1. Medicinal Inorganic Chemistry and the Treatment of Diseaseby
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
K[Au(CN)2] used for tuberculosis
Salvarsan for the treatment of syphilis
The beginning of the 20th century saw metals making an
impact on modern medicine with Erlich’s discovery of the arsenic
organometallic drug Salvarsan for the treatment of syphilis.
The investigation of gold therapy for the treatment of rheumatoid
arthritis resulted from the suggestion that the tubercle bacillus
was the causative agent for this disease. Though ineffective against
tuberculosis gold compounds were found to be efficacious against
rheumatoid arthritis and as a result gold drugs have been in use
since the early part of the twentieth century for the treatment of
rheumatoid arthritis.
Jaouen, G. Bioorganometallics, 2006, 1st Ed. pp. 1-32
Orvig, C. Abrams, M.J. Chem. Rev. 1999, 99, 2201

3. 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

4. Auranofin A diversity of metal compounds is now available: Minor
gastrointestinal ailments by over-the counter
Agents such as bismuth subsalicylate. Lithium carbonate is used
to treat manic depression. One of
the major medical breakthroughs for metal-based drugs was the
serendipitous discovery of the potent anti-tumor activity of the
platinum drug cisplatin. The discovery
of this drug, which is still widely used to treat testicular cancer,
has been a major stimulus for inorganic medicinal chemistry drug
discovery.
Thompson, K.H, Orvig, C.; Science, 2003, 300, 936
Auranofin

5. medicinal inorganic chemistry
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

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
Cotton,F.A.; Wilkinson, G.; Gaus, P.L.; Basic Inorganic Chemistry, 3rd Ed. (1995), pp

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
Over the counter formulation for EDTA and other chelators claim that they flush out man made chemicals and heavy metals (including mercury). Then you take the second bottle to replenish the elements you flushed out. All available freely on the internet???
Possible controversy over the use of these chelators
Andersen, O. Chem. Rev. 1999, 99, 2683

8. Medicinal Inorganic chemistry: Radiopharmaceuticals
Anderson, C.J.; Welch, M.J. Chem. Rev. 1999, 99, 2219
Wang et al. Bioconjugate Chem. 1996, 7, 56
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
Thompson, K.H, Orvig, C.; Science, 2003, 300, 936

10. Behavior in magnetic field Half life and energy of isotopic decay
Physical properties
Role of metals
Coordination
Half life and energy of isotopic decay
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
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

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
Different concepts that are being explored and show this slide before each concept, m

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 $
The platinum anticancer drug cisplatin has made a major contribution to the treatment of testicular
and ovarian cancer
This chance discovery has been the stimulus for research into other metal-based
drugs. Inorganic chemistry offers many opportunities for medicinal chemistry, and the discovery of
metal-based drugs has moved on from chance discovery to rational drug design
bismuth subsalicylate
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 Education 2006, 83

14. Cisplatin
Classic synthesis in inorganic chemistry; pioneered by Dhara in 1970
The stronger trans-directing
influence of the iodo ligand relative to the ammonia
ligand means that the ligand trans to the iodide is more labile
and hence is the one that is displaced, resulting in the
desired cis configuration of the final product.
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

15. Platinum is the reactive adduct for cisplatin (coordination chemistry)
Toxicity was associated with the rapid aquation of cisplatin
allowing it to potentially interact with biological ligands en route
to the target molecule, DNA. This process is slower with anionic
chelating ligands such as O-donor malonates Opening of the
chelate ring allows formation of a monoaqua species, however the
reverse reaction can also occur readily. The chelate is subsequently
more stable than the dichloro complex thus allowing more time
for the drug to reach the target molecule. The monoaquo species
can react with N-donor ligands such as DNA. The subsequent
adduct is sufficiently stable to allow displacement of the second
carboxylate and formation of the DNA cross-link.
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

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
The bulky 2-methylpyridine group in AMD473 hinders the
binding of thiols, as the 5-coordinate intermediate involved
in associative ligand substitution mechanisms is destabilized
by steric interactions. This is believed to be responsible for
its good activity in several cisplatin resistant cell lines
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]
Tamoxifen is currently the most widely used antiestrogen in
adjuvant therapy of hormone-dependent breast cancers. Its
active metabolite is 4-hydroxy-tamoxifen. Since tamoxifen is active only against tumours that are estrogen receptor positive (ER), and frequently gives rise to resistance after prolonged use, the search for related but different agents has intensified considerably over the last few
years. It recently became possible to rationalise this observation when the X-ray crystal structure of the ligand-binding domain (LBD) of estrogen receptor alpha was elucidated.This study showed that the bioligand can bind as an antagonist,
creating a new pocket in a flexible area of the protein and
allowing accommodation of the basic chain. The result of
these conformational effects is to modify the position of
helix 12 of the receptor, preventing it from interacting with
certain effectors present in the target cell and therefore from
carrying out its function as an activator of specific genes. Attention quickly centred on variations on the structure of
the triphenylethylene skeleton, resulting in new specific
estrogen receptor modulators (SERMs) that include toremifene,
droloxifene and idoxifene
The modifications brought show the organic approach but what about a metal based approach?
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
The idea of using a hormonal vector to
deliver cis-platinum at the level of the estrogen receptor
This led us to adjust the strategy and explore the potential in this area of various organometallic groups with possible cytotoxicity, attached
to known SERMs so as to potentialize their
effects
has been the subject of several studies [15] but, as with
compound 6, the antitumoral effects on breast cancers
proved disappointing [16].
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 genotoxic Fenton reaction:
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
Instead of compounds
with coordination bonds, which are inherently quite weak, we
may envisage the use of species
with strong metal ± carbon covalent
bonds, and here we enter
the field of organometallic
chemistry. Metallocenes are in
fact known to have their own
antitumor properties, based on
a different mechanism from
that of the cisplatin complexes.[
22]It should be noted that the molecule exists
both in Z and in E configurations, of which the Z isomer has
been shown to be the most strongly antiestrogenic, but
because the molecule isomerizes in solution, it is the mixture
that is administered
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
Tamoxifen acts in vivo as a particularly well tolerated
cytostatic agent. It should be noted that the molecule exists
both in Z and in E configurations, of which the Z isomer has
been shown to be the most strongly antiestrogenic, but
because the molecule isomerizes in solution, it is the mixture
that is administered.
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 < 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

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
Other metals were investigated but they did not yield any incredible results, the acetae moiety show antiestrogenic properties and could be used a imaging
A. Nguyen et al. J. Organometal. Chem , 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
Different concepts that are being explored and show this slide before each concept, m

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
So if we want to be efficient in drug discovery, we need
Bregman, H.; Caroll, P.J.; Meggers, E. J. Am. Chem. Soc. 2006, 128, 877

31. Outline Target : Kinase; ATP binding site
Known inhibitor: Staurosporine
Metal scaffold
Synthetic approaches and development
Diversity oriented synthesis

32. 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 amino acid domain with a conserved core structure, compromising a binding pocket for ATP
These domains are more or less homologous
These domains including the binding pocket 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
Lets look at this ATP binding
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, 4903–4917
Taube, H. Chem. Rev. 1952, 50, 69

38. Meggers et al.
Defined globular shape
in a fashion similar to staurosporine, but with less synthetic
effort and more extended structural options, we replaced the
indolocarbazole alkaloid scaffold with simple metal complexes
in which the main features of the indolocarbazole aglycon are
retained in the metal-chelating pyridocarbazole ligand (highlighted
in red in Figure 1), thus targeting the metal complexes
1 to the ATP binding site (Figure 1). This places the metal center
within the ribose binding site and gives the opportunity to build
defined globular shapes by assembling ligands around the metal
center. Following this strategy, we recently reported an organoruthenium
half-sandwich scaffold for the highly potent
inhibition of glycogen synthase kinase 3 (GSK3
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
We envisioned that by replacing the indolocarbazole
alkaloid scaffold with metal complex 1, elaborate structures
could be assembled in an efficient manner by variation of
the ligands. Key components of our design are ligands 3 and
4, derived from the indolocarbazole aglycon 2 by just
replacing two carbon against two nitrogen atoms. This
transformation does not change the shape of the ligand but
generates two benzimidazole moieties (bold in the structure
in Abstract) that can function as coordination sites for the
ruthenium center. The remaining four coordination sites at
the ruthenium can become filled by ligands L1-L4 and
substitute for the carbohydrate moiety, with the metal center
serving as a “glue” for holding all parts together
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,

41. Attempts at Coordination4
Cis(Cl)trans(DMSO)
Crystal structure obtained
Proof that 4 can serve as a bidentate ligand
Isomerizes to its most stable isomer
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 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

44. Analysis of IC50 values
Inhibition of some protein kinases with the various compounds (in μM) 3
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
kept together by the central ruthenium ion
imide hydrogen is involved in H-bonding
staurosporine is a nanomolar inhibitor for all tested kinases, except for Abl, against which it has an IC50 of 2 uM.
2 and 3 inhibit AB1 while staurosporine is less potent with this kinase An
important target for inhibition is the tyrosine kinase (TK)
enzyme class. TK activity controls a variety of critical
biological processes including cell growth, differentiation
and motility. Genetic mutation can cause dysregulation of
TK activity leading to cancer and other disease states.1
Perhaps the most well understood cancer associated
with TK activity is chronic myeloid leukemia (CML).
(1) Krause, D. S.; Van Etten, R. A. N. Engl. J. Med. 2005, 353, 172-
187.
This disease was the first human cancer to be associated
with a specific genetic event. CML results from a
reciprocal translocation between chromosomes 9 and 22.
This results in a severely truncated chromosome 22,
termed the “Philadelphia chromosome” (Ph). The
translocation fuses the N-terminal region of the
breakpoint cluster region gene (BCR) with portions of the
Abelson tyrosine kinase gene (ABL). This fusion gene
(BCR–ABL) encodes the constitutively active Bcr–Abl
kinase. Tests in vivo suggest this single recombination is
the sole cause of CML. Because wild-type Abl is not a
vital enzyme, selective inhibition of all Abl activity is a
potential treatment modality for CML.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:
pseudotetrahedral
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
Faul. M et al. J. Org. Chem. 1998, 63, 6053
Piers. E et al. Org. Chem. 2000, 65,
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,
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 3 nM 0.3 nM 50 nM IC50’s against GSK-3a 10 nM 80 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 Alzheimer’s disease
potential for treating diabetes
There are several reasons why
GSK3 inhibitors might be beneficial for the treatment of
diabetes. First, insulin promotes the dephosphorylation
and activation of glycogen synthase by suppressing
GSK3 activity
Second, it has been reported
that the expression of GSK3 is elevated in diabetic
No cytotoxicity = kinectically inert ruthenium center is only an innocent bystander
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 , 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
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