Cisplatin

1
Medicinal Inorganic Chemistry and the Treatment
of Disease
by Laurence Caron March 13th 2008
2
Medicinal Inorganic Chemistry
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 medicine KAu(CN)2 used for tuberculosis Salvarsan for the treatment of syphilis
Jaouen, G. Bioorganometallics, 2006, 1st Ed. pp.
1-32 Orvig, C. Abrams, M.J. Chem. Rev. 1999, 99,
2201
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
diagnostic agents MRI (e.g. Gd, Mn) x-ray (e.g.
Ba, I)
essential elements mineral supplements (e.g. Cu,
Zn, Se)
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
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
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
7
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
8
Medicinal Inorganic chemistry Radiopharmaceutical
s
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
9
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/AboutRadio
logicProcedures/ContrastAgents.aspx Thompson,
K.H, Orvig, C. Science, 2003, 300, 936
10
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
11
diagnostic agents MRI (e.g. Gd, Mn) x-ray (e.g.
Ba, I)
essential elements mineral supplements (e.g. Cu,
Zn, Se)
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
12

• 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

13
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,
49034917 Alderden et al. Journal of Chemical
Education 2006, 83
14
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,
49034917 Alderden et al. J. of Chem. Educ.
2006, 83
15
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,
49034917 Alderden et al. J. Chem. Educ. 2006, 83
16
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
17

• 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

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

ox
Toremifene
Droloxifene
Iodoxifene
S. Top et al. J. Organometal. Chem. 2001, 637,
500 S. Top et al. Chem. Eur. J. 2003, 9, 5223
19
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
20
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
21
Ferrocene

• Fenton reaction

• genotoxic

S. Top et al. J. Organometal. Chem. 2001, 637,
500 Hillard et al. Angew. Chem. Int. Ed. 2006,
45, 285
22
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
23
Synthesis
McMurry coupling
S. Top et al. J. Organometal. Chem. 1997, 541, 355
24
Synthesis
25
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
26
Ferrocifen
4-Hydroxytamoxifen

• Binding affinity lt hydroxytamoxifen for 3
  (sterics of ferrocinyl moiety)
• 3 gt 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
27
Quinone Methide
Hillard et al. Angew. Chem. Int. Ed. 2006, 45, 285
28
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
29

• 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

30
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
31
Outline

1. Target Kinase ATP binding site
2. Known inhibitor Staurosporine
3. Metal scaffold
4. Synthetic approaches and development
5. 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
33
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
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
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
35
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
36
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
37
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,
49034917 Taube, H. Chem. Rev. 1952, 50, 69
38
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
39
Synthetic Approach 1.1 Ligand design
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004,
6, 521
40
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.
41
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
42
New Compounds
1
5
2
3
6
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004,
6, 521
43
Stability
1
2
3

• 3 is stable in a 11 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 11
  water/DMSO solution , ½ life of 8 and 3h
  respectively

Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004,
6, 521
44
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
45
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
46
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
47
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
48
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
49
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
50
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
51
Approach 2 Synthesis of Pyridocarbazoles
Bregman, H. Williams, G. S. Meggers, E.
Synthesis, 2005, 9, 1521
52
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
Stereoselectivity
Complex is pseudotetrahedral and possesses metal
centered chirality
Bregman, H. Williams, G. S. Meggers, E.
Synthesis, 2005, 9, 1521
54
Potency
IC50s against GSK-3a
10 nM
0.3 nM
80 nM
3 nM
50 nM
Bregman, H. Williams, G. S. Meggers, E.
Synthesis, 2005, 9, 1521
55
Glycogen Synthase Kinase 3 ( GSK-3)

• GSK-3 plays a role in insulin signal
  transduction
• potential importance for Alzheimers 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
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

Bregman, H. Carroll, P.J. Meggers, E. J. Am.
Chem. Soc. 2006, 128, 879
57
Rapid scanning of ligands Searching for 3-D
structures
Bregman, H. Carroll, P.J. Meggers, E. J. Am.
Chem. Soc. 2006, 128, 879
58
To the Future
Bregman, H. Meggers, E. Org. Lett. 2006, 8,
5466
59
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!!!)

60
Acknowledgements
Prof. Keith Fagnou Marc Lafrance Megan
ApSimon Catherine Lebel Mégan Bertrand-Laperle Eli
sia 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