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Silica gel supported pyrolysis of an azido-homo-oxa steroid led to rearrangement, presumably by a mechanism similar to that of solution phase Schmidt fragmentation, to produce a group of novel inhibitors for the oncogenic cell cycle regulator Cdc25A phosphatase. Cyano-containing acid 17, one of the best inhibitors in this group, inhibited the activity of Cdc25A protein phosphatase reversibly and noncompetitively with an IC50 value of 2.2 μM. Structure−activity relationships revealed that a phosphate surrogate such as a carboxyl or a xanthate group is required for inhibitory activity, and a hydrophobic alkyl chain, such as the cholesteryl side chain, contributes greatly to the potency. Without the cyano group, acid 26 and xanthate 27 were found to be more selective over Cdc25A (IC50 = 5.1 μM and 1.1 μM, respectively) than toward CD45 (IC50 > 100 μM, in each case), a receptor protein tyrosine phosphatase. Several of these inhibitors showed antiproliferative activities in the NCI 60-human tumor cell line screen. These steroidal derived Cdc25 inhibitors provide unique leads for the development of dual-specificity protein phosphatase inhibitors.

ABSTRACTIntegration of the human immunodeficiency virus type 1 (HIV-1) cDNA is a required step for viral replication. Integrase, the virus-encoded enzyme important for integration, has not yet been exploited as a target for clinically useful inhibitors. Here we report on the identification of new polyhydroxylated aromatic inhibitors of integrase including ellagic acid, purpurogallin, 4,8,12-trioxatricornan, and hypericin, the last of which is known to inhibit viral replication. These compounds and others were characterized in assays with subviral preintegration complexes (PICs) isolated from HIV-1-infected cells. Hypericin was found to inhibit PIC assays, while the other compounds tested were inactive. Counterscreening of these and other integrase inhibitors against additional DNA-modifying enzymes revealed that none of the polyhydroxylated aromatic compounds are active against enzymes that do not require metals (methylases, a pox virus topoisomerase). However, all were cross-reactive with metal-requiring enzymes (restriction enzymes, a reverse transcriptase), implicating metal atoms in the inhibitory mechanism. In mechanistic studies, we localized binding of some inhibitors to the catalytic domain of integrase by assaying competition of binding by labeled nucleotides. These findings help elucidate the mechanism of action of the polyhydroxylated aromatic inhibitors and provide practical guidance for further inhibitor development.

Benzenesulfonyl azide has been found to react with cis–endoand cis–exobicyclo[2•2•1]-5-heptene-2,3-dicarboxylic anhydride to give in both cases, predominantly the more hindered endoaziridine in addition to the exoaziridine in apparent violation of the "exo-addition rule" (3). The stereochemistry of the aziridine rings were determined by nuclear magnetic resonance analysis and by conversion of the endo-aziridine-exo-anhydride to 2-endo-benzenesulfonamidobicyclo[2•2•1]heptane. The endo-aziridine-endo-anhydride has been previously (4) converted into a lactone-N-benzenesulfonyl-lactam.

The thermal reaction of methyl azidoformate and norbornene has been found to proceed via 1,3-dipolar-cycloaddition yielding exotriazoline adduct, 15a. Thermal decomposition of the triazoline results in the loss of nitrogen and the formation of at least 5 products. The major products of the thermal decomposition in decalin were 3-carbomethoxy-3-azatricyclo(3.2.1.02,4 exo)octane, 18a, and N-carbomethoxy-2-norbornimine, 20. In addition, syn-2-norbornene-7-methyl carbamate, 21, and 3-carbomethoxy-3-azatricyclo(3.2.1.02,3 endo)octane, 19a, were isolated. The thermal decomposition of the triazoline adduct is considered to proceed by a multi-step mechanism. The first step is considered to involve heterolytic cleavage of the N3—N4bond togive a zwitterion which may lead to products or rearrange viacarbon–carbon bond cleavage to give a diazoalkyl imine.

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The diimide antitumor agent mitindomide (Ia) is converted to the alcohol (Ib) or the potential prodrugs (Ic) and (Id) ‐ (If).

Sixth instars of the spruce budworm, Choristoneura fumiferana (Clemens), were exposed to an ethanol extract of roots of the composite coltsfoot, Tussilago farfara L., in a laboratory feeding bioassay. The extract had feeding deterrent activity, and the active ingredient, senkirkine, was isolated. Senkirkine, a pyrrolizidine alkaloid, is to our knowledge the first member of this class of compounds shown to have feeding deterrent activity in Lepidoptera. Thirteen additional pyrrolizidine alkaloids were bioassayed to determine possible structure-activity correlations. Most of the pyrrolizidine alkaloids tested were inactive, and high levels of feeding deterrence were not observed in those compounds lacking lactone or diester side chains. The most active compounds, senkirkine and lasiocarpine, bore a, ß unsaturation in the side chain.