No abstract

Efficient replication of HIV-1 requires integration of a DNA copy of the viral genome into a chromosome of the host cell. Integration is catalyzed by the viral integrase, and we have previously reported that phenolic moieties in compounds such as flavones, caffeic acid phenethyl ester (CAPE, 2), and curcumin confer inhibitory activity against HIV-1 integrase. We now extend these findings by performing a comprehensive structure-activity relationship using CAPE analogues. Approximately 30 compounds have been prepared as HIV integrase inhibitors based on the structural lead provided by CAPE, which has previously been shown to exhibit an IC50 value of 7 microM in our integration assay. These analogues were designed to examine specific features of the parent CAPE structure which may be important for activity. Among the features examined for their effects on inhibitory potency were ring substitution, side chain length and composition, and phenyl ring conformational orientation. In an assay which measured the combined effect of two sequential steps, dinucleotide cleavage and strand transfer, several analogues have IC50 values for 3'-processing and strand transfer lower than those of CAPE. Inhibition of strand transfer was assayed using both blunt-ended and "precleaved" DNA substrates. Disintegration using an integrase mutant lacking the N-terminal zinc finger and C-terminal DNA-binding domains was also inhibited by these analogues, suggesting that the binding site for these compounds resides in the central catalytic core. Several CAPE analogues were also tested for selective activity against transformed cells. Taken together, these results suggest that the development of novel antiviral agents for the treatment of acquired immune deficiency syndrome can be based upon inhibition of HIV-1 integrase.

2',3'-Dideoxy purine nucleosides have anti-HIV activity in vitro and the inosine analogue is being clinically evaluated. The instability of these compounds toward acidic conditions complicates oral administration. The effect of the addition of a fluorine atom to the 2'-position was investigated by preparing the fluorine-containing 2'-erythro and 2'-threo isomers of ddA and the threo isomer of ddI. All fluorine-containing compounds were indefinitely stable to acidic conditions which completely decomposed ddI (1) and ddA (2) in minutes. While the fluorine-containing erythro isomer, 5, was inactive, the threo isomers, 2'-F-dd-ara-A (3) and 2'-F-dd-ara-I (4), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH 1 at 37 degrees C prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of 3 and 4 unchanged. The fluorinated analogues also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compounds. The fluorine-containing analogues appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compounds.

The N‐chloro compound, dichloroisocyanuric acid (DCA), has been discharged vs. lithium in organic nonaqueous electrolytes. The normalLi/2MLiClO4 (methyl formate)/DCA system has an open‐circuit voltage of 4.0v. The solubility of DCA in 2MLiClO4 (methyl formate) is 13 w/o (weight per cent) or 0.65M. Chronopotentiometry at platinum electrodes indicates an irreversible electrode reaction false(αna=0.074false) . However there are no separate voltage plateaus at platinum or carbon. Coulometric and battery discharge data are complex, probably because of precipitates formed during the reduction of DCA in the presence of lithium salts in methyl formate. At constant 3.2v discharges, average current densities are 5.8 and 3.4 ma/cm2 at 4 and 8 hr, respectively. Excluding grid and container weights 200 whr/lb is achieved in 8 hr. High energy densities (180 whr/lb) are obtained under constant load at 3–10 hr discharge rates. When the cell is activated immediately prior to discharge, self‐discharge and anode passivation are relatively minor problems.

No abstract

A searcheable database of three-dimensional structures has been developed from the chemistry database of the NCI Drug Information System (DIS), a file of about 450,000 primarily organic compounds which have been tested by NCI for anticancer activity. The DIS database is very similar in size and content to the proprietary databases used in the pharmaceutical industry; its development began in the 1950s; and this history led to a number of problems in the generation of 3D structures.

No abstract

A series of 15 2,5-diaziridinyl-3,6-bis(alkylamino)-1,4-benzoquinone derivatives was synthesized and evaluated as central nervous system antitumor agents in the murine intracerebral L1210 and ependymoblastoma brain tumor systems. Intraperitoneal activity was evaluted in the leukemia L1210, P388, and B16 melanocarcinoma tumor models. The more hydrophilic hydroxyalkylamino compounds were the most effective in the intraperitoneal ascites systems (L1210, P388) with the dihydroxypropylamino (18) and hydroxyethylamino (17) analogues producing long-term survivors. The simple, more lipophilic mono- and dialkylamino derivatives were most effective in the intracerebral systems. Multiple long-term survivors were obtained with the methyl (13), ethyl (14), and dimethylamino (20) compounds in the ependymoblastoma brain tumor system. The parent amino analogue 12 was very active in several tumor models. The relationship between structure, activity, and water solubility are discussed.