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RESEARCH ARTICLE
Contents Vol 67(9)

The Preparation of Macrocyclic Calpain Inhibitors by Ring Closing Metathesis and Cross Metathesis*

Seth A. Jones A , Joanna Duncan A , Steven G. Aitken B , James M. Coxon B and Andrew D. Abell A C
+ Author Affiliations
- Author Affiliations

A School of Chemistry and Physics, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia.

B Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand.

C Corresponding author. Email: andrew.abell@adelaide.edu.au

Australian Journal of Chemistry 67(9) 1257-1263 https://doi.org/10.1071/CH14121
Submitted: 7 March 2014  Accepted: 16 April 2014   Published: 15 May 2014

Abstract

Ring closing metathesis and cross metathesis approaches to a new macrocyclic peptidomimetic aldehyde 2 have been developed, with the former route being the most convenient. Aldehyde 2 is a potent inhibitor of calpain II (IC50 of 45 nM) with comparable activity to the benchmark acyclic inhibitor SJA6017 4. Both compounds contain an N-terminal 4-fluorophenylsulfonyl group. The P2 Ile analogue of 2 (16) is significantly less active (IC50 of 2000 nM) which reflects an unusually subtle importance of the P2 residue for active site binding.


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