Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against Pneumocystis carinii in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines.

All products of the dirhodium tetraacetate catalyzed reactions of ethyl diazoacetate with furan, 2-methylfuran, 2,5-dimethylfuran, 2-ra-octylfuran, methyl furcate and methyl /3-(«-furyl)acrylate were isolated and characterized. They consist mostly of exo-cyclopropanecarboxylates and 1,4-diacyl-1,3-butadienes and some 3-(acylmethyl)furans. Treatment of the crude reaction mixtures with iodine or boron trifluoride furnishes 1,4-diacyl-1 (E) ,3 (E)-butadienes. Horner-Emmons condensation with the latter dicarbonyl compounds leads to l,6-diacyl-l,3,5-hexatrienes. Proper combinations of methyl -diazopropionate, furans, and -phosphono esters afford segments of retinol and /3-carotene, while combinations of -diazo ketones, furans, and «-phosphono ketones yield LTB3-like leukotrienes. Finally, dirhodium tetraacetate promoted decomposition of ethyl diazoacetate in l,2-bis(2-furyl)ethane and iodine treatment gives a diketo diester, whose reduction, dehydration, and hydrolysis leads to the naturally occurring dodecahexaenic dicarboxylic acid, corticrocin.

Furans with side-chains at C(2) of various lengths terminating in diazomethyl keto groups are shown to undergo Rh*(OAc),-catalyzed furan unravelling with the production of 2-cyclopentenone, 2-cyclohexenone, and 2-cycloheptenone to each of whose olefinic C(p) is attached an acrylaldehyde unit. Interposition of a cyclohexane or a methylaminomethylene moiety between the furan and diazoketo functions leads to the formation of a hydroindenone and pyrrolone, respectively. Replacement of the diazomethylketo terminus by an cc-diazoethylketo system or a a-diazo-b-keto-ester function produces 2-substituted 2-cycloalkenones. A furan with a C,, diazomethylketo-terminating side-chain at C(3) is described to be transformed into a 4-formylmethylidene-2-cyclohexenone.Introduction. -In a recent, broad study of the decomposition of ethyl diazoacetate,

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