Novel antineoplastic agents with efficacy against multidrug resistant tumor cells.

A novel series of pentafluorobenzenesulfonamides has been shown to inhibit the growth of a variety of human tumor cell lines. Among the cell types against which these agents were evaluated were the multidrug resistant (MDR) cell lines MCF-7/ADR and P388/ADR. The cytotoxic activity of members of this series of compounds was not affected by the multidrug resistant pump in MCF-7/ADR or P388/ADR cells.

A novel class of cyclic beta-dicarbonyl leaving groups and their use in the design of benzisothiazolone human leukocyte elastase inhibitors.

Human leukocyte elastase (HLE) has been proposed to be a primary mediator of pulmonary emphysema, and inhibitors of this enzyme should be effective in the treatment of emphysema and other pulmonary diseases. We have discovered a novel class of alicyclic and heterocyclic leaving groups which share one common structural feature, a cyclic beta-dicarbonyl. This design concept for leaving groups has not been previously reported. A structure-activity relationship has been developed and the concept extended to several types of alicyclic and heterocyclic beta-dicarbonyl systems. This work led to the identification of a potent (K*i of 0.066 nM) and tissue stable (in vitro: blood t1/2 = 160 min, liver t1/2 > 240 min) benzisothiazolone HLE inhibitor, WIN 65936 (13b).

Associations of the bacterial mutagenicity of halogenated 2(5H)-furanones with their MNDO-PM3 computed properties and mode of reactivity with sodium borohydride.

Electrophilicity as a general basis for both the mutagenicity and nucleophile inactivation of halogen-substituted 2(5H)-furanones was tested. Lowest unoccupied molecular orbital (LUMO) energy levels and stabilities of 2(5H)-furanone radical anions and C-2, C-3, and C-4 anionic hydride adducts were computed with MNDO-PM3 for each of 10 compounds. These three computed sets of values were considered electrophilicity indicators. Each individual value from a given indicator set was plotted against the logarithm of the Salmonella typhimurium (TA100) mutagenicities (log Mm) for each of the corresponding compounds. Highest occupied molecular orbital (HOMO) energy levels for the 10 compounds were also computed. Strong negative correlations were obtained from the plots of LUMO and radical anion stability against log Mm of the 10 compounds. Also, a negative correlation was observed for the plot of the stability of the C-4 anionic hydride adduct for a smaller set of six compounds possessing a 4-(chloromethyl)-2(5H)-furanone structure and having the same HOMO characteristics. HOMO energies failed to correlate with mutagenicity. Neither computed atomic charge nor 13C chemical shift values for the larger compound group of 10 correlated well with mutagenicity or with each other. Sodium borohydride and borodeuteride reductions of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone demonstrated experimentally that hydride became attached to C-4.