Oxetane Based Peptidomimetics: Potential New Tools
for Drug Discovery and Chemical Biology
Nicola H. Powell,§ Guy J. Clarkson,§ Rebecca Notman,§ Piotr Raubo,¶ Nathaniel G. Martin¶ and Mike Shipman§
§Department
of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. Tel: +44 2476 523186;
E-mail: m.shipman@warwick.ac.uk ¶AstraZeneca, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK.
Oxetane Modified Peptides: Why?
Oxetane Peptidomimetics: Structural Insights by XRD
Conventional
peptide:
Peptide based drugs1 present significant challenges with
respect to bioavailability and biostability, partly because they are
labile in vivo to the action of peptidases and proteases.
Chemical modification of the peptide bond is an established
strategy to improve the effectiveness of a drug candidate by
increasing its bioavailability, serum half-live and selectivity for
the target receptor.2 Here, we report a new type of peptide
bond isostere, in which the heterocyclic oxetane nucleus is
used as a replacement for the carbonyl group within the
peptide backbone.3
O
H
N
R
N
H
R
Leu-GOx-Ile:
O
H
N
O
H 3N
Oxetane modified
peptide (OMP):
H
N
R
R
•  Observe anti-parallel sheet-like
arrangement in the solid state.
O
H
N
N
H
•  Aminooxetane unit acts as Hbond donor and acceptor.
•  ‘Normal’ zwitterionic structure
seen i.e. secondary amine not
protonated
R
O
CO2
O
R
O
O
H
N
N
H
This approach has a number of attractive features:
•  Oxetanes are excellent bioisosteric replacements in conventional, small-molecule drug
discovery where they often enhance metabolic stability and lipophilicity;4
O
H 3N
•  Oxetane modified peptides (OMPs) should have greatly reduced vulnerability to proteases;
R
•  Any α-amino acid in a peptide chain could be replaced providing enormous opportunity to
control structure and function;
O
H
N
N
H
CO2
O
H
•  Conformational changes will provide access to new peptide “structural space”;
O
ω
ω = 180°
Phe-GOx-Ile, ω = 60.2°
Leu-GOx-Ile, ω = 55.7°
R = Phe or Leu
•  OMP residues should participate in H-bonding interactions, as both donor and acceptor;
H
N
cf
N
Nitrogen hybridization and dihedral angle changes occur upon aminooxetane substitution allowing access to new peptide “structural space”.
•  OMPs should be relatively easy to make.
Simple Preparation Of Oxetane Containing Peptidomimetics
Step 1: Introduction of Oxetane by Conjugate Addition
H 2N
O
O2N
1. RCH2NO 2
2. MsCl, Et3N
O
R1
R
R
Et 3N, CH2Cl2
R = H or Bn
H
N
O2N
O
O2N
CO2R 2
O2N
CO2Me
O2N
O
CO2Bn
H
N
O2N
H
N
CO2Bn
64%
CO2Me
O
OH
48%
CO2Bn
O
H
N
O
O
62%
CO2Bn
H
N
O2N
O
O
H
N
N
H
CO2
H 3N
H
N
N
H
CO2
R1
O
H 3N
Ph
H 3N
N
H
O
Ph
CO2
H 3N
O
CO2
H
N
CO2
O
O
H
N
N
H
CO2
H 3N
N
H
O
56%
H
N
44%
O
H
N
N
H
Ph
CO2
58%
O
CO2Bn
O
H
N
N
H
53%
73%
Ph
N
H
O
H 3N
R
O
H
N
O2N
59%
O2N
O
H 3N
52%
O
56%
H
N
O2N
H
N
O2N
CO2Bn
O
58%
O HO
O
H
N
O2N
O
83%
CO2Bn
CO2Bn
CO2Bn
AA-GOx-AA
e.g.
H
N
O2N
O
(R)-, 68%
(S)-, 65%
O2N
H
N
1. In, THF, aq. HCl
2. N-Z-amino acid
EDC, HOBt, NMM
3. H 2, Pd/C, MeOH
R1
O
Ph
H
N
H
N
R1
O
e.g.
Step 2: Nitro Group Reduction/Homologation
CO2R 2
O
41%
44%
Additional types of modifications (chemistry not shown):
O
N
H
64%
CO2Bn
H
N
H 3N
A practical route to aminooxetane containing tripeptides has
been established with full scope currently being explored.
O
N
H
CO2
H
N
H 2N
O
at N-terminus
O
Ph
O
OH
N
H
Cbz
H
N
H
N
N
H
O
O
at C-terminus
O
Ph
O
Phe
CO2Me
HN
Ph
NH
O
cyclic
Oxetane Peptidomimetics: Molecular Dynamics Simulations
Future Work
In H2O:
•  Demonstrate that these peptidomimetics are useful in medicinal chemistry programmes;
•  Conformations explored by Leu-Gly-Ile are
dominated by extended structures with C
and N termini separated by >7 Å.
50%
43%
•  Most populated cluster of Leu-GOx-Ile is
folded with C and N termini separated by 3–
4 Å. Close contact between the terminal –
CO2– and –NH3+ ions.
•  Further generalise the chemistry, and translate the methodology to the solid-phase;
•  Investigate how various secondary structural motifs of peptides are influenced by the
introduction of one or more oxetane modified residues.
Acknowledgements
We thank EPSRC, the Royal Society and AstraZeneca for financial support. We
acknowledge the Centre for Scientific Computing at the University of Warwick for the
provision of computing facilities. The Oxford Diffraction Gemini XRD system was obtained
through the Science City Advanced Materials project: Creating and Characterising Next
Generation Advanced Materials.
References
47%
44%
Snapshots of the two most populated
clusters of Leu-Gly-Ile (top) and Leu-GOxIle (bottom), with percentages of total
structures accounted for by each cluster.
Normalised distribution of the distance
between the C- and N-termini: Leu-Gly-Ile
(black) and Leu-GOx-Ile (red dotted).
In MD simulations, turn-like features are favoured.
1.  A. A. Kaspar and J. M. Reichert, Drug Discovery Today 2013, 18, 807.
2.  For reviews, see I. Avan et al, Chem. Soc. Rev. 2014, 43, 3575; R. M. J. Liskamp et al,
ChemBioChem 2011, 12, 1626; A. Grauer and B. König, Eur. J. Org. Chem. 2009, 5099;
J. Vagner et al, Curr. Opin. Chem. Biol. 2008, 12, 292.
3.  N. H. Powell et al, Chem. Commun. 2014, 8797. For related work by Carreira, see M.
McLaughlin et al, Org. Lett. 2014, 16, 4070.
4.  G. Wuitschik et al, J. Med. Chem. 2010, 53, 3227.