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Biotechnology and Applied Biochemistry (2003) 37, (273–282) (Printed in Great Britain)

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Bifunctional constructs of aspirin and ibuprofen (non-steroidal anti-inflammatory drugs; NSAIDs) that express antibacterial and alkylation activities

Ronald Bartzatt*¹, Suat L. G. Cirillo†, Jeffrey D. Cirillo† and Laura Donigan*

*University of Nebraska, College of Arts & Sciences, Chemistry Department, Durham Science Center, 6001 Dodge Street, Omaha, NE 68182, U.S.A. , and †University of Nebraska-Lincoln, Department of Veterinary & Biomedical Sciences, 203 VBS, Fair Street, Lincoln, NE 68563, U.S.A.

Key words: antibacterial, anticancer, aspirin, cytotoxic, ibuprofen, tripeptide.

Abbreviations used: NSAID, non-steroidal anti-inflammatory drug; N-mustard, nitrogen mustard; TPSA, molecular polar surface area; COX, cyclo-oxygenase; DAP, 2,6-diaminopimelic acid.

¹To whom correspondence should be addressed (e-mail bartzatt@mail.unomaha.edu).

Ibuprofen and aspirin are two common non-steroidal anti-inflammatory drugs (NSAIDs). Both NSAIDs have a carbonyl carbon [-C(O)-], which was utilized to attach a nitrogen mustard (N-mustard) ester group or a tripeptide group. The tripeptide consisted of a L-Gly-D-Ala-D-Ala sequence, where D-Ala-D-Ala is the reactive site for antibacterial activity and L-Gly serves as a linker to the NSAID carrier drug. The aspirin tripeptide and N-mustard show significant antibacterial activity at 5.0×10^-5 M against penicillin-susceptible or -resistant Escherichia coli. The partition coefficients (logKow)logP of aspirin and ibuprofen tripeptide drugs were -1.05 and 2.23, respectively. The NSAIDs served as carrier drugs of the N-mustard group which expressed alkylation activity directed towards the nucleophilic primary amine of p-chloroaniline. Hydrolysis of the N-mustard agents yielded the parent structure of aspirin (or ibuprofen) and an N-mustard moiety, 2-[bis(2-chloroethyl)amino]ethanol. The (logKow)logP for the N-mustard structures of aspirin and ibuprofen were 2.61 and 5.63, respectively. The (logKow)logP value of 2-[bis(2-chloroethyl)amino]ethanol was 0.56. Fluorescamine was utilized to determine unreacted p-chloroaniline at known time intervals, which permitted calculation of rate constants and rate equations. The aspirin N-mustard agent expressed strong antibacterial activity against a penicillin-resistant bacteria and first-order alkylation kinetics. The ibuprofen N-mustard and 2-[bis(2-chloroethyl)amino]ethanol followed second-order alkylation kinetics. All N-mustard and tripeptide compounds showed zero violations of the Rule of 5. Values of TPSA (molecular polar surface area), C logP and molecular dipoles were calculated.

Received 5 November 2002/14 January 2003; accepted 17 January 2003

Published as Immediate Publication 17 January 2003, DOI 10.1042/BA20020108

Portland Press Ltd © 2001