3,4-Epoxy-1-butene, an active metabolite of 1,3-butadiene, was reacted with guanosine, deoxyguanosine and calf thymus DNA. The products were isolated and positively identified using various spectroscopic techniques. Treatment of calf thymus-DNA with 3,4-epoxy-1-butene yielded two N7-guanine adducts of equal stability. Depurination by neutral hydrolysis showed that 7-(2-hydroxy-3-buten-1-yl)guanine (compound I) was formed in greater quantities compared to its regioisomer 7-(1-hydroxy-3-buten-2-yl)guanine (compound II); spontaneous depurination experiments showed that compound I was released in the highest proportion. The circular dichroism spectral studies with R and S 3,4-epoxy-1-butene revealed that the reaction mechanism at aqueous neutral pH media is more similar to SN2-type rather than SN1-type. The HPLC-electrochemical detection method used to carry out the DNA alkylation study provides a rapid and sensitive quantitation of N7 guanine adducts in biological fluids. This serves as a useful tool for further human biomonitoring experiments.

[reaction: see text] The synthesis of four bioactive analogues of the somatostatin (SRIF-14) mimetic, beta-d-glucoside (+)-2, in which the C1 indole side chain is replaced with indole surrogates, has been achieved. These congeners, possessing the naphthyl, benzothiophene, benzyl, and benzofuran substituents, were predicted to satisfy the electrostatic requirements of the tryptophan binding pocket of SRIF. Unlike the previously described C4 picolyl and pyrazinyl congeners, these ligands bind the hSST4 receptor.

The preparation and reactions of several new (η3-allyl)molybdenum complexes are described. Functionalization of a carbon−carbon double bond adjacent to the π-allyl unit proceeds stereoselectively, and the stereochemical outcome of this reaction is discussed in light of the Curtin−Hammett principle. It is shown that carbonyl groups can also be functionalized with moderate stereoselectivity, and this behavior is rationalized on the basis of conformational analysis using molecular mechanics calculations.

Cyclic hexapeptides represent a class of compounds with important, diverse biological activities. We report herein that the antibody 16G3 catalyzes the cyclization of D-Trp-Gly-Pal-Pro-Gly-Phe⅐p-nitrophenyl ester (8a) to give c-(D-Trp-Gly-Pal-Pro-Gly-L-Phe) (11a). The antibody does not, however, catalyze either epimerization or hydrolysis. The resulting rate enhancement of the cyclization by 16G3 (22-fold) was sufficient to form the desired product in greater than 90% yield. In absolute rate terms, the turnover of 16G3 is estimated to be 2 min ؊1 . The background rate of epimerization of 8a was reduced from 10 to 1% and hydrolysis from 50 to 4% in the presence of 16G3. As expected, the catalytic effects of 16G3 were blocked by the addition of an amount of the hapten equal to twice the antibody concentration. We also synthesized three diaste- S everal years ago, we undertook the generation of antibodies to catalyze peptide bond formation in part because manmade catalysts of peptide bond formation had not been described (1). We were also intrigued by the contrast between medicinal chemistry and antibody design. Generally, the former seeks by design or screening to discover small molecules that interact with macromolecules such as enzymes or receptors leading to enzyme inhibitors or to hormone͞neurotransmitter agonists͞antagonists. In contrast, catalytic antibody research involves the synthesis of haptens, designed to generate novel macromolecules (antibodies), which in turn are capable of catalyzing predetermined chemical reactions. The Design of Hapten 1a: Novel Chemistry and the Generation ofAntibody 16G3 for Bimolecular Peptide Bond Formation. We reported the synthesis of hapten 1a (Fig. 1), designed to induce the formation of antibodies capable of catalyzing the formation of dipeptides of the general structure acetyl-XXX-D-Trp⅐NH 2, wherein XXX represents hydrophobic L-amino acids typified by L-Phe (1). This endeavor generated antibody 16G3, which gave rate enhancements on the order of 2 ϫ 10 4 over the background reaction with pleasingly high turnover rates (Ϸ2 min Ϫ1 ). Our study of the kinetics implicated a sequential mechanism with no preferred order of substrate binding and no evidence for acylation of the antibody by the ester before peptide bond formation. Antibody 16G3 did not, however, catalyze either the hydrolysis or racemization of the active ester. The generation of antibodies that catalyze nonsolvolytic bimolecular bond formation is a greater challenge than the production of antibodies designed to catalyze solvolysis because an important requirement for the former is to prevent hydrolysis. The acylating agents employed in these coupling reactions were the p-nitrophenyl esters of acetyl-XXX. Although the hapten had been designed to generate antibodies that can catalyze the formation only of dipeptides, we subsequently found that antibody 16G3 also catalyzes the coupling of the p-nitrophenyl ester of N-acetyl-LPhe with D-Trp-Gly⅐NH 2 and the p-nitrophenyl ester of N-acetylGly-L-Phe with D-Trp-Gly⅐N...