Search:
Computing and Library Services - delivering an inspiring information environment

Acylating agents as enzyme inhibitors and understanding their reactivity for drug design

Sykes, Nicholas O., Macdonald, Simon J.F. and Page, Michael I. (2002) Acylating agents as enzyme inhibitors and understanding their reactivity for drug design. Journal of Medicinal Chemistry, 45 (13). pp. 2850-2856. ISSN 0022-2623

Metadata only available from this repository.

Abstract

A series of bicyclic trans-fused -lactones and -lactams have been previously described for the inhibition of human neutrophil elastase and as possible development candidates. During the discovery program, it had been assumed that their acylating power was due in part to the inherent strain energy in the bicyclic structure that was released upon ring opening. This is now shown not to be the case, and in fact, these compounds are no more reactive than simple but analogous -lactams and -lactones. The strain energy is not released in the transition state for alkaline hydrolysis or alcoholysis because the reaction proceeds with rate-limiting formation of the tetrahedral intermediate. A reactivity index of kOH is proposed as a simple guide to determine the usefulness of a potential inhibitor as an enzyme acylating agent

Item Type: Article
Subjects: Q Science > Q Science (General)
Q Science > QD Chemistry
Schools: School of Applied Sciences
School of Applied Sciences > Biomolecular Sciences Research Centre
Related URLs:
References:

(1) Page, M. I. Enzyme Inhibition. In Comprehensive Medicinal
Chemistry; Sammes, P. G., Ed.; Pergamon Oxford, 1990; Vol. 2,
pp 61-87.
(2) (a) Wharton, C. W. The Serine Proteinases. In Comprehensive
Biological Catalysis; Sinnott, M., Ed; Academic Press: London,
1997; Vol. 1, Chapter 11, pp 345-379. (b) Underwood, D. J.;
Green, B. G.; Chabin, R.; Mills, S.; Doherty, J. B.; Finke, P. E.;
MacCoss, M.; Shah, S. K.; Burgey, C. S.; Dickinson, T. A.; Griffin,
P. R.; Lee, T. E.; Swiderek, K. M.; Covey, T.; Westler, W. M.;
Knight, W. B. Mechanism of inhibition of human leukocyte
elastase by beta lactams. 2. Stability, reactivation kinetics, and
products of â lactam derived E-I complexes. Biochemistry 1995,
34, 14344-14355. (c) Katzenellenbogen, J. A.; Rai, R.; Dai, W.
Enol-lactone derivatives as inhibitors of human neutrophil
elastase and trypsin like proteases. Bioorg. Med. Chem. Lett. 2,
1992, 11, 1399-1404. (d) Knight, W. B.; Maycock, A. L.; Green,
B. G.; Ashe, B. M.; Gale, P.; Weston, H.; Finke, P. E.; Hagmann,
W. K.; Shah, S. K.; Doherty, J. B. Mechanism of inhibition of
human leukocyte elastase by two cephalosporin derivatives.
Biochemistry 1992, 31, 4980-4986. (e) Kam, C.-M.; Fujikawa,
K.; Powers, J. C. Mechanism-based isocoumarin inhibitors for
trypsin and blood coagulation serine proteases: new anticoagulants.
Biochemistry 1988, 27, 2547-2557. (f) Navia, M. A.;
Springer, J. P.; Lin, T. Y.; Williams, H. R.; Firestone, R. A.;
Pisano, J. M.; Doherty, J. B.; Finke, P. E.; Hoogsteen, K.
Crystallographic study of a beta-lactam inhibitor complex with
elastase at 1.84 Å resolution. Nature 1982, 327, 79-82. (g) Copp,
L. J.; Krantz, A.; Spencer, R. W. Kinetics and mechanism of
human leukocyte elastase inactivation by ynenol lactones.
Biochemistry 1987, 26, 169-178. (h) Gelb, M. H.; Abeles, R. H.
Substituted isatoic anhydrides: selective inactivators of trypsin
like serine proteases. J. Med. Chem. 1986, 29, 585-589. (i) Gelb,
M. H.; Abeles, R. H. Mechanism of inactivation of chymotrypsin
by 3-benzyl-6-chloro-2-pyrone. Biochemistry 1984, 23, 6569-
6604.
(3) Slater, M. J.; Laws, A. P.; Page, M. I. The relative catalytic
efficiency of beta lactamase catalysed acyl and phosphyl transfer.
Bioorg. Chem. 2001, 29, 77-95.
(4) Beardsell, M.; Hinchliffe, P. S.; Wood, J. M.; Wilmouth, R. C.;
Schofield, C. J.; Page, M. I. Beta-sultamssa novel class of serine
protease inhibitors. Chem. Commun. 2001, 497-498.
(5) Page, M. I. Enzyme Catalysis. In Comprehensive Medicinal
Chemistry; Sammes, P.,G., Ed.; Pergamon: Oxford, 1990; Vol.
2, pp 45-60.
(6) (a) Laws, A. P.; Page, M. I. The effect of the carboxyl group on
the chemical and beta-lactamase reactivity of beta-lactam
antibiotics. J. Chem. Soc., Perkin Trans. 2 1989, 1577-1581.
(b) Laws, A. P.; Layland, N. J.; Proctor, D. G.; Page, M. I. The
roles of the carboxy group in beta-lactam antibiotics and lysine-
234 in beta-lactamase I. J. Chem. Soc., Perkin Trans 2 1993,
17-21.
(7) Metz, W. A.; Peet, N. P. Elastase inhibitors. Prog. Inflammation
Res. 1999, 9, 853-868.
(8) (a) Bode, W.; Wei, A. Z.; Huber, R.; Meyer, E.; Travis, J.;
Neuman, S. X-Ray crystal structure of the complex of human
leukocyte elastase (PMN elastase) and the third domain of the
turkey ovomucoid inhibitor. EMBO J. 1986, 5, 2453-2458. (b)
Navia, M. A.; McKeever, B. M.; Springer, J. P.; Lin, T. Y.;
Williams, H. R.; Fluder, E. M.; Dorn, C. P.; Hoogsteen, K.
Structure of human neutrophil elastase in complex with a
peptide chloromethyl ketone inhibitor at 1.84 Å resolution. Proc.
Natl. Acad. Sci. U.S.A. 1989, 86, 7-11.
(9) Bode, W.; Meyer, E., Jr.; Powers, J. C. Human and porcine
pancreatic elastase. X-ray crystal structures, mechanism, substrate
specificity, and mechanism-based inhibitors. Biochemistry
1989, 28, 1951-1962.
(10) (a) Takahashi, L. H.; Radhakrishan, R.; Rosenfeld, R. E., Jr.;
Meyer, E. F., Jr.; Trainer, D. A. Crystal structure of the covalent
complex formed by a peptidyl R, R-difluoro-â-keto amide with
porcine pancreatic elastase at 1.78 Å resolution. J. Am. Chem.
Soc. 1989, 111, 3368-3374. (b) Renaud, A.; Lestienne, P.;
Hughes, D. L.; Bieth, J. G.; Dimicoli, J.-L. Mapping the S¢
Subsites of porcine pancreatic and human leukocyte elastases.
J. Biol. Chem. 1983, 258, 8312-8316.
(11) (a) Edwards, P. D.; Meyer, E. F., Jr.; Vijayalakshmi, J.; Tuthill,
P. A.; Andisk, D. A.; Gomes, B.; Strimpler, A. Design, synthesis
and kinetic evaluation of a unique class of elastase inhibitors.
The peptidyl alpha ketobenzoxazoles and the X-ray crystal
structure of the covalent complex between porcine pancreatic
elastase and Ac-Ala-Pro-Val-2-benzoxazole. J. Am. Chem. Soc.
1992, 114, 1854-1863. (b) Costanzo, M. J.; Maryanoff, B. E.;
Hecker, L. R.; Schott, M. R.; Yabut, S. C.; Zhang, H.-C.; Andrade-
Gordon, P.; Kauffman, J. A.; Lewis, J. M.; Krishnan, R.;
Tulinsky, A. Potent thrombin inhibitors that probe the S1¢
subsite: tripeptide transition state analogues based on a heterocycle
activated carbonyl group. J. Med. Chem. 1996, 39,
3039-3043. (c) Bernstein, P. R.; Gomes, B. C.; Kosmider, B. J.;
Vacek, E. P.; Williams, J. C. Nonpeptidic inhibitors of human
leukocyte elastase. 6. Design of a potent intratracheally active,
pyridone based trifluoromethyl ketone. J. Med. Chem. 1995, 38,
212-215. (d) Edwards, P. D.; Andisik, D. W.; Strimpler, A. M.;Gomes, B.; Tuthill, P. A. Nonpeptidic inhibitors of human
neutrophil elastase. 7. Design synthesis and in vitro activity of
pyridopyrimidine trifluoromethyl ketones. J. Med. Chem. 1996,
39, 1112-1124. (e) Angelastro, M. R.; Bey, P.; Burhart, J. P.;
Chen, T.-M.; Cregge, R. J.; Durham, S. L.; Farr, R. A.; Gallion,
S. L.; Hare, C. M.; Hoffmann, R. V.; Huber, E. W.; Janusz, M.
L.; Kim, H.-O.; Koehl, J. R.; Marquart, A. L.; Mehdi, S.; Metz,
W. A.; Peet, N. P.; Schreuder, H. A.; Sunder, S.; Tardif, C.
Inhibition of human neutrophil elastase. 4. Design, synthesis,
X-ray crystallographic analysis, and structure-activitiy relationships
for a series of nonpeptidic, orally active pentafluoroethyl
ketones. J. Med. Chem. 1998, 41, 2461-2480.
(12) (a) Macdonald, S. J. F.; Belton, D. B.; Buckley, D. M.; Spooner,
J. E.; Anson, M. S.; Harrison, L. A.; Mills, K.; Upton, R. J.; Dowle,
M. D.; Smith, R. A.; Molloy, C.; Risley, C. Syntheses of trans-
5-oxohexahydropyrrolo[3,2-b]pyrroles and trans-5-oxohexahydrofuro[
3,2-b]pyrroles (pyrrolidine trans-lactams and translactones):
new pharmacophores for elastase inhibition J. Med.
Chem. 1998, 41, 3919-3922. (b) Macdonald, S. J. F.; Dowle, M.
D.; Harrison, L. A.; Spooner, J. E.; Shah, P.; Johnson, M. R.;
Inglis, G. G. A.; Clarke, G. D. E.; Belton, D. J.; Smith, R. A.;
Molloy, C. R.; Dixon, M.; Murkitt, G.; Godward, R. E.; Skarzynski,
T.; Singh, O. M. P.; Kumar, K. A.; Hodgson, S. T.; McDonald,
E.; Hardy, G. W.; Finch, H.; Fleetwood, G.; Humphreys, D. C.
Intracellular inhibition of human neutrophil elastase by orally
active pyrrolidine-trans-lactams Bioorg. Med. Chem. Lett. 2001,
11, 243-246. (c) Macdonald, S. J. F.; Dowle, M. D.; Harrison, L.
A.; Shah, P.; Johnson, M. R.; Inglis, G. G. A.; Clarke, G. D. E.;
Smith, R. A.; Humphreys, D.; Molloy, C. R.; Amour, A.; Dixon,
M.; Murkitt, G.; Godward, R. E.; Padfield, T.; Skarzynski, T.;
Singh, O. M. P.; Kumar, K. A.; Fleetwood, G.; Hodgson, S. T.;
Hardy, G. W.; Finch, H. The discovery of a potent, intracellular,
orally bioavailable, long duration inhibitor of human neutrophil
elastase-GW311616A a development candidate. Bioorg. Med.
Chem. Lett. 2001, 11, 895-898.
(13) (a) Page, M. I. Structure-activity relationships: chemical. In
The Chemistry of â-Lactam Antibiotics; Page, M. I., Ed.; Blackie:
Glasgow, 1992; Chapter 2, pp 79-100. (b) Page, M. I. The
mechanisms of reactions of beta-lactam antibiotics. Adv. Phys.
Org. Chem. 1987, 23, 165-270. (c) Page, M. I. The mechanisms
of reactions of â-lactam anytibiotics. Acc. Chem. Res. 1984, 17,
144-151.
(14) Allinger, N. L.; Tribble, M. T.; Miller, M. A.; Westz, D. H.
Conformational analysis. LXIX. An improved force field for the
calculation of the structures and energies of hydrocarbons. J.
Am. Chem. Soc. 1971, 93, 1637-1648.
(15) King, J. F.; Rathore, R.; Lam, J. Y. L.; Gao, L. E. R.; Klassen,
D. F. pH optimization of nucleophilic reactions in water. J. Am.
Chem. Soc. 1992, 114, 3028-3033.
(16) (a) Groutas, W. C.; Houser-Archield, N.; Chong, L. S.; Venkateraman,
R.; Epp, J. B.; Huang, H.; McClenahan, J. J. Efficient
inhibition of human leukocyte elastase and cathepsin G by
saccharin derivatives. J. Med. Chem. 1993, 36, 3178-3184. (b)
Hlasta, D. J.; Bell, M. R.; Boaz, N. W.; Court, J. J.; Desai, R. C.;
Franke, C. A.; Mura, A. J.; Subramanyam, D.; Dunlap, R. P. A
Benzisothiazolone class of potent selective mechanism based
inhibitors of human leukocyte elastase. Bioorg. Med. Chem Lett.
1994, 4, 1801-1804.
(17) (a) Wood, J. M.; Page, M. I. The mechanisms of sulfonyl transfer
in strained cyclic sulfonamides. Trends Heterocycl. Chem., in
press. (b) Terrier, F.; Kizilian, E.; Gaumont, R.; Faucher, N.;
Wakselman, C. R-Sulfonyl carbanions. combined kinetic, thermodynamic,
and NMR approaches for the study of the ionization
of benzyltriflones in Me2SO and H2O-MeSO2 mixtures. J. Am.
Chem. Soc. 1998, 120, 9496-9503.
(18) Hinchliffe, P. S.; Wood, J. M.; Davis, A.M.; Austin, R. P.; Beckett,
R. P.; Page, M. I. Unusual steric effects in sulfonyl transfer
reactions. J. Chem. Soc., Perkin Trans. 2 2001, 1503-1505.
(19) Huisgen, R.; Ott, H, Die konfiguration der carbonestergruppe
und die sondereigenschaften der lactone (the configuration of
the ester group and the special properties of lactones). Tetrahedron
1959, 6, 253-261. Blackburn, G. M.; Dodds, H. L. H.
Strain effects in acyl transfer reactions. Part 3. Hydroxide and
buffer catalysed hydrolysis of small and medium ring lactones.
J. Chem. Soc., Perkin Trans. 2 1974, 377-382.
(20) Macchia, B.; Gentili, D.; Macchia, M.; Mamone, F.; Martinelli,
A.; Orlandini, E.; Rossello, A.; Cercignani, G.; Perotti, R.;
Allegretti, M.; Asti, C.; Caselli, G. Synthesis, inhibitory activity
towards human leukocyte elastase and molecular modelling
studies of 1-carbomyl-4-methyleneaminoxyazetadinones. Eur. J.
Med. Chem. 2000, 35, 53-67.
(21) (a) Smith, G. B.; Schoenewaldt, E. F. Stability of N-formidoylthienamycin
in aqueous solution. J. Pharm. Sci. 1981, 70, 272-
276. (b) Proctor, P.; Gensmantel, N. P.; Page, M. I. The Chemical
Reactivity of Penicillins and Other â-Lactam Antibiotics. J.
Chem. Soc. Perkin Trans. 2 1982, 1135-1192. (c) Proctor, P.;
Page, M. I. The Mechanism of â-Lactam Ring Opening in
Cephalosporins. J. Am. Chem. Soc. 1984, 106, 3820-3825. (d)
Fersht, A. R.; Kirby, A. J. The hydrolysis of aspirin. J. Am. Chem.
Soc. 1967, 89, 4857-4863 (e) Haginaka, J.; Nakagawa, T.; Uno,
T. Stability of clavulanic acid in aqueous solutions. Chem.
Pharm. Bull. 1981, 29, 3334-3341.

Depositing User: Sara Taylor
Date Deposited: 11 Feb 2008 12:01
Last Modified: 20 Oct 2008 10:28
URI: http://eprints.hud.ac.uk/id/eprint/522

Item control for Repository Staff only:

View Item

University of Huddersfield, Queensgate, Huddersfield, HD1 3DH Copyright and Disclaimer All rights reserved ©