the chemistry and biology of the marine macrolides ......data generated by j. gertsch, f. diaz, i....
TRANSCRIPT
Karl-Heinz Altmann
ETH Zürich
EFMC-YSN MedChemBioOnline
May 26, 2020
The Chemistry and Biology of the Marine Macrolides
Zampanolide and Dactylolide
Zampanolide
Zurwerra 2012
Rhizoxin F
Neuhaus, Liniger 2013
Peloruside (analog)
Wullschleger 2013
Ripostatin B
Glaus 2012
Pyridomycin (analogs)
Horlacher 2013
Mycolactones A/B
Gersbach 2011
Mandelalide A
Brütsch 2016
Doliculide
Tao 2015
Michaolide F
Schiess, unpublished
Tiacumycin B
Aglycone
Glaus 2015
Isoxeniolide A
Betschart, unpublished
(Nominal) Leiodolide A
Edenharter, unpublished
Fumitremorgin C
Zechner, unpublished
Disciformycin B
Waser, unpublished
Guineensine
Bartholomäus, 2019
Salarin C (analog)
Schroff 2018
Bioactive Natural Products: Targets
(-)-Zampanolide
Isolated from the sponge
Fasciospongia rimosa
Inhibition of human cancer cell
growth with nM IC50 values
(Tanaka & Higa, 1996)
Promotion of tubulin assembly
(Field et al., 2009)
(_)-Zampanolide: A Marine Macrolide with a Unique Structure
Microtubule Structure and Dynamic Instability
Microtubules
(Cytoplasm)
DNA
(Nucleus)
(+)-End
(-)-End
aba/b-Tubulin
(+) end
(-) end
a
b
a
ab-Tubulinheterodimers
Polymerization enhancers- Taxol, Taxotere- Epothilones- Discodermolide- Eleutherobine, Sarcodyctin
Polymerization inhibitors- Colchicine- Vincristine, Vinblastine- Many others
Microtubules:- hollow fibers 22-24 nm- 12-13 protofilments
Microtubule
stabilization
Taxanes, epothilones
Microtubule
Dynamics
Inhibition of tubulin
polymerisation
Vinca alkaloids, colchicine
cryptophicins, synthetics
Tubulin Polymerization Inhibitors and MSA
G2
S
G1
Cell Cycle
DNA (Chromosomes)
Microtubules
Mitosis
Suppression of microtubule dynamics
Potent inhibition of cancer cell growth
in vitro (nM/sub-nM IC50s)
Tubulin Modulators: G2/M Arrest and Apoptosis
Tubulin
modulators
Tubulin Polymerization Inhibitors and MSA
Vinblastine: 1963 Eribulin: 2010
(+) end
(-) end
a
b
a
ab-Tubulinheterodimers
Polymerization enhancers- Taxol, Taxotere- Epothilones- Discodermolide- Eleutherobine, Sarcodyctin
Polymerization inhibitors- Colchicine- Vincristine, Vinblastine- Many others
Microtubules:- hollow fibers 22-24 nm- 12-13 protofilments
Microtubule stabilization
Microtubule
Dynamics
Inhibition of tubulin
polymerisation
Taxol: 1993
Epothilones A/B
(Myxobacteria)
Discodermolide
(Sponge)
Laulimalide
(Sponge)
Eleutherobin
(Soft coral) Cyclostreptin
(Streptomyces)
Zampanolide
(Sponge)
Non-Taxane Natural Product Microtubule Stabilizers
Dictyostatin
(Sponge)
Peloruside A
(Sponge)
(+)-Dactylolide (-)-Dactylolide
Isolated from a sponge of
the genus Dactylospongia
Inhibition of human cancer cell
growth with mM IC50 values
(Cutignano et al., 2001)
?
(_)-Zampanolide and (+)-Dactylolide:
Stereochemical Divergence in NP Biosynthesis
(-)-Zampanolide
Isolated from the sponge
Fasciospongia rimosa
Inhibition of human cancer cell
growth with nM IC50 values
(Tanaka & Higa, 1996)
Promotion of tubulin assembly
(Field et al., 2009)
Esterification
HWE
Epoxide
opening
Stannylation/
iodination
Prins
reaction Iodide displacement/
olefination
“Aza-aldol”
(_)-Dactylolide: Retrosynthesis
(_)-Dactylolide and (_)-Zampanolide: Binding to Microtubules
Z F
Stabilized microtubules
Kb (37 °C) (M)
(-)-Zampanolide 25.8 x 107
(-)-Dactylolide 0.14 x 107
Taxol 1.07 x 107
J. J. Field, et al. Chem. Biol. 2012, 19, 686.
Flutax-2
(-)-Dactylolide/(-)-Zampanolide:
Inhibition of Cancer Cell Proliferation
Data generated by J. Gertsch, F. Diaz, I. Barasoain
Cell line
A549
MCF-7
HCT116
A2780
3.2
6.5
7.2
3.0
149
68
249
-
IC50 [nM]
302
248
210
1'252
53
42
88
-
-
-
-
9'488
-
-
-
10'550
Dactylolide and Zampanolide:
Inhibition of Cancer Cell Proliferation
Data generated by J. Gertsch, F. Diaz, I. Barasoain
Cell line
A2780
A2780AD
0.81
2.68
15'382
11'299
IC50 [nM]
1'254
1'252
10'500
12'445
9'488
12'848
(-) (+)
(-)-Zampanolide: Irreversible Binding to Microtubules
ZF
% F
luta
x b
ou
nd
Preincubation time [h]
Control (DMSO)
(-)-Zampanolide (syn)
(-)-Zampanolide (nat)
(-)-Dactylolide
J. J. Field, et al. Chem. Biol. 2012, 19, 686.
Tubulin-Zampanolide Complex at 1.8 Å Resolution
A. Prota, M. Steinmetz, K.-H. Altmann, et al. Science 2013, 339, 587.
Microtubule Structure and Dynamic Instability
Microtubules
(Cytoplasm)
DNA
(Nucleus)
(+)-End
(-)-End
aba/b-Tubulin
Protofilament
M-Loop Structuring as the Trigger for Microtubule Assembly?
Straight
(Protofilament)
Curved
A. Prota, M. Steinmetz, K.-H. Altmann, et al. Science 2013, 339, 587.
Tubulin Inhibitors in Drug Discovery: The Future ?
Acknowledgements
Chemistry
Dr. Didier Zurwerra
Dr. Florian Glaus
Dr. Leo Betschart
Dr. Tobias Brütsch
Michel Jordi
Stefano Vezossi
Dr. Simone Berardozzi
Biology/Biochemistry/
Structural Studies
Dr. J. Fernando Díaz
Dr. Jessica Field
Dr. Ruth Matesanz
Dr. Isabel Barasoain
Dr. Benet Perra
Prof. Peter Miller
Prof. Jürg Gertsch
Prof. Michel Steinmetz
Dr. Andrea Prota
ETH Zürich
Swiss National
Science Foundation
NOVARTIS
ROCHE
COST