Regioselective Palladium Catalyzed Cross-Coupling Reactions of...

Regioselective Palladium Catalyzed Cross-CouplingReactions of 2,4,7-Trichloroquinazoline and Progress

Towards Small-Molecule Inhibitors for Protein Kinase D

Kara GeorgeWipf Group Research Topic Seminar

5 June 2010

Kara George @ Wipf Group Page 1 of 78 12/5/2010

Regioselective Cross-Coupling Reactionsof 2,4,7-Trichloroquinazoline

N

N

Cl

Cl

Cl N

N

R3

R2

R1


Quinazoline Scaffold: ��Overview and Biological Significance

§  Quinazoline skeleton is present in a variety of biologically active compounds

-  Among the most potent tyrosine kinase and cellular phosphorylation

inhibitors

-  Exhibit remarkable activity as antitubercular, antiviral, antibacterial, and

anticancer agents

N

N

1

2

34

4a5

6

788a

Fry, D. W.; Kraker, A. J.; McMichael, A.; Ambroso, L. A.; Nelson, J. M.; Leopold, W. R.; Connors, R. W.; Bridges, A. J. Science. 1999, 265, 1093.

Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. J. Org. Chem. 2009, 74, 4934.

NMeO

N

NH2

N

MeO

N

O

O

Prazosin

NO

N

HNOMeO

MeO

ErlotinibNMeO

N

HNO

Cl

F

NO

Iressa


Regioselective Pd-Catalyzed Cross-Couplingof 2,4,7-Trichloroquinazoline

Can we use consecutive Suzuki cross-coupling reactions to accesstricarbosubstituted quinazolines?

N

N

Cl

Cl

Cl N

N

R3

R2

R1

R1B(OH)2 R2B(OH)2 R3B(OH)2


Regioselective Pd-Catalyzed Cross-Couplingof 2,4,7-Trichloroquinazoline

N

N

Cl

Cl

Cl N

N

R3

R2

R1

R1B(OH)2 R2B(OH)2 R3B(OH)2

Can we use consecutive Suzuki cross-coupling reactions to accesstricarbosubstituted quinazolines?


Bond Dissociation Energy of Halo-Pyrimidines:Relationship to Regioselectivity

Lowest C-Cl BDE at the 4-position, followed by the 2-position, then the 5-position

N

N

1

2

34

5

6N

N94.9

93.8Cl

Cl N

N96.5

99.6

Cl

Cl

N

N95.1Cl N

N93.7

Cl

N

N99.0Cl

Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6632.




Stille cross-coupling

N

N

1

2

34

5

6N

N94.9

93.8Cl

Cl N

N96.5

99.6

Cl

Cl

N

N95.1Cl N

N93.7

Cl

N

N99.0Cl

N

N

Cl

Cl

PdCl2(PPh3)2

DMF, 70 °C, 7 h

PhSnBu3

N

N

Cl

Ph

77%

PdCl2(PPh3)2

DMF, 130 °C, 15 h

PhSnBu3N

N

Ph

Ph

54%

Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6632.Solberg, J.; Undheim, K. Acta Chem. Scand. 1989, 43, 62.





N

N

1

2

34

5

6N

N94.9

93.8Cl

Cl N

N96.5

99.6

Cl

Cl

N

N95.1Cl N

N93.7

Cl

N

N99.0Cl

N

NCl

Cl

PdCl2(PPh3)2

DMF, 100 °C, 7 h N

NCl

Ph70%

PhSnBu3






N

N

1

2

34

5

6N

N94.9

93.8Cl

Cl N

N96.5

99.6

Cl

Cl

N

N95.1Cl N

N93.7

Cl

N

N99.0Cl

N

N

ClCl

ClN

NCl

Cl

Ph

71%

PdCl2(PPh3)2

DMF, 70 °C, 3 hPh

SnBu3





Suzuki cross-coupling

N

N

1

2

34

5

6N

N94.9

93.8Cl

Cl N

N96.5

99.6

Cl

Cl

N

N95.1Cl N

N93.7

Cl

N

N99.0Cl

Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6632.Schomaker, J. M.; Delia, T. J. J. Org. Chem. 2001, 66, 7125.

N

N

Ph

ClCl N

N

Cl

ClCl N

N

Ph

ClPh

N

N

Ph

PhPh

5% Pd(OAc)2, 10% PPh3aq. Na2CO3, PhB(OH)2 (1 equiv)

DME, reflux, 18 h

88%

5% Pd(OAc)2, 10% PPh3aq. Na2CO3, PhB(OH)2 (2 equiv)

DME, 70 °C, 24 h

88%

93%

PhB(OH)2 (3.3 equiv)


Bond Dissociation Energy of Halo-Quinazolines:Relationship to Regioselectivity

Lowest C-Cl BDE at the 4-position, followed by the 2-position All positions on the phenyl ring have similar C-Cl BDEs (96-97 kcal/mol) and 5-6

kcal/mol higher than the 2-position

N

N

1

2

345

6

78

N

N

94.6

91.996.397.3

96.996.9Cl






Pd-catalyzed couplings of trialkylalanes

N

N

1

2

345

6

78

N

N

94.6

91.996.397.3

96.996.9Cl

N

N

Cl

Cl N

N

Me

Cl N

N

MePd(PPh3)4, AlMe3

THF, reflux

76% 80%

Pd(PPh3)4, Al(i-Bu)3

THF, reflux

Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6632.Mangalagiu, I.; Benneche, T.; Undheim, K. Acta Chem. Scand. 1996, 50, 914.Mangalagiu, I.; Benneche, T.; Undheim, K. Tetrahedron Lett. 1996, 37, 1309.





Pd-catalyzed couplings of trialkylalanes

N

N

1

2

345

6

78

N

N

94.6

91.996.397.3

96.996.9Cl

Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6632.Mangalagiu, I.; Benneche, T.; Undheim, K. Acta Chem. Scand. 1996, 50, 914.Mangalagiu, I.; Benneche, T.; Undheim, K. Tetrahedron Lett. 1996, 37, 1309.

N

N

Cl

Cl N

N

Me

Cl

Pd(PPh3)4, AlMe3

THF, reflux

47%

Br

N

N

Me

Cl16%

Br Me





Sonagashira cross-coupling

N

N

1

2

345

6

78

N

N

94.6

91.996.397.3

96.996.9Cl

N

N

Cl

Cl N

N

Cl

Bu

N

N

Bu

Bu

PdCl2(PPh3)2, CuI

NEt3, 20 °C, 20 h

H Bu 55%

65 °C

66%

Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6632.Mangalagiu, I.; Benneche, T.; Undheim, K. Acta Chem. Scand. 1996, 50, 914.





Sonagashira cross-coupling

N

N

1

2

345

6

78

N

N

94.6

91.996.397.3

96.996.9Cl

N

N

Cl

Cl

Br

N

N

Cl

Bu

Br

N

N

Cl

Cl

BuPdCl2(PPh3)2, CuI

NEt3, 20 °C, 20 h

H Bu 67% 22%

Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6632.Mangalagiu, I.; Benneche, T.; Undheim, K. Acta Chem. Scand. 1996, 50, 914.






N

N

1

2

345

6

78

N

N

94.6

91.996.397.3

96.996.9Cl

Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6632.Charpiot, B.; Brun, J.; Donze, I.; Naef, R.; Stefani, M.; Mueller, T. Biorg. Med. Chem. Letters. 1998, 8, 2891.

N

N

Cl

Cl

O

O N

N

Cl

O

O

OBnBnO

BnO

BnO

SnBu3

PdCl2(PPh3)2, xylene110 °C, 3 h





Consecutive Pd-catalyzed Suzuki cross-couplings

N

N

1

2

345

6

78

N

N

94.6

91.996.397.3

96.996.9Cl


Cross-Coupling at C-2

Cross-Couplingat C-4

N

N

Cl

Cl

Cl N

N

Cl

R2

R1N

N

Cl

R2

Cl N

N

R3

R2

R1

Cross-coupling at C-7

R1B(OH)2R2B(OH)2 R3B(OH)2


Regioselective Suzuki Cross-Coupling at C-4

NH2Cl

OH

O

NCl

N

OH

OH NCl

N

Cl

Cl

H2O, 35% NaOH KOCN, 40 °C;

then AcOH, RT, 6 h

POCl3, N,N-dimethylaniline

reflux, 6 h

79% 56%

NCl

N

Cl

Cl

NCl

N

Cl

O5% Pd(OAc)2, 15% PPh3aq. Na2CO3

DME, 80 °C, 16 h

86%

O

B(OH)21.1 equiv.

NCl

N

ClNCl

N

Cl NCl

N

ClNCl

N

Cl

S

71%73% 33%50%

Curd, F. H. S.; Landquist, J. K.; Rose, F. L. J. Chem. Soc. 1948, 1759.



NH2Cl

OH

O

NCl

N

OH

OH NCl

N

Cl

Cl


then AcOH, RT, 6 h


reflux, 6 h

79% 56%

NCl

N

Cl

Cl

NCl

N

Cl


DME, 80 °C, 16 h

86%

O

B(OH)21.1 equiv.

NCl

N

ClNCl

N

Cl NCl

N

ClNCl

N

Cl

S

71%73% 33%50%




NCl

N

Cl

5% Pd(OAc)2, 15% PPh3aq. Na2CO3

DME, reflux, 22 h

O

NCl

N

O

CH3

B(OH)2

85%1.1 equiv.

NCl

N

O

S

77%

S B(OH)25% Pd(OAc)2, 15% PPh3aq. Na2CO3

DME, reflux, 15 hNCl

N

Cl

O

1.1 equiv.

NCl

NCH3

S

45%

CH3

B(OH)2NCl

N

Cl

S5% Pd(OAc)2, 15% PPh3aq. Na2CO3

DME, reflux, 24 h

1.1 equiv.



NCl

N

Cl


DME, reflux, 22 h

O

NCl

N

O

CH3

B(OH)2

85%1.1 equiv.

NCl

N

O

S

77%



N

Cl

O

1.1 equiv.

NCl

NCH3

S

45%

CH3

B(OH)2NCl

N

Cl


DME, reflux, 24 h

1.1 equiv.


Alternative Route to Sequential Cross-CouplingReactions of 2,4,7-Trichloroquinazoline

Competitive hydrolysis at C-4

New Approach

NCl

N

S

Cl NCl

N

S

R1

OO

NCl

N

S

R1

[O]



Deactivation of C-4

N

N

Cl

Cl

Cl N

N

Cl

R2

R1N

N

Cl

R2

Cl N

N

R3

R2

R1





R1B(OH)2

N

N

Cl

OH

ClNCl

N

Cl

Cl


DME, 80 °C, 16 hB(OH)2

1.1 equiv.

NCl

N

Cl

33%




New Approach

NCl

N

S

Cl NCl

N

S

R1

OO

NCl

N

S

R1

[O]



Deactivation of C-4

N

N

Cl

Cl

Cl N

N

Cl

R2

R1N

N

Cl

R2

Cl N

N

R3

R2

R1





R1B(OH)2

N

N

Cl

OH

ClNCl

N

Cl

Cl


DME, 80 °C, 16 hB(OH)2

1.1 equiv.

NCl

N

Cl

33%




Initial Approach

N

N

Cl

OH

ClNCl

N

Cl

Cl


DME, 80 °C, 16 hB(OH)2

1.1 equiv.

NCl

N

Cl

33%

NCl

N

S

Cl NCl

N

S

R1

OO

NCl

N

S

R1

[O]



Deactivation of C-4

N

N

Cl

Cl

Cl N

N

Cl

R2

R1N

N

Cl

R2

Cl N

N

R3

R2

R1





R1B(OH)2




New Approach

N

N

Cl

OH

ClNCl

N

Cl

Cl


DME, 80 °C, 16 hB(OH)2

1.1 equiv.

NCl

N

Cl

33%

NCl

N

S

Cl NCl

N

S

R1

OO

NCl

N

S

R1

[O]



Deactivation of C-4

N

N

Cl

Cl

Cl N

N

Cl

R2

R1N

N

Cl

R2

Cl N

N

R3

R2

R1





R1B(OH)2



NCl

N

S

NCl

N

Cl

Cl NCl

N

S

Cl

HSPh, NaH

THF, 0 °C, 18 h

75%


DME, reflux, 23 h S

87%S(HO)2B

NCl

N

S

S mCPBA, CH2Cl20 °C - RT, 1.5 h

Na2WO4, H2O2MeOH, 50 °C, 24 h

Oxone, MeOH:H2O 0 °C - RT, 24 h

N

N

Cl

OH

NCl

N

S

S

OO

S


Pd-Catalyzed, Cu-Mediated Cross-Coupling

ArB(OH)2cat. Pd, CuTC

THF, 50 °CHetAr SMe HetAr Ar

Pd (0)

PdL

L SR

Het

Pd SR Cu

O

OSB

O

R' OH

HHetL

L

PdL

L SR

Het

CuO

OS

PdL

L R'

Het

R'B(OH)2

CuTC

Het R' Het SR

Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979.


Catalytic Cycle:Pd-Catalyzed, Cu-Mediated Cross-Coupling



Pd (0)

PdL

L SR

Het

Pd SR Cu

O

OSB

O

R' OH

HHetL

L

PdL

L SR

Het

CuO

OS

PdL

L R'

Het

R'B(OH)2

CuTC

Het R' Het SR






Pd (0)

PdL

L SR

Het

Pd SR Cu

O

OSB

O

R' OH

HHetL

L

PdL

L SR

Het

CuO

OS

PdL

L R'

Het

R'B(OH)2

CuTC

Het R' Het SR






Pd (0)

PdL

L SR

Het

Pd SR Cu

O

OSB

O

R' OH

HHetL

L

PdL

L SR

Het

CuO

OS

PdL

L R'

Het

R'B(OH)2

CuTC

Het R' Het SR


(OH)2BTCCuSR





Efficient Pd-catalyzed, Cu-mediated coupling of heteroaromatic thioethers with boronicacids by Liebeskind and co-workers

Preparation of bis-fuctionalized pyridopyrimidine derivatives by Guillaumet and co-workers

N

N

Me

SMe

B(OH)2

NO2

4% Pd2(dba)3, 16% P(2-furyl)3CuTC (1.4 equiv), THF, 50 °C

N

N

Me

NO2

74%

N

N

N

Cl

Cl

N

N

N

S

Cl

N

N

N

R2

R1

N

N

N

S

R1

Deactivation of C-4

5% Pd(PPh3)4Na2CO3 (2 equiv)DME/H2O, 75 °C

R1B(OH)2

5% Pd(PPh3)4CuTC (2.2 eq)

THF, 50 °C

R2B(OH)2

Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979.Abdellatif, T.; Routier, S.; Akssira, M.; Leger, J.-M.; Jarry, C.; Guillaumet, G. Org. Lett. 2007, 9, 4673.


A Third Approach:Pd-Catalyzed, Cu-Mediated Cross-Coupling



New Approach:


N

N

Cl

Cl

Cl

N

N

R3

R2

R1


Deactivation of C-4

N

N

S

ClCl N

N

S

R1Cl

N

N

R2

R1Cl

Pd-catalyzed, Cu-mediatedCross-Coupling at C-4

R1B(OH)2

R2B(OH)2 R3B(OH)2


Regioselective Pd-Catalyzed Cross-Coupling at C-2

NCl

N

S

NCl

N

S

NCl

N

S

NCl

N

S

CF3

NCl

N

S

NCl

N

S

NCl

N

S

NCl

N

S

S

NH

O NCl

N

S

O

NCl

N

S

N

99% 79%

66% 53%

92% 90% 95% 93%

89% 89%

NCl

N

Cl

Cl

i-PrSH, NaH

THF, 0 °C, 16 hNCl

N

S

Cl94%

5% Pd(OAc)2, 15% PPh3aq. Na2CO3, R1B(OH)2

DME, 75 °C NCl

N

S

R1

Wipf, P.; George, K. M. Synlett. 2010, 644.


Regioselective Pd-Catalyzed Cross-Coupling at C-2

NCl

N

S

NCl

N

S

NCl

N

S

NCl

N

S

CF3

NCl

N

S

NCl

N

S

NCl

N

S

NCl

N

S

S

NH

O NCl

N

S

O

NCl

N

S

N

99% 79%

66% 53%

92% 90% 95% 93%

89% 89%

NCl

N

Cl

Cl

i-PrSH, NaH

THF, 0 °C, 16 hNCl

N

S

Cl94%

5% Pd(OAc)2, 15% PPh3aq. Na2CO3, R1B(OH)2

DME, 75 °C NCl

N

S

R1



Pd-Catalyzed, Cu-Mediated Cross-Coupling at C-4

NCl

N

NCl

N

NCl

N

NCl

NO NCl

NO

NCl

NS

CF3

NCl

N

O

89% 89% 86%

87% 97% 91%

83%

NCl

N

R1 NCl

N

R2

R1

S5% Pd(PPh3)4, CuTC (2.2 eq)

R2B(OH)2 (2.2 eq)

THF, 50 °C



Final Cross-Coupling at C-7

N

NNCl

N

B(OH)2

5% Pd(OAc)2, 15% PPh3aq. Na2CO3 (3.1 equiv)

DME, reflux, 24 h

50% conversion

O O

(2 equiv)

N

N

CF3

NCl

N

CF3


DME, reflux, 34 h

81%

B(OH)2

(4 equiv)O O




N

NNCl

N

B(OH)2


DME, reflux, 24 h

50% conversion

O O

(2 equiv)

N

N

CF3

NCl

N

CF3


DME, reflux, 34 h

81%

B(OH)2

(4 equiv)O O




N

N

O

NCl

N10% Pd(OAc)2, 30% PPh3

aq. Na2CO3 (6.1 equiv)

DME, reflux, 22 h

O

B(OH)2

86%(4 equiv)

N

N

O

NCl

N

O


DME, reflux, 34 h

66%(4 equiv)

NH

B(OH)2

NH



Subsequent Regioselective Cross-CouplingReactions of 2,4,7-Trichloroquinazoline

NCl

N

Cl

Cl




NCl

N

S

Cl

NCl

N

S

NCl

N

NCl

N

S

NCl

N

S

NCl

N

S

NCl

N

S

NCl

N

S

NCl

N

S

NCl

N

S

NS

O

NH

CF3

O

NCl

N

NCl

N

NCl

NO

NCl

NO

NCl

NS

CF3

NCl

N

S

N

N

O

NCl

N

O

N

NO

CF3

SNCl

N

N

N

O

NH

NCl

N

O



Introduction: Protein Kinase D

PKD1: PKD/PKCµ

PKD2

PKD3: PKDυ (PKCυ)

PKD

Constitutes a novel family of serine/threonine kinases and diacylglycerol(DAG) receptors that belong to the Ca2+/calmodulin-dependent kinase(CaMK) superfamily

Three PKD isoforms: PKD1 (PKCµ), PKD2, PKD3 (PKCυ) PKD has been linked to a diverse set of signal transduction pathways

involved in tumor development and cancer progression

AP

P

C1 AC PH KinaseC1a C1b

S

C1a C1b

C1a C1b

Wang, Q. J. Trends in Pharmacol. Sci. 2006, 27, 317.For reviews see: Rozengurt, E.; Rey, O.; Waldron, R. T. J. Bio. Chem 2005, 280, 13205. LaValle, C. R.; George, K. M.; Sharlow, E. R.; Lazo, J. S.; Wipf, P.; Wang, Q. J. BBA Rev. Cancer. 2010, in press



PKD1: PKD/PKCµ

PKD2

PKD3: PKDυ (PKCυ)

PKD

AP

P


S

C1a C1b

C1a C1b

Wang, Q. J. Trends in Pharmacol. Sci. 2006, 27, 317.

O

O

H3C(H2C)12

CH3

CH3O

O

CH3

H

H

OH

HH3C

H3C

O HO

OH

phorbol ester (PMA)

OHO

O R1

OO

R2

Diacylglycerol (DAG)

Autoinhibition

Protein-ProteinInteractions

PKCs

P P



PKD1: PKD/PKCµ

PKD2

PKD3: PKDυ (PKCυ)

PKD

AP

P


S

C1a C1b

C1a C1b


O

O

H3C(H2C)12

CH3

CH3O

O

CH3

H

H

OH

HH3C

H3C

O HO

OH

phorbol ester (PMA)

OHO

O R1

OO

R2


Autoinhibition


PKCs

P P



PKD1: PKD/PKCµ

PKD2

PKD3: PKDυ (PKCυ)

PKD

AP

P


S

C1a C1b

C1a C1b


O

O

H3C(H2C)12

CH3

CH3O

O

CH3

H

H

OH

HH3C

H3C

O HO

OH

phorbol ester (PMA)

OHO

O R1

OO

R2


Autoinhibition


c/nPKCs

P P


Protein Kinase D Signaling Pathway


PKD

p p

Mitochondria Nucleus

Stimuli

Receptors

II. Regulation of class IIa HDAC

IV. Oxidative stress response

ERK1/2

I. Modulation of signaling pathways

RIN1

p14-3-3

Ras

Raf

MEK

MEKK

MKK

JNK

c-Junp

III. Membrane orprotein trafficking

TGN

PKD

p p

PKCηGbγ

PI4K IIIβp

PKD

p pp

PKCδ

Src

AbI

PKD

p p

Oxidative Stress

ROS

IKKcomplex

MnSODNF-κB

HDAC IIa

p14-3-3

HDAC IIaHDAC IIa

pPKD

p p

MEF2

14-3-3

X




PLC

PKD

p p


Stimuli

Receptors



ERK1/2


RIN1

p14-3-3

Ras

Raf

MEK

MEKK

MKK

JNK

c-Junp


TGN

PKD

p p

PKCηGbγ

PI4K IIIβp

PKD

p pp

PKCδ

Src

AbI

PKD

p p

Oxidative Stress

ROS

IKKcomplex

MnSODNF-κB

HDAC IIa

p14-3-3

HDAC IIaHDAC IIa

pPKD

p p

MEF2

14-3-3

X




PLCDAG

PKD

p p


Stimuli

Receptors



ERK1/2


RIN1

p14-3-3

Ras

Raf

MEK

MEKK

MKK

JNK

c-Junp


TGN

PKD

p p

PKCηGbγ

PI4K IIIβp

PKD

p pp

PKCδ

Src

AbI

PKD

p p

Oxidative Stress

ROS

IKKcomplex

MnSODNF-κB

HDAC IIa

p14-3-3

HDAC IIaHDAC IIa

pPKD

p p

MEF2

14-3-3

X




PLCnPKC

DAG

PKD

p p


Stimuli

Receptors



ERK1/2


RIN1

p14-3-3

Ras

Raf

MEK

MEKK

MKK

JNK

c-Junp


TGN

PKD

p p

PKCηGbγ

PI4K IIIβp

PKD

p pp

PKCδ

Src

AbI

PKD

p p

Oxidative Stress

ROS

IKKcomplex

MnSODNF-κB

HDAC IIa

p14-3-3

HDAC IIaHDAC IIa

pPKD

p p

MEF2

14-3-3

X




PLCnPKCPKD

DAG

PKD

p p


Stimuli

Receptors



ERK1/2


RIN1

p14-3-3

Ras

Raf

MEK

MEKK

MKK

JNK

c-Junp


TGN

PKD

p p

PKCηGbγ

PI4K IIIβp

PKD

p pp

PKCδ

Src

AbI

PKD

p p

Oxidative Stress

ROS

IKKcomplex

MnSODNF-κB

HDAC IIa

p14-3-3

HDAC IIaHDAC IIa

pPKD

p p

MEF2

14-3-3

X




PLCnPKCPKD

p p DAG

PKD

p p


Stimuli

Receptors



ERK1/2


RIN1

p14-3-3

Ras

Raf

MEK

MEKK

MKK

JNK

c-Junp


TGN

PKD

p p

PKCηGbγ

PI4K IIIβp

PKD

p pp

PKCδ

Src

AbI

PKD

p p

Oxidative Stress

ROS

IKKcomplex

MnSODNF-κB

HDAC IIa

p14-3-3

HDAC IIaHDAC IIa

pPKD

p p

MEF2

14-3-3

X




PLCnPKCPKD

p p DAG

PKD

p p


Stimuli

Receptors



ERK1/2


RIN1

p14-3-3

Ras

Raf

MEK

MEKK

MKK

JNK

c-Junp


TGN

PKD

p p

PKCηGbγ

PI4K IIIβp

PKD

p pp

PKCδ

Src

AbI

PKD

p p

Oxidative Stress

IKKcomplex

MnSODNF-κB

HDAC IIa

p14-3-3

HDAC IIaHDAC IIa

pPKD

p p

MEF2

14-3-3

X

ROS


Chemical Inhibitors of PKD

ATP competitive Staurosporine and staurosporine-derived compounds

Gschwendt, M.; Dieterich, S.; Rennecke, J.; Kittstein, W.; Mueller, H.-J.; Johannes, F.-J. FEBS Letters 1996, 392, 77.Martiny-Baron, G.; Kazanietz, M. G.; Mischak, H.; Blumberg, P. M.; Kochs, G.; Hug, H.; Marme, D.; Schachtele, C. J. Biol. Chem. 1993, 268, 9194.Zang, R.; Mueller, H.-J.; Kielbassa, K.; Marks, F. Biochem. J. 1994, 304, 641.

Abbreviation: n.d., not determined

HNO

N NOCH3OCH3

HN CH3

Staurosporine

HN OO

N NH

O

NGö 6983

HNO

N NCH3 CNGö6976

HNO

N NOCH3

CO2CH3OH

K252a

PKC!

330 nM7 nM

2.3 nM 17 nM

Inhibitor

StaurosporineGö 6983Gö 6976K252a

PKC"

430 nM6 nM n.d.

18 nM

PKC#

>10,000 nM10 nM

>10,000 nM 3000 nM

PKC$

330 nM7 nM

6.2 nM 15 nM

PKC%

>10,000 nM 60 nM

>10,000 nM 10 nM

PKCµ/PKD

40 nM20,000 nM

20 nM7 nM



ATP competitive Resveratrol

In vitro IC50 (PKD) = 52 - 200 μM In vivo IC50 (PKD) = 760 μM

Stewart, J. R.; Christman, K. L.; O’Brian, C. A. Biochem. Pharmacol. 2000, 60, 1355.Haworth, R. S.; Avkiran, M. Biochem. Pharmacol. 2001, 62, 1647.

HO

OH

OH

Resveratrol


First Potent and Selective Inhibitor of PKD: CID755673

Non-competitive with respect to ATP and substrate Effective at blocking PKD-mediated cell functions Reduced cell migration, invasion, and proliferation in prostate cancer cells

CID755673

O

NHHO

O

Kinase

PKD1PKD2PKD3PLK1CAKAKT

PKC!PKC"

CAMPK!

IC50 (µM)

0.5 ± 0.030.3 ± 0.0020.2 ± 0.0220.3 ± 10.915.3 ± 1.8 18.6 ± 2.0

not significantno activity40.5 ± 4.6

Sharlow, E. R.; Giridhar, K. V.; LaValle, C. R.; Chem, J.; Leimgruber, S.; Barrett, R.; Bravo-Altamirano, K.; Wipf, P.; Lazo, J.; Wang, Q. J. J. Biol.Chem. 2008, 283, 33516.


First Potent and Selective Inhibitor of PKD: CID755673

Cellular activity relatively weak: IC50 = 10 - 30 µM

May possess unintended PKD-independent effects

CID755673

O

NHHO

O

Torres-Marquez, E.; Sinnett-Smith, J.; Guha, S.; Kui, R.; Waldron, R. T.; Rey, O.; Rosengurt, E. Biochem. Biophys. Res. Comm. 2010, 391, 63.



Monovich, L.; Vega, R. B.; Meredith, E.; Miranda, K.; Rao, C.; Capparelli, M.; Lemon, D. D.; Phan, D.; Koch, K. A.; Chapo, J. A.; Hood, D. B.; McKinsey, T.A. FEBS Letters 2010, 584, 631.

PKD1PKD2PKD3CaMKI!CaMKII"CaMKII#CaMKII!CaMKIVMARK1MARK2SIK1GRK5PKC!PKC$

IC50 (µM)

10210210960326124277222-3

Kinase % Inhibition at1µM BPKDi

0.0010.0090.001n.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d.

N

N

H2N

O

NH

N

NH

BPKDi

Blocks signal-dependent phosphorylation and nuclear export of class IIaHDACs in cardiomyocytes, thereby suppressing hypertrophy of these cells

ATP competitive



Harikumar, K. B.; Kunnumakkara, A. B.; Ochi, N.; Tong, Z.; Deorukhkar, A.; Sung, B.; Kelland, L.; Jamieson, S.; Sutherland, R.; Raynham, T.; Carles, M.;Bagherazadeh, A.; Foxton, C.; Boakes, A.; Farooq, M.; Maru, D.; Diagaradjane, P.; Matsuo, Y.; Sinnett-Smith, J.; Gelovani, J.; Krishnan, S.; Aggarwal, B. B.;Rozengurt, E.; Ireson, C. R.; Guha, S. Mol. Cancer Ther., 2010, 9, 1136.

CRT0066101

N

N

NR2

R1 NH2

HOR3

First orally bioavailable PKD inhibitor Blocks pancreatic cancer growth both in vitro and in vivo Specificity confirmed in an in vitro assay comprisising a panel of >90 protein

kinases ATP competitive

Kinase

PKD1PKD2PKD3

IC50 (µM)

0.0010.0030.002


Conclusion and Future Work

Methoxy derivative successfully synthesized and biological testing is inprogress

Optimize deprotection and submit for biological testing

Photoaffinity labeled derivative to gain insight into binding site


Acknowledgements

Dr. Wipf Dr. Wang, Courtney LaValle, Dr. Karla Bravo-Altamirano Wipf group members past & present NMR & MS facilities NIH, University of Pittsburgh Arts & Science Fellowship


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