the chemistry and biology of the marine macrolides ......data generated by j. gertsch, f. diaz, i....

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Karl-Heinz Altmann ETH Zürich EFMC-YSN MedChemBioOnline May 26, 2020 The Chemistry and Biology of the Marine Macrolides Zampanolide and Dactylolide

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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Schiess, unpublished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Betschart, unpublished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Edenharter, unpublished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Zechner, unpublished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Waser, unpublished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

(_)-Zampanolide: Retrosynthesis

“Aza-aldol”

THP Ring Construction

Fragment Assembly and Ring Closure

Total Synthesis of (_)-Dactylolide and (_)-Zampanolide

(_)-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.

13-Desmethylene-(-)-Dactylolide/(-)-Zampanolide

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