1

2

Medicinal Inorganic Chemistry

HO

H2N As As

As

OH

NH2

OH

NH2

HO

H2N

As As

As

HO

H2N

OH

NH2

As

As

HO

OH

NH2

NH2

Jaouen, G. Bioorganometallics, 2006, 1st Ed. pp. 1-32Orvig, C. Abrams, M.J. Chem. Rev. 1999, 99, 2201

3000 BC :

2500 BC :

400 BC :

1600s :

Early 1900s :

Egyptians used Cu to sterilize water

Chinese empire uses Au in a variety of medicine

Hippocrates used Hg

Paracelsus pioneered the use of minerals in medicine using Sb, As, Mg salt

Metals started making an impact on modern medicineK[Au(CN)2] used for tuberculosis

Salvarsan for the treatment of syphilis

3

Outline

1. Traditional applications of inorganic compounds:

2. Inorganic compounds that utilize reactivity of metals

3. Inorganic compound that utilizes both the structure of metal and their reactivity in biological system

4. Inorganic compounds that utilize the unique structural opportunities of metals

- Chelation- Imaging properties

4

Thompson, K.H, Orvig, C.; Science, 2003, 300, 936

5

medicinal inorganic chemistry

therapeutic agents (e.g. Li, Pt, Au, Bi)

radiopharmaceuticals diagnostic (e.g.99mTc) therapeutics (e.g. 186Re)

enzyme inhibitors

diagnostic agents MRI (e.g. Gd, Mn) x-ray (e.g. Ba, I)

essential elements mineral supplements (e.g. Cu, Zn, Se)

chelation

therapy

Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512 Orvig, C. Abrams, M.J. Chemical Reviews, 1999, 99, 2201

6

Medicinal Inorganic chemistry: Essential Elements

“Organic” elements: C, H, N, O

Macronutrients: Na, K, Mg, Ca, S, P, Cl, Si, Fe

Micronutrients: V, Cr, Mn, Co, Ni, Cu, Zn, Mo, W, Se, F, I

http://fr.wikipedia.orgCotton,F.A.; Wilkinson, G.; Gaus, P.L.; Basic Inorganic Chemistry, 3rd Ed. (1995), pp. 729-753 http://www.daviddarling.info/encyclopedia/V/vitamin_B12.html

Vitamin B12Heme

7

Medicinal Inorganic chemistry: Chelation Therapy

Used for metal intoxication

1941: Citrate is used for acute lead intoxication

HO

OO-

O O-

O

-O

Since then, other chelating agents have come into clinical use:

DMSA

H2N NH

HN

NH2

TETAEDTA

COOHN

COOHNHOOC

HOOC HS

HS

OH

O

O

OH

Andersen, O. Chem. Rev. 1999, 99, 2683

8

Medicinal Inorganic chemistry: Radiopharmaceuticals

Anderson, C.J.; Welch, M.J. Chem. Rev. 1999, 99, 2219Wang et al. Bioconjugate Chem. 1996, 7, 56http://www.doemedicalsciences.org/Jaouen, G. Bioorganometallics, 2006, 1st Ed. pp. 1-32

OCH3

N N

O

TcOC

OC CO

9

Medicinal Inorganic chemistry: Diagnostic Agents

Contrast agents:

- X-Ray:

I, Ba, BaSO4

Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512www.asrt.org/content/ThePublic/AboutRadiologicProcedures/ContrastAgents.aspxThompson, K.H, Orvig, C.; Science, 2003, 300, 936

MRI:

10

Role of metals

Half life and energy of

isotopic decay

Behavior in magnetic field

Physical properties

Coordination

Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512 Orvig, C. Abrams, M.J. Chem. Rev. 1999, 99, 2201

11

medicinal inorganic chemistry

therapeutic agents (e.g. Li, Pt, Au, Bi)

radiopharmaceuticals diagnostic (e.g.99mTc) therapeutics (e.g. 186Re)

enzyme inhibitors

diagnostic agents MRI (e.g. Gd, Mn) x-ray (e.g. Ba, I)

essential elements mineral supplements (e.g. Cu, Zn, Se)

chelation

therapy

Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512 Orvig, C. Abrams, M.J. Chemical Reviews, 1999, 99, 2201

12

Bioactivity is at the metal center

Cisplatin

Metal is the structural scaffold

Pyridocarbazole ruthenium complexes

Bioactivity is related to reaction caused by the metal center

Tamoxifen

13

Therapeutic Agents

Pharmaceutical industry usually dominated by organic drugs

Certain Inorganic drugs have proven their utility: Li, Bi

Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed. 1999, 38, 1512Fricker, S.P. Dalton Trans., 2007, 4903–4917 Alderden et al. Journal of Chemical Education 2006, 83

Most important inorganic pharmaceuticals on the market:

Cisplatin

•Discovered by chance by Rosenberg

•Used in the treatment of various cancers (testicular and ovarian)

•Approved for Clinical use in 1978

• World wide sales are around 2 billion U.S $

PtClH3N

H3N Cl

14

Cisplatin

Classic synthesis in inorganic chemistry; pioneered by Dhara in 1970

Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed. 1999, 38, 1512Fricker, S.P Dalton Trans., 2007, 4903–4917 Alderden et al. J. of Chem. Educ. 2006, 83

K2 PtCl

Cl

Cl

ClK2 Pt

I

I

I

I

- 4 KClPt

NH3

I

I

NH3

K PtNH3

I

I

I

intermediate

- 2KI

2 NH3excess

KI

2 AgNO3

PtNH3

H2O

H2O

NH3(NO3)2

excessKCl

PtCl

Cl

H3N

NH3

Cisplatin- 2 KNO3

- AgI

PtNH3

Cl

Cl

NH3

Stereoselectivity

15

Platinum is the reactive adduct for cisplatin (coordination chemistry)

Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed. 1999, 38, 1512Fricker, S.P. Dalton Trans., 2007, 4903–4917 Alderden et al. J. Chem. Educ. 2006, 83

PtClH3N

H3N Cl

16

Cisplatin : Severe side effects (toxicity to kidneys and nervous system)

Resistance

PtOH3N

H3NO

O

O

Carboplatin

Widespread clinical use

Less toxic and fewer side effects

Bidentate ligand is more stable; slower reaction in the body

The Search Continues

NH2

NH2

Pt

O

O

O

O Oxaliplatin

Colon cancer N

PtNH3Cl

Cl

AMD473

Overcome resistance

Sterics govern activity

Alderden et al. J. Chem. Educ. 2006, 83

17

Bioactivity is at the metal center

Cisplatin

Metal is the structural scaffold

Pyridocarbazole ruthenium complexes

Bioactivity is related to reaction caused by the metal center

Tamoxifen

18

Tamoxifen• Selective estrogen receptor modulator (SERM)• The estrogen receptor plays a key role in the proliferation of

hormone-dependent tumours

• Successful drugs but only active against ER+ tumors (60 %) and has developed resistance

ON

ON

OH

[ox]

ON

Cl

ON

HO

ON

I

Toremifene Droloxifene Iodoxifene

S. Top et al. J. Organometal. Chem. 2001, 637, 500S. Top et al. Chem. Eur. J. 2003, 9, 5223

19

Metal Based Approach

NH2

NH2

Pt

O

O

O

O

OH

O(CH2)2N(CH3)2

Jaouen and coworker:

Pt-N coordination bonds are too weak

- Hydrolyses too quickly

What other organometallic groups can be used?

NH2

NH2

Pt

O

O

O

O

Oxaliplatin

S. Top et al. J. Organometal. Chem. 2001, 637, 500

ON

OH

Hormonal vector

20

Organometallic Approach: Metallocenes

S. Top et al. J. Organometal. Chem. 2001, 637, 500S. Top et al. Chem. Eur. J. 2003, 9, 5223

M

Organometallic chemistry:

- Strong metal-carbon covalent bonds instead of weak coordination bonds

Antitumor activity:

- different mechanism from that of cisplatin complexes

Ferrocene:

- 18 electrons inert gas configuration: very stable

- Chemistry is similar to ordinary aromatic compounds

- Lipophilic

Fe

21

FerroceneFenton reaction:

S. Top et al. J. Organometal. Chem. 2001, 637, 500Hillard et al. Angew. Chem. Int. Ed. 2006, 45, 285

genotoxic

FeFe

Fe2+

+ O2

Fe3+

+ O2

. -.

Fe

Fe2+

+ O2

. - 2H+

Fe

Fe3+

. + H2O2

Fe

Fe2+

+ H2O2

+

Fe

Fe3+

. + OH-+ OH

.

+

+

+

22

ON

OH

Fe

Ferrocene

ON

OH

(Z)-4-Hydroxytamoxifen

Both effects coexist together: Anti-tumor and Anti-oestrogen propertiesS. Top et al. Chem. Comm. 1996, 955S. Top et al. J. Organometal. Chem. 1997, 541, 355

Jaouen and coworkers:

Fe

23

Synthesis

McMurry coupling

S. Top et al. J. Organometal. Chem. 1997, 541, 355

Fe(EtCO)2O

(H3PO4)n80%

Fe O + O

R2

TiCl4/ZnTHF

66%

Fe

R1

1:R1 =OH,R2 =O(CH2)4Br

R1

2(Z+E) :R1 =OH, R2 =O(CH2)4Br

R2

24

Synthesis

FeO

+ O

OMe

Ti(0) or Ti(II)

(Zn: reducing agent)

O

R1 R2

O

R4R3

O

R1R2

O

R4R3

O

R1R2

O

R4R3

O

R2R1

O

R4R3

O O+

Fe

OMe

FeOMe

+

Ti(0)

25

Synthesis

Ferrocifens

S. Top et al. J. Organometal. Chem. 2001, 637, 500S. Top et al. Chem. Eur. J. 2003, 9, 5223

FeFe

OR

HH+H+

Fe

OR

OROH

OH

ZE

OH

Isomerization in protic solvents

HNMe2, HClEtOH, 80 C

autoclave

34%Fe

O

OH

N

3 (Z+E)

Fe

O

R2

Br

2 (Z+E)

26

Ferrocifen

• Binding affinity < hydroxytamoxifen for 3 (sterics of ferrocinyl moiety)

• 3 > lipophilic

• Antiproliferative activity on breast cancer cells : 3 = OH-TAM for ER(+)

• Ferrocifen show remarkable antiproliferative behaviour against ER- tumors

4-Hydroxytamoxifen

Fe

O

OH

N

3(Z+E)

OH

ON

(E+Z)

S. Top et al. J. Organometal. Chem. 2001, 637, 500S. Top et al. Chem. Eur. J. 2003, 9, 5223

27

Quinone Methide

Hillard et al. Angew. Chem. Int. Ed. 2006, 45, 285

Fe

OH

Fe

OH

+

N

Fe

O

Fe

O

Fe

O

- e- -pyH+

- e-/- H+

28

Continuation of the Ferrocifen Series

• Activity is twofold :

• basic chain : primary antagonist effect

• ferrocene : [ox]/[red] genotoxic aspect

• carbon chain length is important

Fe

OH

O(CH2)nNMe2

O

OH

(Z)HO

O Fe OH

OH

(E+Z)

ReOC CO

CO

A. Nguyen et al. J. Organometal. Chem. 2007, 692, 1219

29

Bioactivity is at the metal center

Cisplatin

Metal as a structural scaffold

Pyridocarbazole ruthenium complexes

Bioactivity is related to reaction caused by the metal center

Tamoxifen

30

Structural DiversityNatural products display a high diversity of molecular skeletons:

• distinctive 3-D conformations

• Defined structures are important for their unique biological properties

Important challenge

Bregman, H.; Caroll, P.J.; Meggers, E. J. Am. Chem. Soc. 2006, 128, 877

31

Outline

1. Target : Kinase; ATP binding site

2. Known inhibitor: Staurosporine

3. Metal scaffold

4. Synthetic approaches and development

5. Diversity oriented synthesis

32

Protein Kinases:

Phosphorylation of proteins : turn them on or off

Due to their involvement in various forms of cancers, PTKs have become prominent targets for therapeutics

Regulate the majority of cellular pathways e.g DNA replication, cell growth Most kinases contain a 250-300 amino acid domain with a conserved core structure, compromising a binding pocket for ATP These domains are more or less homologous

Protein Kinases

Blume-Jensen. P.; Hunter, T. Nature, 2002, 411, 355Fischer, P.M. Curr. Med. Chem. 2004, 11, 1583

33

ATP Binding

N

N

NHN

N

H

H

Glu81

O

HN Leu83

N N

N O

O

O

NH

H

Glu81

O

HN Leu83

• ATP-binding site is an ubiquitous “receptor” in nature

• Most kinase inhibitors mimic mainly the adenine portion of ATP

• Approach is limited in terms of selectivity

N

N

NN

N

H

H

Glu81

O

HN Leu83

Ribose-PPP

Fischer, P.M. Curr. Med. Chem. 2004, 11, 1583

34

Bioorganometallic Chemistry: Staurosporine•discovered in 1977 while screening for microbials

• has gained great interest since it was reported to be potent against protein kinases

•Relatively potent; IC50 in the nanomolar range

Down side: Lacks specificity

Omura, S. et al. J. Antibiotics, 1994, 48, 535M. Yang et al. Bioorg. Med. Chem. Lett. 2007, 17, 326

NN

N

H

O

O

OHMeO2C

EtSSEt

CEP-1347

N

N

H

O

OiPr

O

ON

CEP-7055

Derivatives with modulated specificities are in preclinical trials as anticancer drugs

N N

N O

H

O

O

NH

35

Organometallic ChemistryMeggers and coworkers: coordinate a known bioligand (staurosporine) to an inert metal center

Bioligand Structural Specificity

M

C N

Y

NH

NHH

X

OCH2CH3

Inorganic compounds as structural scaffolds for the design of specific enzyme inhibitors

36

A Metal for StructureMetals can be envisioned as hypervalent carbons

– new specificity can be achieved– remove the limits imposed by the organic framework

Transition metals provide an expanded set of coordination geometries for the generation of molecular diversity

MC B

D A

ME B

D C

A

ME B

D C

A

F

MB

C

A

D

E MG B

E C

A

D

F

Octahedral with 6 different substituents can form 30 different stereoisomers

C

CC

XC

D

A

BC

Meggers, E. Curr. Opin. Chem. Biol. 2007, 11, 287

37

Ru(II)

Fricker, S.P. Dalton Trans., 2007, 4903–4917Taube, H. Chem. Rev. 1952, 50, 69

• hexavalent coordination sphere that cannot be easily obtained by any organic element

• kinetically inert coordinative bonds

• stabilities that are comparable to purely organic molecules

RuN

N

N

N

2+ NN

2ClO4-

not attacked by boiling conc. HCl or concentrated alkalis

38

Meggers et al.

copying the structural features of small organic molecule inhibitors

metal plays solely a structural role

access to new areas of chemical space

Zhang, L. Caroll, P. Meggers, E.; Org. Lett. 2004, 6, 521Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521Bregman, H, Caroll, P.J. Meggers, E. J. Am. Chem. Soc. 2006, 128, 877

Defined globular shape

39

Synthetic Approach: 1.1 Ligand design

Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

NN

N

H

O

NN

NN

XN

H

L1

L2L3

L4

NH

NH

N

H

O

NH

O O

O

NN

NN

XN

H

O

(X=CO),(X=CH2)

40

Synthesis

NN

NH

NH

NN

NN

N

TBDMS

O

1) NaH, DMF

2)

N

TBDMS

OO

Br Br

O

33 %

TBAF, DCM

71 %

NN

NN

N

H

OO

NN

NH

NH

NN

NN

N

Bn

O

1) NaH, DMF

2)

N

Bn

OO

Br Br

O

35 %

NaBH4, ETOH

90 %NN

NN

N

Bn

OHO

1) Reflux in Ac2O2) Zn, Reflux

89 %

NN

NN

N

Bn

O

TFA, H2SO4,Anisole, reflux

76 %

NN

NN

N

H

O

Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521Woodward, R.B. Sondheimer, F. Taub, D. HEusler, K. McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223-4251.

4

5

6

7

41

Attempts at Coordination

Crystal structure obtained

Proof that 4 can serve as a bidentate ligand

Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

Cis(Cl)trans(DMSO)

NN

NN

N

Bn

OO

+ cis-RuCl2(DMSO)4

Toluene, reflux

NN

NN

N

Bn

OO

Ru

Cl

SS OOCl

4

42

NN

NN

NTBDMS

OO

TBAF, DCM

NN

NN

NH

OO

RuCl

ClS

S

O

O

Ru(COD)(CH3CN)2Cl2 NN

NN

NTBDMS

OO

Ru ClCl

NN

NN

HN O Ethanol, reflux

Ru(bpy)2(EtOH)22+

NN

NN

NH

OO

Ru ClCl

NN

NN

NH

O

Ru

N

N

N

N

2+

cis-RuCl2(DMSO)4

New Compounds

Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

1

2

3

5

6

43

Stability

• 3 is stable in a 1:1 water/DMSO solution for 12 h

• 3 can withstand a 2-mercaptoethanol for 3 hours without decomposition

•1 and 2 slowly release bidentate ligand in 1:1 water/DMSO solution , ½ life of 8 and 3h respectively

Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

1 2 3

NN

NN

NH

O

Ru

N

N

N

N

2+NN

NN

NH

OO

Ru ClCl

NN

NN

NH

OO

RuCl

ClS

S

O

O

44

compound Ab1 RSK1 Src PKCα ZAP70staurosporine 2 <1 <1 <1 <1

7 25 30 >100 >100 >1006 20 25 60 >100 501 10 8 30 >100 402 2 8 40 >100 303 5 8 30 50 40

Analysis of IC50 values

POTENCY and SPECIFICITY

Inhibition of some protein kinases with the various compounds (in μM)

NN

N

H

O

O

NH

O

NN

NN

N

H

OO

7 NN

NN

N

H

O

6

NN

NN

N

Bn

OO

RuCl

ClS

S

O

O

1

NN

NN

N

H

OO

RuClCl

2

NN

NN

N

H

O

Ru

N

N

N

N

2+

HH

3

Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

45

Analysis

• The activity of compound 2 requires the entire assembly

NN

NN

N

H

OO

NN

NN

N

Bn

OO

RuClCl

• Potency is strongly reduced by 25

NN

NN

N

H

OO

RuClCl

Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

Ru(COD)(CH3CN)2Cl2

2

Abl: chronic myeloid leukemia

46

The team looked to different cores and a new compound was found:

New Core Structures

NN

NN

N

H

OO

NNH

N

H

OO

NN

N

H

OO

Ru

CO

Was identified from a screen of different Ru complexes against a panel of protein kinases

• IC50 is 3 nM for GSK-3a and 10 nM for GSK-3B

• high degree of selectivity

Meggers, E. J. Am. Chem. Soc. 2004, 126, 13594

2 Synthetic approaches were used

47

N

t-BuOK (3 equiv),DMF, 4 A M.S

50 %

SEM

O

O

O

NH

1) (COCl)2,Et2O

2) NaOMe,- 60oC

NH

O

O

O

93 %

1) NaH, THF

2) Me3Si(CH2)2OCH2Cl

82 %

N

O

H2N

+

hv, MeCN, Mg LampAir, I2 cat.

63 %

N

SEM

HN OO

NN

SEM

HN OO

N

N

SEM

HN

O

O

NO

HH

N

SEM

HN OHO

N

O

N

SEM

HN OO

N

HO H

p.t.

N

SEM

HN OO

N

t-BuOK

Faul. M et al. J. Org. Chem. 1998, 63, 6053Piers. E et al. Org. Chem. 2000, 65, 530-535Berlinck, R. G. S.; Britton, R.; Piers, E.; Lim, L.; Roberge, M.; Moreira da Roche, R.; Andersen, R. J. J. Org. Chem. 1998, 63, 9850Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521

1

Approach 1: Synthesis of pyridocarbazoles

48

Photocyclization: electrocyclic reaction

Faul. M et al. J. Org. Chem. 1998, 63, 6053Piers. E et al. Org. Chem. 2000, 65, 530-535Berlinck, R. G. S.; Britton, R.; Piers, E.; Lim, L.; Roberge, M.; Moreira da Roche, R.; Andersen, R. J. J. Org. Chem. 1998, 63, 9850 Rawal, V.H.; Jones, R.J.; Cava, M.p. Tett. Lett. 1985, 26, 2423

N

HN OO

N

hvMeCN

heat

N

HN OO

N N

HN OO

NSEM

Air,I2 cat.

SEMSEM

HH

hv

hv

hv

heat

H

H

Pd/C cat.MeCN

N

N

NN

N

N

N

N

hv

SOMO

6 conrotatory

49

Approach 1: Synthesis of pyridocarbazoles

Kita, Y.; Haruta, J.; Fujii, T.; Segwawa, J. Synthesis 1981, 451Bregman, H. Williams, G. S. Meggers, E. Synthesis, 2005, 9, 1521

LiBF4, MeCN-H2Oreflux

100 %NH

HN OO

NNH

N OO

N

TBDMS

MeCN, reflux

93 %N

SEM

HN OO

N

OOSi

tertbutyldimethylsilyloxymethoxyethene

No base is required, volatile side product

OOSi HN

O

O

N

O

OR

R

R

R

N

O

O

R

R

Si O

O+

OOSi

50

Approach 2: Synthesis of Pyridocarbazoles

N

H

N

NHH2N

+

O

N

AcOH

HNN

NH

HNNH

NH

NH

N

NHH

NH2

N

NHH

HN

N NH

H

- H+

-NH3

Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521Thummel, R. P.; Hegde, V. J. Org. Chem. 1989, 54, 1720Caixach, J.; Capell, R.; Galvez, C.; Gonzalez, A.; Roca, N. J. Heterocycl. Chem. 1979, 16, 1631

51

NH

N OO

N

TBS

Br

hvMeCN

heatNH

N OO

N

TBS

HBr

- HBr

NH

N OO

N

TBS

Approach 2: Synthesis of Pyridocarbazoles

NO O

BrBr

TBS

1) LiHMDS, THF-15oC

2) THF, -15oC to r.tNH

N OO

N

TBS

Br

68 %

NH

N OO

N

TBS

hv, pyrex filterMeCN

64 %N

H

N

Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521

52

N

1)DIPEADMF,2) TBSOTf

71 %

NO O

BrBr

TBS

NH

N OO

N

TBS

Br

NH

N OO

N

TBS

O

+

O

HNNH2HCl

t-BuOHreflux

100%

O

NH

NN N

HN

HO

1)TMSpolyphosphate120oC63 %

2)BBr3, DCM87 %

NH

N

TBSO TBSO1)LiHMDS,THF,

2) THF,

TBSOhv, pyrex filterMeCN

78 %

58 %

Library of Analogues

Analogs with enhanced features were used to test the affinity of the pocket

Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521

53

Cyclometallation

NH

N OO

N

TBS1) [Ru(Cp)(CO)(MeCN)2]

+PF6-

K2CO3 (1 Eq)

2) TBAF, DCM NN

N

H

OO

Ru

CO

NH

N OO

N

TBS

Ru

CO

N

N

N OO

N

TBS

Ru

CO

H

K2CO3

-H+ N

N OO

N

TBS

Ru

CO

TBAF

Complex is pseudotetrahedral and possesses metal centered chirality

Stereoselectivity

Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521

54

Potency

NN

N

H

OO

Ru

CO

NN

N

H

OO

Ru

CO

NN

N

H

OO

Ru

CO

HO

NN

N

H

OO

Ru

CO

HO

IC50’s against GSK-3a

10 nM 0.3 nM 80 nM

N N

N O

H

O

O

NH

50 nM

Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521

3 nM

55

Glycogen Synthase Kinase 3 ( GSK-3)

NN

N

H

OO

Ru

CO

HO

IC50 of 0.3 nM

• GSK-3 plays a role in insulin signal transduction• potential importance for Alzheimer’s disease• potential for treating diabetes

N

NHNHN

N

HN

N

N

Cl

Cl

CHIR 99201

IC50 of 40 nM;

Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521 Cohen, P.; Goedert, M. Nat. Rev. Drug Discov. 2004, 3, 479

potent and selective

• compares to best published organic GSK-3 inhibitors

56

Diversity Oriented Synthesis

What about other targets?

Exploring small-molecule chemical space:

• common precursor : less synthetic effort and more extended structural options

•Purified by flash chromatography

•Four leaving groups

NN

NTBS

OO

RuCl

UV-lightCH3CN

60 %NN

NTBS

OO

Ru NN

N Cl

TBAFCH3CN

90 %NN

NH

OO

Ru NN

N ClNH

N OO

N

TBS

[Ru(C6H6)Cl2]2CH3CN, K2CO3

69 %

Bregman, H.; Carroll, P.J.; Meggers, E. J. Am. Chem. Soc. 2006, 128, 879

57

Bregman, H.; Carroll, P.J.; Meggers, E. J. Am. Chem. Soc. 2006, 128, 879

Rapid scanning of ligands: Searching for 3-D structures

58

To the Future

Bregman, H.; Meggers, E. Org. Lett. 2006, 8, 5466

59

Conclusion

• Exploit the unique features of metallic elements

• Metals are not always toxic

• Metals can be used as hypervalent carbon

• New ways to address problems that medicinal chemistry faces (NOT better!!!)

THINK

60

Acknowledgements

Prof. Keith FagnouMarc LafranceMegan ApSimonCatherine LebelMégan Bertrand-LaperleElisia VillemureNicole BlaquiereHo-Yan SunSophie RousseauxDaniel ShoreDerek SchipperDavid StuartDoris LeeDavid LapointeDaniel BlackBenoît LiegaultChris WhippMalcolm Huestis