New developments and findings - CHIMICA OGGI/Chemistry Today

Matteo Zanda
FOCUS ON FLUORINE CHEMISTRY
The trifluoroethylamine function
as peptide bond replacement
New developments and findings
SERENA BIGOTTI 1 , FRANCESCA OLIMPIERI 1 , SREEJITH SHANKAR P. 1 ,
GIOVANNI PINNA 1 , STEFANO ALTOMONTE 1 , MATTEO ZANDA 1,2 *
*Corresponding author
1. C.N.R. – Istituto di Chimica del Riconoscimento Molecolare, and Dipartimento di Chimica
Materiali ed Ingegneria Chimica “G. Natta” del Politecnico di Milano, via Mancinelli 7, Milano, I-20131, Italy
2. Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, United Kingdom
ABSTRACT
T h e x e n o b i o t i c
trifluoroethylamine peptide
bond replacement is keeping up the pace as an
important new option in the arena of drug discovery.
Recent developments and findings are highlighted herein.
introduction
Peptide drugs are generally more expensive to
synthesize and less stable than small molecule drugs.
Moreover, due to their low bioavailability, which in turn is
due to rapid hydrolysis by endogenous proteases,
peptides clear faster from the body and usually need to
be injected rather than swallowed as a pill. However, they
can be much more potent than small molecules, show
higher specificity, have fewer toxicology problems, don’t
accumulate in organs or face drug-drug interaction
challenges that affect small molecules (1). For these
reasons, the design and synthesis of metabolically stable
peptide analogs that can either mimic or block the
bioactivity of natural peptides or enzymes is an important
area of medicinal chemistry and drug discovery. Isosteric
replacement of a scissile peptide bond represents a
viable and popular approach in the rational design of
peptide mimics and surrogates. Indeed, many
therapeutically useful peptidomimetics incorporating any
of the peptide isosteres that are currently available have
been described (2).
the trifluoroethylamine function
Many amide replacements are known which retain the
geometry of the amide bond or maintain the
hydrogen bond-accepting properties of the amide.
However, only a few functional groups, which are capable
of preserving the hydrogen bond-donating properties of
the amide have been described. Among them, one can
mention sulfonamides, anilines, secondary alcohols,
hydrazines, and certain heterocycles. The main issue for
identifying a truly effective NH amide replacement can be
recast as how to minimize the basicity of an NH donor so
that a NH +
2 moiety is not formed at physiological pH. In
fact, such charged groups are poorly tolerated deep in
the active site of a protein where binding interactions
cannot compensate for the energetic cost of desolvation
(3). Recently, the stereogenic trifluoroethylamine function
was proposed by our group as an effective mimic of the
peptide bond (4). Indeed, a trifluoroethyl group can
replace the carbonyl of an amide and generate a
metabolically stable, essentially non-basic amine that
maintains the excellent hydrogen bond donor ability of an
amide (5). The main properties featured by the
trifluoroethylamino group are: (1) low NH basicity, (2) a
CH(CF 3 )NHCH backbone angle close to 120°, (3) a C-CF 3
bond substantially isopolar with the C=O, (4) structural
analogy with the tetrahedral proteolytic transition state.
Furthermore, the sp 3 hybridization of all the atoms forming
the stereogenic trifluoroethylamine moiety is expected to
allow for a better orientation of the atoms in the receptors
active sites, thus optimizing the energetically favourable
interactions (hydrogen-bonds, van der Waals,
hydrophobic, etc.). Following a first group of publications
describing peptidomimetic structures incorporating a
trifluoroethylamine unit replacing the retro-peptide bond
(7-11), we next reported the stereo controlled synthesis of
brand new peptidomimetics, very close to natural
peptides, having a fluoroalkyl backbone modification:
y[CH(CF 3 )NH]Gly-Peptides 1 (Figure 3, R = H) (12). In this
case, the trifluoroethylamine function replaces a native
peptidic amide-bond. These peptidomimetics were
obtained by means of a stereo controlled aza-Michael
reaction involving a-amino-acid esters as nucleophiles and
activated fluorinated olefins as Michael acceptors.
Figure 1. Peptidomimetics incorporating a trifluoroethylamine
surrogate of the native peptide bond.
recent progress
This work has been recently expanded to novel
peptidomimetics featuring –CH(R F )NH- units, having
different degree of fluorination, as peptide bond
chimica Oggi / cHEMISTRY TOdaY - vol 27 n 3 / May/June 2009 - Focus on Fluorine chemistry
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FOCUS ON FLUORINE CHEMISTRY
Figure 2. Merck’s Odanacatib (MK-0822).
Entered Phase III Clinical trials.
Picomolar inhibitor of Cathepsin K.
Selective towards other proteinases in cell
based assays.
Metabolically stable, has successfully
completed Phase II trials.
surrogates (13, 14). The key step in
the synthesis consisted of a stereo
selective aza-Michael addition of
chiral a-amino acid esters to
b-fluoroalkyl-a-nitroethenes. The
diastereoselection of the process was influenced by the
electro negativity, rather than by the steric bulk, of the
fluorinated residue R F in b-position of the nitroalkene
acceptors. Replacement of a single F atom of R F by a
hydrogen or methyl group brought about a dramatic drop
of stereo control, whereas Br, Cl and CF 3 , albeit bulkier
than F, provided fairly worse results in terms stereo control
(Scheme 1). The trifluoroethylamine strategy has recently
found the first validation in drug discovery. In fact, the
Merck company developed a trifluoroethylamine
compound, Odanacatib (MK-0822), that is now in phase III
clinical studies for the therapy of osteoporosis (15).
Odanacatib is a highly potent and metabolically stable
inhibitor of Cathepsin K, a cysteine proteinase thought to
be responsible for degradation of type I collagen in
osteoclastic bone resorption that represents a highly
promising target for the therapy of osteoporosis.
Encouraging results were also observed for women
affected by bone metastases deriving from breast cancer.
Volume: 23
Number: 3
Term: MAY/JUNE 2005
Scheme 1. Synthesis and elaboration of fluoroethylamine aza-Michael adducts into the target
peptidomimetics.
Scheme 2. Multikilogram synthesis of Odanacatib.
Volume: 24
Number: 3
Term: MAY/JUNE 2006
It is worth noting that the trifluoromethyl group does not
make any lipophilic interactions with the enzyme, as
demonstrated by an X-ray structure of a complex
between one trifluoroethylamine compound structurally
related to Odanacatib and Cathepsin K, but rather is
directed away from the active site, into water (16).
Recently, the Merck company described a synthetic
methodology suitable for preparing kilogram quantities of
Odanacatib (Scheme 2) (17, 18).
The body of experimental results listed above suggests
important considerations for a successful use of the
trifluoroethylamine function as a peptide/retropeptide
bond mimic.
- When the amide or peptide bond to be replaced by
the trifluoroethylamine unit is one of the reasons for
the low bioavailability of the parent unfluorinated
molecule, the strategy can be highly successful.
Indeed the trifluoroethylamine unit seems to have
high metabolic stability.
Previously on Fluorine chemistry
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- The trifluoromethyl group, contrarily to the
carbonyl oxygen, is a weak hydrogen-bond
acceptor (19). The trifluoroethylamine function can
b e t h e r e f o r e a n e f f e c t i v e p e p t i d e b o n d
replacement only if the carbonyl group of the
original ligand’s amide/peptide-bond is not
involved in essential hydrogen-bonding with the
receptor.
- The NH of the trifluoroethylamine unit is a good
h y d r o g e n - b o n d d o n o r , d u e t o t h e s t r o n g
electronwithdrawing effect exerted by the CF 3
group, and could be always considered a good
mimic of a peptidic NH.
- The sp 3 N atom of the trifluoroethylamine function
is a bad hydrogen bond acceptor and has very
little Lewis basicity, in close analogy with the
peptide bond.
- The geometry and spatial orientations of the
interactions (including hydrogen-bonds) between
the original planar amide/peptide-moiety and the
receptor can be optimized by the sp 3 tetrahedral
configuration of the trifluoroethylamine unit.
In conclusion, the trifluoroethylamino function is an
increasingly promising peptide- and amide-bond
replacement that is expected to find extensive
application in medicinal chemistry and drug discovery.
acknowledgements
We thank Politecnico di Milano and C.N.R. for
economic support.
references and notes
1. A. Loffet, J. Peptide Science, 8, pp. 1-7 (2002).
2. M.D. Fletcher, M.M. Campbell, chem. Rev., 98, pp. 763-795
(1998).
3. W.C. Black, M.D. Percival, chemBiochem., 7, pp. 1525-1535
(2006).
4. M. Sani, A. Volontario et al., chemMedchem., 2, pp. 1693-
1700 (2007).
5. M. Zanda, New J. chem., 28, pp. 1401-1411 (2004).
6. A. Volonterio, P. Bravo et al., Org. Lett., 2, pp. 1827-1830
(2000).
7. A. Volonterio, P. Bravo et al., Tetrahedron Lett., 41, pp. 6517-
6521 (2000).
8. A. Volonterio, P. Bravo et al., Tetrahedron Lett., 42, pp. 3141-
3144 (2001).
9. A. Volonterio, S. Bellosta et al., Eur. J. Org. chem., pp. 428-
438 (2002).
10. M. Sani, P. Bravo et al., collect. czech. chem. commun.,
67, pp. 1305-1319 (2002).
11. A. Volonterio, S. Bellosta et al., chem. Eur. J., 9, pp. 4510-
4522 (2003).
12. M. Molteni, A. Volonterio et al., Org. Lett., 5, pp. 3887-3890
(2003).
13. S. Bigotti, A. Volonterio et al., Synlett., pp. 958-962 (2008).
14. S. Bigotti, S. V. Meille et al., J. Fluorine chem., 129, pp. 767-
774 (2008).
15. Y.J. Gauthier, N. Chauret et al., Bioorg. Med. chem. Lett.,
18, pp. 923-928 (2008).
16. C.S. Li, D. Deschenes et al., Bioorg. Med. chem. Lett., 16,
pp. 1985-1989 (2006).
17. P.D. O’Shea, C. Chen et al., J. Org. chem., 74, pp. 1605-
1610 (2009).
18. For a further recent work on bioactive trifluorethylamine
peptidomimetics: L. Formicola, X. Maréchal et al. Bioorg.
Med. chem. Lett., 19, pp. 83-86 (2009).
19. J.D. Dunitz, R. Taylor, chem. Eur. J., 3, pp. 89-98 (1997). &
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