Biomedical Engineering Reference
In-Depth Information
diversity. This ranges from cutting-edge technologies for their synthesis, such as
split-and-pool production of large peptidic macrocycles or oligonucleotide-templated
synthesis of peptidic macrocycles, to the efficient synthesis of small macrocycles or
semipeptidic macrocycles. The past decade has also witnessed the emergence of
large libraries of semipeptidic or nonpeptidic macrocycles that recapitulate some of
the chemical motifs found in natural products and even some hybrid structures that
borrow conserved recognition domains from macrocycles, such as rapamycin, further
diversified by peptidic fragments [12]. These strategies represent a solid foundation
on which to exploit the potential of macrocycles for drug discovery, and promise to
deliver new macrocyclic compounds combining the best of two worlds and enabling
broad coverage of the chemical space. In terms of molecular properties, macrocycles
are often qualified as outliers relative to more traditional small molecules, which often
makes them, at first glance, less attractive because more challenging. However, that
same characteristic also endows them with a higher potential to identify novel drug
candidates off the beaten path [95], as already demonstrated in numerous examples
such as those reported in this chapter.
Acknowledgment
I am grateful to Dr. Mark L. Peterson for critically reviewing this manuscript.
REFERENCES AND NOTES
1. (a) E. M. Driggers, S. P. Hale, J. Lee, N. K. Terrett,
Nat. Rev. Drug. Discov
.
2008
,
7
, 608-
624; (b) N. T. Terrett,
Drug Discov. Today Technol
.
2010
,
7
, e97-e104; (c) E. Marsault,
M. L. Peterson,
J. Med. Chem
.
2011
,
54
, 1961-2004.
2. M. Colombo, I. Peretto,
Drug Discov. Today
.
2008
,
13
, 677-684.
3. C. A. Lipinski,
J. Pharmacol. Toxicol. Methods
.
2000
,
44
, 235-249.
4. (a) C. M. Dobson,
Nature
.
2004
,
432
, 824-828; (b) J. Zuegg, M. A. Cooper,
Curr. Top.
Med. Chem
.
2012
,
12
, 1500-1513.
5. A. L. Nelson, E. Dhimolea, J. M. Reichert,
Nat. Rev. Drug Discov
.
2010
,
9
, 767-774.
6. O. Sperandio, C. H. Reynes, A. C. Camproux, B. O. Villoutreix,
Drug Discov. Today
.
2010
,
15
, 220-229.
7. (a) T. Rezai, B. Yu, G. L. Millhauser, M. P. Jacobson, R. S. Lokey,
J. Am. Chem. Soc
.
2006
,
128
, 2510-2511; (b) D. F. Veber, S. R. Johnson, H. Y. Cheng, B. R. Smith, K. W.
Ward, K. D. Kopple,
J. Med. Chem
.
2002
,
45
, 2615-2623.
8. http://www.ensemblediscovery.com/pipeline/index.html.
9. (a) M. S. Butler, A. D. Buss,
Biochem. Pharmacol
.
2006
,
71
, 919-929; (b) M. S. Butler,
Nat. Prod. Rep
.
2005
,
22
, 162-195; (c) A. Gradillas, J. Perez-Castells,
Angew. Chem. Int.
Ed. Engl
.
2006
,
45
, 6086-6101; (d) A. Parenty, X. Moreau, J. M. Campagne,
Chem. Rev.
2006
,
106
, 911-939; (e) C. Adessi, C. Soto,
Curr. Med. Chem
.
2002
,
9
, 963-978.
10. L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W. Brandt,
Mol. Divers
.
2005
,
9
, 171-186.
11. (a) C. Gilon, D. Halle, M. Chorev, Z. Selinger, G. Byk,
Biopolymers
1991
,
31
, 745-750;
(b) D. Shan, M. G. Nicolaou, R. T. Borchardt, B. Wang,
J. Pharm. Sci.
1997
,
86
, 765-767;
