Diapositiva 1

THIOPEPTIDE ANTIBIOTICS: CENTRAL CORE
MODIFICATIONS AND BARINGOLIN ANALOGS
Xavier
a Institute
a,*
Just-Baringo ,
Paolo
a
Bruno ,
Fernando
a,
b
Albericio
and Mercedes
a,
c,*
Álvarez
for Research in Biomedicine, Barcelona Science Park-University of Barcelona, Baldiri Reixac 10, E-08028 Barcelona, Spain.
b Department of Organic Chemistry, University of Barcelona, E-08028 Barcelona.
c Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona
xavier.just@irbbarcelona.org – mercedes.alvarez@irbbarcelona.org
1. RETROSYNTHESIS
2. BARINGOLIN AND ANALOGS
Baringolin is a thiopeptide1 of the thiocillin familly with promising antibacterial activity. It was isolated from Kocuria
sp. in Alicante’s coast (southern Spain).2 A modular approach from building blocks 1−5 was developed for its total
synthesis, which permitted to obtain the synthetic thiopeptide, as well as to synthesize a series of analogs for SAR
studies.
3. CENTRAL CORE MODIFICATIONS
Using the same strategy that was entitled for the
synthesis of baringolin’s central core, a series of
2,3,6-trisubstituted pyridines were obtained in a
modular fashion. The use of pyridine 11 granted
complete control of the regioselectivity.5
4. ANTIBACTERIAL ACTIVITY
Variation
sites
Starting from 2,6-dichloronicotinic acid 6, the two alpha positions were differentiated, yielding pyridine 7.3 This
allowed a totally regiocontrolled synthesis of the polyheterocyclic core based in palladium-catalyzed crosscouplings with thiazoles 84 and 9. The orthogonal protecting groups permitted the selective elongation of all three
branches. Using the peptidic tail analogues and either thiazoline 4 or thiazole 9 fragments, baringolin was obtain
along with five analogs (10−14).
Compound
S. aureus
P. acnes
Baringolin
0.25
0.125
10
0.25
0.125
11
0.5
0.5
12
4
0.5
13
0.5
8
14
0.5
8
15
>8
4
16
>8
4
17
2
2
18
1
8
19
0.03
0.06
aMinimum inhibitory concentration. bBelow limit of detection.
MICa (µg/mL)
B.subtilis
0.25
0.25
0.5
8
0.5
1
>8
8
8
8
0.03
5. CONCLUSIONS
Solubility (mg/mL)
M. luteus
0.5
0.5
1
2
2
2
2
4
>8
>8
0.5
PB 0.1 M
BLDb
BLDb
BLDb
BLDb
BLDb
BLDb
BLDb
BLDb
0,023
0,007
0,018
Along with baringolin and analogs 10−14, other compounds (15−14) without peptidic tails were also synthesized
and tested. Whereas the length of the peptidic tail had little effect, the thiazoline moiety was found to be
necessary for a broader strain activity. However, Compound 19, of the thiazole series, but with a cyclohexanoic
acid moiety overcame such limitation and displayed improved potency against all strains.
References
1. (a) Bagley, M. C.; Dale, J. W.; Merritt, E. A.; Xiong, X. Chem. Rev. 2005, 105, 685. (b) Hughes, R. A.; Moody, C. J.
Angew. Chem. Int. Ed. 2007, 46, 7930.
2. (a) L. M. Canedo Hernandez, F. Romero Millan, A. Fernandez Medarle, R. I. Fernandez Chimeno, J. C. Hidalgo Villar
(Instituto Biomar, S.A., Spain). Peptides as bioactive compounds. WO 2012062906, May 18, 2012. (b) Just-Baringo,
X.; Bruno, P.; Ottesen, L.; Albericio, F.; Álvarez, M. Angew. Chem. Int. Ed. 2013, 52, 7818-7821.
3. Hirokawa, Y.; Fujiwara, I.; Suzuki, K.; Harada, H.; Yoshikawa, T.; Yoshida, N.; Kato, S. J. Med. Chem. 2003, 46, 702-715.
The synthetic strategy described herein has
permitted the synthesis of barngolin and also
the first library of fully synthetic thiopeptide
analogues. Modifications such as replacing the
thiazoline fragment for a thiazole one, or
modifying the length of the peptidic tail were
easily introduced.
Biological assessment of analogs has
determined that the thiazoline moiety
broadens the scope of activity of the natural
product when compared to the more oxidized
analogue. However, intorduction of a
cyclohexanoic moiety overcame this limitation
and improved potency against all strains.
4. Just-Baringo, X.; Bruno, B.; Albericio, F.; Álvarez, M. Tetrahedron Lett. 2011, 52, 5435–5437.
5. Just-Baringo, X; Albericio, F.; Álvarez, M. Eur. J. Org. Chem. 2013, IN PRESS.
Acknowledgements
We gratefully acknowledge support from the Spanish Science and Innovation Ministry, CICYT (CTQ2012-30930) and
the Generalitat de Catalunya (2009SGR 1024). XJ thanks ISCIII for a PFIS grant.