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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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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


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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


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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


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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


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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


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  • Bioactivity is at the metal center

    Cisplatin

  • Bioactivity is related to reaction caused by the metal center

    Tamoxifen

  • Metal is the structural scaffold

  • Pyridocarbazole ruthenium complexes


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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


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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


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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


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The Search Continues

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 at the metal center

    Cisplatin

  • Bioactivity is related to reaction caused by the metal center

    Tamoxifen

  • Metal is the structural scaffold

  • Pyridocarbazole ruthenium complexes


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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

[ox]

Toremifene

Droloxifene

Iodoxifene

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

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


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Metal Based Approach

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


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Organometallic Approach: Metallocenes

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


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Ferrocene

Fenton reaction:

  • genotoxic

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

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


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Ferrocene

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


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Synthesis

McMurry coupling

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


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Synthesis


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Synthesis

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


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Ferrocifen

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


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Quinone Methide

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


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Continuation of the Ferrocifen Series

  • 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


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  • Bioactivity is at the metal center

    Cisplatin

  • Bioactivity is related to reaction caused by the metal center

    Tamoxifen

  • Metal as a structural scaffold

  • Pyridocarbazole ruthenium complexes


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Structural Diversity

  • 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


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Outline

  • Target : Kinase; ATP binding site

  • Known inhibitor: Staurosporine

  • Metal scaffold

  • Synthetic approaches and development

  • Diversity oriented synthesis


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Protein Kinases

  • 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


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ATP Binding

  • 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

  • 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

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


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A Metal for Structure

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


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Ru(II)

  • 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


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Meggers et al.

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


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Synthetic Approach: 1.1 Ligand design

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


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Synthesis

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.


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Attempts at Coordination

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


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New Compounds

1

5

2

3

6

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


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Stability

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


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3

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


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Analysis

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


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New Core Structures

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


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Approach 1: Synthesis of pyridocarbazoles

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

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


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Approach 1: 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


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Approach 2: Synthesis of Pyridocarbazoles

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


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Approach 2: Synthesis of Pyridocarbazoles

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


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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


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Cyclometallation

Stereoselectivity

Complex is pseudotetrahedral and possesses metal centered chirality

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


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Potency

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


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Glycogen Synthase Kinase 3 ( GSK-3)

  • 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


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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

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


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Rapid scanning of ligands: Searching for 3-D structures

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


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To the Future

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


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Conclusion

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!!!)


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Acknowledgements

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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