4H-3,1-Benzoxazin-4-ones are alternate substrate inhibitors of the serine proteinase human leukocyte elastase (HL elastase) and form acyl enzyme intermediates during enzyme catalysis. We have synthesized a large variety of benzoxazinones using specific methods that have been adapted to achieve the pattern of ring substitution dictated by theoretical considerations. The results of the inhibition of HL elastase by 175 benzoxazinones are reported herein with reference to hydrophobicity constants D, alkaline hydrolysis rates kOH-, inhibition constants Ki, and their component acylation and deacylation rate constants, kon and koff, respectively. The ranges for the compounds are considerable; alkaline hydrolysis rates and kon span 6, koff covers 5, and ki spans 8 orders of magnitude. Multiple regression on this large data set has been used to isolate the contributions of electronic and steric effects, as well as other factors specific to compound stability and elastase inhibition. Essentially, a simple electronic parameter is sufficient to account for almost all the variance in the alkaline hydrolysis data, indicating that electronic factors are the major determinants of this type of benzoxazinone reactivity. Factors that significantly enhance the potency of benzoxazinones I are R5 alkyl groups and electron withdrawal by R2. Bulk in R7 and R8 and compound hydrophobicity are not significant, but substitution in R6 is highly unfavorable as are substituents linked via carbon to C2. The physiochemical factors that underlie these trends in Ki are further analyzed in terms of equations that describe kon and koff. A conclusion that emerges is that chemically stable, potent benzoxazinone inhibitors of HL elastase with inhibition constants in the nanomolar range can be designed with (1) R5 alkyl groups to inhibit enzyme-catalyzed deacylation, (2) small alkyl substituents linked via heteroatoms to C2 to enhance acylation and limit deacylation rates, and (3) strongly electron-donating groups at C7 to stabilize the oxazinone ring to nucleophilic attack. Thus, 2-(isopropylamino)-5-n-propyl-7-(dimethylamino)benzoxazinone 95 has kOH = 0.01 M-1 s-1, which extrapolates to a half-life at pH 7.4 of over 8.5 years, and 2-ethoxy-5-ethylbenzoxazinone 38 has Ki = 42 pM.
GEORGE JUST, T. J. LIAK. MU-ILL LIM, PIERRE POTVIN, and YOULA S. TSANTRIZOS. Can. J . Chem. 58,2024Chem. 58, (1980. The conversion of the Diels-Alder adduct of methyl P-nitroacrylate wlth furan to the title compounds and to D,L-2.5-anhydroglucose derivatives 1s described.GEORGE JUST, T. J. LIAK, MU-ILL LIM. PIERRE POTVIN et YOULA S. TSANTRIZOS. Can. J. Chem. 58,2024Chem. 58, (1980. On dkcrit la transformation du produit de la rkaction Dlels-Alder du mCthyle P-nitroacrylate avec le furane en dkrivis du DL-23-anhydroglucose, en D,L-2'-Ppi-showdomycine, et en showdomycine.As part of a programme to synthesize C-5a, accompanied by varying amounts of 6a. From nucleosides, we were interested in developing a the relative ratios of 5a to 6a as a function of reacmethod to prepare an arabinose derivative 8, bear-tion time, it was obvious that 5a was transformed to ing at the anomeric center a functionalized carbon 6a. Compound 5a was characterized as its acetate atom, which could serve as a precursor for the 5b. At this point, it became apparent that the synthesis of compounds such as ara-showdomycin tetrahydropyranyl protecting group obscured the (9b).nmr spectrum of 5a and 5b enough to make some of Reaction of furan with methyl P-nitroacrylate the assignments doubtful. The reaction sequence gave the known adducts l a and l b (1). Prolonged was therefore repeated with the dimethyl-terttreatment with m-chloroperbenzoic acid gave butylsilyl ether lactone 4e, providing 5e and 6b; 5e epoxides 2a and 2b, which upon treatment with was characterized as its pivalate Sf. Since Just and diazabicyclo[5.4.0]undec-Sene (DBU) gave ole-Ouellet (3) subsequently established in the analofinic epoxide 3. As expected (2a), nmr analysis of gous carbocyclic series that the pivalate group inthis compound revealed that the stereochemistry teracted with the hydroxy group generated in the of the epoxide function was exo, since the coupling subsequent ozonolysis-reduction sequence 5 + 7, constant between the bridgehead protons and the it was decided to block the hydroxy group in 5e as endo-protons cr to the epoxide was 0 Hz (dihedral its dimethyl-tert-butylsilyl ether 5g (4). Silylation angle -90" (2b)). of 5e proceeded in an unpredictable manner, proTreatment of endo-carbomethoxy epoxide 2b viding the disilylation product 5g, except for one with acetic acid and hydrochloric acid at 95°C for instance, in low yield. 2 h gave lactone 4a in 60% yield. There is ample Ozonolysis of the olefin 5g, followed by treatprecedent that lactonizations of this type proceed ment with dimethyl sulfide and the reduction of the in the manner depicted, and it has been recently resulting keto aldehyde, obtained in part as its hyreconfirmed in an unambiguous manner for a drate, with 4 equivalents of lithium tri-tert-butoxyclosely related system (12). aluminum hydride, gave diol ester 7d. Selective Attempts to acylate hydroxy lactone 4a with silylation of 7d gave the trisilyl ether 7f. That the acetic anhydride or pivaloyl chloride in pyridine silylation had proceeded wi...
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