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Medicinal Inorganic Chemistry and the Treatment of Disease. by Laurence Caron March 13th 2008 . Medicinal Inorganic Chemistry. Jaouen, G. Bioorganometallics , 2006, 1st Ed. pp. 1-32 Orvig, C. Abrams, M.J. Chem. Rev. 1999 , 99 , 2201. Outline.

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Slide1 l.jpg

Medicinal Inorganic

Chemistry

and the

Treatment of Disease

by

Laurence Caron

March 13th 2008


Medicinal inorganic chemistry l.jpg
Medicinal Inorganic Chemistry

Jaouen, G. Bioorganometallics, 2006, 1st Ed. pp. 1-32

Orvig, C. Abrams, M.J. Chem. Rev.1999, 99, 2201


Outline l.jpg
Outline

  • Traditional applications of inorganic compounds:

  • Inorganic compounds that utilize reactivity of metals

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

  • Inorganic compounds that utilize the unique structural opportunities of metals

- Chelation

- Imaging properties


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


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

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

medicinal inorganic chemistry

enzyme inhibitors

chelation therapy

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

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

Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512

Orvig, C. Abrams, M.J. Chemical Reviews, 1999, 99, 2201


Medicinal inorganic chemistry essential elements l.jpg
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

Vitamin B12

Heme

http://fr.wikipedia.org

Cotton,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


Medicinal inorganic chemistry chelation therapy l.jpg
Medicinal Inorganic chemistry: Chelation Therapy

Used for metal intoxication

1941: Citrate is used for acute lead intoxication

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

TETA

EDTA

DMSA

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


Medicinal inorganic chemistry radiopharmaceuticals l.jpg
Medicinal Inorganic chemistry: Radiopharmaceuticals

Anderson, C.J.; Welch, M.J. Chem. Rev. 1999, 99, 2219

Wang et al. Bioconjugate Chem.1996, 7, 56

http://www.doemedicalsciences.org/

Jaouen, G. Bioorganometallics, 2006, 1st Ed. pp. 1-32


Medicinal inorganic chemistry diagnostic agents l.jpg
Medicinal Inorganic chemistry: Diagnostic Agents

Contrast agents:

- X-Ray:

I, Ba, BaSO4

MRI:

Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512

www.asrt.org/content/ThePublic/AboutRadiologicProcedures/ContrastAgents.aspx

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


Slide10 l.jpg

Behavior in magnetic field

Physical properties

Role of metals

Half life and energy of isotopic decay

Coordination

Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512

Orvig, C. Abrams, M.J. Chem. Rev.1999, 99, 2201


Slide11 l.jpg

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

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

medicinal inorganic chemistry

enzyme inhibitors

chelation therapy

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

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

Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512

Orvig, C. Abrams, M.J. Chemical Reviews, 1999, 99, 2201


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  • Bioactivity is related to reaction caused by the metal center

    Tamoxifen

  • Metal is the structural scaffold

  • Pyridocarbazole ruthenium complexes


Therapeutic agents l.jpg
Therapeutic Agents

  • Pharmaceutical industry usually dominated by organic drugs

  • Certain Inorganic drugs have proven their utility: Li, Bi

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 $

Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed.1999, 38, 1512

Fricker, S.P. Dalton Trans., 2007, 4903–4917

Alderden et al. Journal of Chemical Education2006, 83


Cisplatin l.jpg
Cisplatin

  • Classic synthesis in inorganic chemistry; pioneered by Dhara in 1970

Stereoselectivity

Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed.1999, 38, 1512

Fricker, S.P Dalton Trans., 2007, 4903–4917

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


Slide15 l.jpg

Platinum is the reactive adduct for cisplatin (coordination chemistry)

Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed.1999, 38, 1512

Fricker, S.P. Dalton Trans., 2007, 4903–4917

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


The search continues l.jpg
The Search Continues chemistry)

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

Resistance

Carboplatin

Widespread clinical use

Less toxic and fewer side effects

Bidentate ligand is more stable; slower reaction in the body

AMD473

Overcome resistance

Sterics govern activity

Oxaliplatin

Colon cancer

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


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  • Bioactivity is related to reaction caused by the metal center

    Tamoxifen

  • Metal is the structural scaffold

  • Pyridocarbazole ruthenium complexes


Tamoxifen l.jpg
Tamoxifen chemistry)

  • 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

[ox]

Toremifene

Droloxifene

Iodoxifene

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

S. Top et al.Chem. Eur. J.2003, 9,5223


Metal based approach l.jpg
Metal Based Approach chemistry)

Jaouen and coworker:

Hormonal vector

Oxaliplatin

Pt-N coordination bonds are too weak

- Hydrolyses too quickly

What other organometallic groups can be used?

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


Organometallic approach metallocenes l.jpg
Organometallic Approach: Metallocenes chemistry)

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

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

S. Top et al. Chem. Eur. J. 2003, 9, 5223


Ferrocene l.jpg
Ferrocene chemistry)

Fenton reaction:

  • genotoxic

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

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


Ferrocene22 l.jpg
Ferrocene chemistry)

Jaouen and coworkers:

(Z)-4-Hydroxytamoxifen

Both effects coexist together: Anti-tumor and Anti-oestrogen properties

S. Top et al. Chem. Comm. 1996, 955

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


Synthesis l.jpg
Synthesis chemistry)

McMurry coupling

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


Synthesis24 l.jpg
Synthesis chemistry)


Slide25 l.jpg

Synthesis chemistry)

Ferrocifens

Isomerization in protic solvents

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

S. Top et al. Chem. Eur. J. 2003, 9, 5223


Ferrocifen l.jpg
Ferrocifen chemistry)

4-Hydroxytamoxifen

  • 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

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

S. Top et al. Chem. Eur. J. 2003, 9, 5223


Quinone methide l.jpg
Quinone Methide chemistry)

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


Continuation of the ferrocifen series l.jpg
Continuation of the Ferrocifen Series chemistry)

  • Activity is twofold :

    • basic chain : primary antagonist effect

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

    • carbon chain length is important

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


Slide29 l.jpg

  • Bioactivity is related to reaction caused by the metal center

    Tamoxifen

  • Metal as a structural scaffold

  • Pyridocarbazole ruthenium complexes


Structural diversity l.jpg
Structural Diversity chemistry)

  • Natural 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


Outline31 l.jpg
Outline chemistry)

  • Target : Kinase; ATP binding site

  • Known inhibitor: Staurosporine

  • Metal scaffold

  • Synthetic approaches and development

  • Diversity oriented synthesis


Protein kinases l.jpg
Protein Kinases chemistry)

  • 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

Blume-Jensen. P.; Hunter, T. Nature, 2002, 411, 355

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


Atp binding l.jpg
ATP Binding chemistry)

  • 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

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


Bioorganometallic chemistry staurosporine l.jpg
Bioorganometallic Chemistry: Staurosporine chemistry)

  • 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

Derivatives with modulated specificities are in preclinical trials as anticancer drugs

Omura, S. et al. J. Antibiotics, 1994, 48, 535

M. Yang et al. Bioorg. Med. Chem. Lett. 2007, 17, 326


Organometallic chemistry l.jpg
Organometallic Chemistry chemistry)

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

Structural

Specificity

Bioligand

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


A metal for structure l.jpg
A Metal for Structure chemistry)

Metals 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

Octahedral with 6 different substituents can form 30 different stereoisomers

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


Ru ii l.jpg
Ru(II) chemistry)

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

  • kinetically inert coordinative bonds

  • stabilities that are comparable to purely organic molecules

not attacked by boiling conc. HCl or concentrated alkalis

Fricker, S.P. Dalton Trans., 2007, 4903–4917

Taube, H. Chem. Rev. 1952, 50, 69


Meggers et al l.jpg
Meggers et al. chemistry)

Defined globular shape

  • 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, 521

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

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


Synthetic approach 1 1 ligand design l.jpg
Synthetic Approach: 1.1 Ligand design chemistry)

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


Synthesis40 l.jpg
Synthesis chemistry)

5

7

4

6

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

Woodward, R.B. Sondheimer, F. Taub, D. HEusler, K. McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223-4251.


Attempts at coordination l.jpg
Attempts at Coordination chemistry)

4

Cis(Cl)trans(DMSO)

Crystal structure obtained

Proof that 4 can serve as a bidentate ligand

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


New compounds l.jpg
New Compounds chemistry)

1

5

2

3

6

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


Stability l.jpg
Stability chemistry)

1

2

3

  • 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


Analysis of ic 50 values l.jpg

3 chemistry)

Analysis of IC50 values

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

POTENCY and SPECIFICITY

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


Analysis l.jpg
Analysis chemistry)

Abl: chronic myeloid leukemia

Ru(COD)(CH3CN)2Cl2

  • The activity of compound 2 requires the entire assembly

2

  • Potency is strongly reduced by 25

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


New core structures l.jpg
New Core Structures chemistry)

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

  • 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

2 Synthetic approaches were used

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


Approach 1 synthesis of pyridocarbazoles l.jpg
Approach 1: Synthesis of pyridocarbazoles chemistry)

1

Faul. M et al. J. Org. Chem. 1998, 63, 6053

Piers. E et al. Org. Chem. 2000, 65, 530-535

Berlinck, R. G. S.; Britton, R.; Piers, E.; Lim, L.; Roberge, M.; Moreira da Roche, R.; Andersen, R. J. J. Org. Chem. 1998, 63, 9850

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


Photocyclization electrocyclic reaction l.jpg
Photocyclization: electrocyclic reaction chemistry)

6 

conrotatory

Faul. M et al. J. Org. Chem. 1998, 63, 6053

Piers. E et al. Org. Chem. 2000, 65, 530-535

Berlinck, 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


Approach 1 synthesis of pyridocarbazoles49 l.jpg
Approach 1: chemistry)Synthesis of pyridocarbazoles

No base is required, volatile side product

Kita, Y.; Haruta, J.; Fujii, T.; Segwawa, J. Synthesis 1981, 451

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


Approach 2 synthesis of pyridocarbazoles l.jpg
Approach 2: Synthesis of Pyridocarbazoles chemistry)

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

Thummel, R. P.; Hegde, V. J. Org. Chem. 1989, 54, 1720

Caixach, J.; Capell, R.; Galvez, C.; Gonzalez, A.; Roca, N. J. Heterocycl. Chem. 1979, 16, 1631


Approach 2 synthesis of pyridocarbazoles51 l.jpg
Approach 2: Synthesis of Pyridocarbazoles chemistry)

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


Library of analogues l.jpg
Library of Analogues chemistry)

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

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


Cyclometallation l.jpg
Cyclometallation chemistry)

Stereoselectivity

Complex is pseudotetrahedral and possesses metal centered chirality

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


Potency l.jpg
Potency chemistry)

IC50’s against GSK-3a

0.3 nM

3 nM

10 nM

80 nM

50 nM

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


Glycogen synthase kinase 3 gsk 3 l.jpg
Glycogen Synthase Kinase 3 ( GSK-3) chemistry)

  • GSK-3 plays a role in insulin signal transduction

  • potential importance for Alzheimer’s disease

  • potential for treating diabetes

IC50 of 40 nM;

IC50 of 0.3 nM

  • potent and selective

  • compares to best published organic GSK-3 inhibitors

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

Cohen, P.; Goedert, M. Nat. Rev. Drug Discov. 2004, 3, 479


Diversity oriented synthesis l.jpg
Diversity Oriented Synthesis chemistry)

  • 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

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


Slide57 l.jpg

Rapid scanning of ligands: Searching for 3-D structures chemistry)

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


To the future l.jpg
To the Future chemistry)

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


Conclusion l.jpg
Conclusion chemistry)

THINK

  • 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!!!)


Acknowledgements l.jpg
Acknowledgements chemistry)

Prof. Keith Fagnou

Marc Lafrance

Megan ApSimon

Catherine Lebel

Mégan Bertrand-Laperle

Elisia Villemure

Nicole Blaquiere

Ho-Yan Sun

Sophie Rousseaux

Daniel Shore

Derek Schipper

David Stuart

Doris Lee

David Lapointe

Daniel Black

Benoît Liegault

Chris Whipp

Malcolm Huestis


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