solubility of metronidazole in various solvents was determined at 25 degrees. From the pH-dependence of its aqueous solubility, the pKa of the conjugate acid of metronidazole was estimated to be 2.62, which agreed well with the pKa values of other nitroimidazoles. Metronidazole phosphate behaved as a zwitterionic compound in an acidic medium with a minimum solubility at pH 2.0. At pH 7, its solubility was approximately 50 times that of metronidazole. The phosphate ester was so soluble at pH higher than 7 that it was difficult to measure the solubility accurately. In human serum, the hydrolysis of metronidazole phosphate followed zero-order kinetics at an initial concentration of 0.25 mg/ml or higher, presumably due to enzyme saturation (0.035 mg/ml/hr at 37 degrees). A reversed-phase HPLC procedure was adopted to monitor the appearance of metronidazole and the disappearance of metronidazole phosphate. Subcutaneous administration of metronidazole phosphate to rats produced a blood level of bioactivity comparable to that observed after administration of metronidazole.