Transcript Cisplatin - University of Ottawa

1
Medicinal Inorganic Chemistry
3000 BC : Egyptians used Cu to sterilize water
2500 BC : Chinese empire uses Au in a variety of medicine
400 BC : Hippocrates used Hg
1600s : Paracelsus pioneered the use of minerals in medicine using Sb, As, Mg salt
Early 1900s : Metals started making an impact on modern medicine
K[Au(CN)2] used for tuberculosis
Salvarsan for the treatment of syphilis
HO
NH 2
OH
NH 2
H 2N
HO
As
As
OH
As
As
NH 2
As As
H2 N
H 2N
NH2
HO
HO
OH
Jaouen, G. Bioorganometallics, 2006, 1st Ed. pp. 1-32
Orvig, C. Abrams, M.J. Chem. Rev. 1999, 99, 2201
As As
NH 2
OH
2
Outline
1. Traditional applications of inorganic compounds:
- Chelation
- Imaging properties
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
3
4
Thompson, K.H, Orvig, C.; Science, 2003, 300, 936
essential elements
mineral supplements
(e.g. Cu, Zn, Se)
chelation
therapy
diagnostic agents
MRI (e.g. Gd, Mn)
x-ray (e.g. Ba, I)
medicinal inorganic chemistry
therapeutic agents
(e.g. Li, Pt, Au, Bi)
Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512
Orvig, C. Abrams, M.J. Chemical Reviews, 1999, 99, 2201
enzyme
inhibitors
radiopharmaceuticals
diagnostic (e.g.99mTc)
therapeutics (e.g. 186Re)
5
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, 3 rd Ed. (1995), pp. 729-753
http://www.daviddarling.info/encyclopedia/V/vitamin_B12.html
6
Medicinal Inorganic chemistry:
Chelation Therapy
O
Used for metal intoxication
O-
HO
O-
-
O
1941: Citrate is used for acute lead intoxication
O
O
Since then, other chelating agents have come into clinical use:
O
COOH
HOOC
HS
N
N
OH
COOH
HOOC
OH
HS
O
EDTA
H2N
N
H
H
N
NH2
TETA
DMSA
7
Andersen, O. Chem. Rev. 1999, 99, 2683
Medicinal Inorganic chemistry:
Radiopharmaceuticals
O
OCH 3
N
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
N
Tc
OC
OC CO
8
Medicinal Inorganic chemistry:
Diagnostic Agents
Contrast agents:
MRI:
- X-Ray:
I, Ba, BaSO4
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
9
Behavior in
magnetic field
Physical
properties
Role of metals
Coordination
Half life and
energy of
isotopic decay
10
Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512
Orvig, C. Abrams, M.J. Chem. Rev. 1999, 99, 2201
essential elements
mineral supplements
(e.g. Cu, Zn, Se)
chelation
therapy
diagnostic agents
MRI (e.g. Gd, Mn)
x-ray (e.g. Ba, I)
medicinal inorganic chemistry
therapeutic agents
(e.g. Li, Pt, Au, Bi)
Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512
Orvig, C. Abrams, M.J. Chemical Reviews, 1999, 99, 2201
enzyme
inhibitors
radiopharmaceuticals
diagnostic (e.g.99mTc)
therapeutics (e.g. 186Re)
11

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
12
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
H 3N
H3 N
Cl
Pt
Cl
•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 Education 2006, 83
13
Cisplatin
 Classic synthesis in inorganic chemistry; pioneered by Dhara in 1970
K2
Cl
excess
KI
Cl
- 4 KCl
Cl
Cl
Pt
K2
I
I
2 NH3
I
Pt
I
Pt
I
I
- 2KI
K
I
Pt
I
NH3
NH3
I
NH3
2 AgNO3
intermediate
- AgI
Stereoselectivity
Cl
Cl
H3N
Pt
NH3
Cl
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
Cl
Pt
NH3
excess
KCl
NH3
Cisplatin
- 2 KNO 3
H2O
H2O
Pt
NH3
NH3
(NO 3)2
14
H 3N
Cl
Pt
H3 N
Cl
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
15
The Search Continues
Cisplatin :
Severe side effects (toxicity to kidneys and nervous system)
Resistance
Carboplatin
O
Widespread clinical use
O
H 3N
Pt
Less toxic and fewer side effects
O
H3 N
O
Bidentate ligand is more stable; slower reaction in the body
O
O
O
NH 2 Pt
O
Oxaliplatin
Cl
Colon cancer
Cl
NH 2
NH 3
Pt
N
AMD473
Overcome resistance
Sterics govern activity
16
Alderden et al. J. Chem. Educ. 2006, 83

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
17
Tamoxifen
• Selective estrogen receptor modulator (SERM)
• The estrogen receptor plays a key role in the proliferation of hormonedependent tumours
OH
[ox]
N
N
O
O
• Successful drugs but only active against ER+ tumors (60 %) and has
developed resistance
I
HO
Cl
N
O
Toremifene
S. Top et al. J. Organometal. Chem. 2001, 637, 500
S. Top et al. Chem. Eur. J. 2003, 9, 5223
N
N
O
Droloxifene
O
Iodoxifene
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Metal Based Approach
Jaouen and coworker:
OH
OH
O
O
N
O
O
NH 2 Pt
O
O
NH 2
O(CH2 )2 N(CH3 )2
Hormonal vector
O
O
NH 2 Pt
Oxaliplatin
O
NH 2
Pt-N coordination bonds are too weak
- Hydrolyses too quickly
What other organometallic groups can be used?
19
S. Top et al. J. Organometal. Chem. 2001, 637, 500
Organometallic Approach:
Metallocenes
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
Fe
- 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:
+
Fe
+
O2
Fe
Fe2+
.
+
O2
.-
Fe3+
+
Fe
+
O2
.- +
2H
+
Fe
Fe2+
.
+
H2O2
Fe3+
+
Fe
+
Fe .
H2O2
Fe2+
+
OH
-
+ OH
.
Fe3+
 genotoxic
S. Top et al. J. Organometal. Chem. 2001, 637, 500
Hillard et al. Angew. Chem. Int. Ed. 2006, 45, 285
21
Ferrocene
Jaouen and coworkers:
OH
OH
Fe
Fe
N
N
O
O
(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
22
Synthesis
R1
R1
Fe
(EtCO)2O
(H3PO4)n
80 %
Fe
O
+
TiCl4/Zn
THF
O
66 %
Fe
R2
1:
R1 = OH, R 2 = O(CH2) 4Br
R2
2 (Z+E) :
R1 = OH, R2 = O(CH2)4Br
McMurry coupling
23
S. Top et al. J. Organometal. Chem. 1997, 541, 355
Synthesis
24
Synthesis
O
O
Br
N
HNMe2, HCl
EtOH, 80 C
autoclave
Fe
R2
Fe
34 %
3 (Z+E )
2 (Z+E )
Isomerization in
protic solvents
OR
OR
H+
Fe
Ferrocifens
OH
OH
E
S. Top et al. J. Organometal. Chem. 2001, 637, 500
S. Top et al. Chem. Eur. J. 2003, 9, 5223
OH
H+
H
Fe
OH
Fe
OR
Z
25
Ferrocifen
O
O
N
Fe
OH
( E+Z )
3 ( Z+E )
N
OH
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
26
S. Top et al. J. Organometal. Chem. 2001, 637, 500
S. Top et al. Chem. Eur. J. 2003, 9, 5223
Quinone Methide
N
O
OH
OH
-pyH+
- e-
Fe
Fe +
Fe
O
O
- e-/- H+
Fe
Fe
27
Hillard et al. Angew. Chem. Int. Ed. 2006, 45, 285
Continuation of the Ferrocifen Series
OH
• Activity is twofold :
•
basic chain : primary antagonist effect
•
ferrocene : [ox]/[red] genotoxic aspect
• carbon chain length is important
Fe
O(CH2)nNMe2
OH
OH
HO
(Z )
O
O
Fe
OC
Re
CO
CO
OH
(E+Z )
A. Nguyen et al. J. Organometal. Chem. 2007, 692, 1219
28

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
29
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
30
Bregman, H.; Caroll, P.J.; Meggers, E. J. Am. Chem. Soc. 2006, 128, 877
Outline
1. Target : Kinase; ATP binding site
2. Known inhibitor: Staurosporine
3. Metal scaffold
4. Synthetic approaches and development
5. Diversity oriented synthesis
31
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
32
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
NH
O
O
Ribose-PPP
NN
HH
N
N
NNH
NN
NN
HH
N
NN
O
H
HH
OO
Glu81
Glu81
H
NN Leu83
Leu83
N Leu83
O
Glu81
33
Fischer, P.M. Curr. Med. Chem. 2004, 11, 1583
Bioorganometallic Chemistry:
Staurosporine
H
N
N
O
N
O
•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
O
NH
H
H
Derivatives with
modulated specificities
are in preclinical trials
as anticancer drugs
N
N
O
O
SEt
EtS
OiPr
N
O
N
N
O
O
N
MeO2 C
OH
CEP-1347
CEP-7055
34
Omura, S. et al. J. Antibiotics, 1994, 48, 535
M. Yang et al. Bioorg. Med. Chem. Lett. 2007, 17, 326
Organometallic Chemistry
Meggers and coworkers: coordinate a known bioligand (staurosporine) to
an inert metal center
H
Y
NH
OCH2CH3
M
X
C N
NH
Bioligand
Structural
Specificity
Inorganic compounds as
structural scaffolds for the design
of specific enzyme inhibitors
35
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
A
A
E
C
C
C
D
D
B
C
C
X
A
M
C
D
M
B
C
E
M
B
D
C
F
B
A
A
E
M
A
B
C
D
F
G
M
B
E
C
D
Octahedral with 6 different substituents can form 30 different stereoisomers
Meggers, E. Curr. Opin. Chem. Biol. 2007, 11, 287
36
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
N
N 2+
N
Ru
N
N
N
Fricker, S.P. Dalton Trans., 2007, 4903–4917
Taube, H. Chem. Rev. 1952, 50, 69
2ClO4-
not attacked by boiling
conc. HCl or concentrated
alkalis
37
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
38
Synthetic Approach: 1.1 Ligand design
H
H
N
O
X
N
N
N
N
N
N
N
O
O
L1
L4
L3
O
L2
NH
H
H
N
O
X
N
N
H
N
H
N
N
O
N
N
(X=CO),
(X= CH2)
39
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521
Synthesis
TBDMS
N
O
O
N
N
1) NaH, DMF
N
N
N
H
N
H
2)
TBDMS
N
N
O
N
O
N
TBAF, DCM
N
N
71 %
N
7
Br
33 %
Bn
N
N
1) NaH, DMF
N
H
N
H
2)
Bn
N
O
Bn
N
O
O
N
O
5
O
Br
H
O
N
HO
O
NaBH 4, ETOH
N
N
N
N
90 %
N
N
N
N
4
Br
1) Reflux in Ac2 O
2) Zn, Reflux
Br
35 %
89 %
Bn
H
N
N
O
O
N
N
TFA, H 2 SO 4,
Anisole, reflux
N
N
N
N
76 %
N
N
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.
40
Attempts at Coordination
Bn
Bn
N
O
O
N
O
O
Toluene, reflux
N
N
N
N
+
N
ci s-RuCl2 (DMSO) 4
N
4
O
S
N
Ru
Cl
N
S
O
Cl
Cis(Cl)trans(DMSO)
Crystal structure obtained
Proof that 4 can serve as a bidentate
ligand
41
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521
New Compounds
H
N
O
N
cis-RuCl2(DMSO)4
N
N
O
O
Ru
S
S
N
Cl
Cl
1
O
TBDMS
N
O
O
N
N
N
N
TBDMS
N O
O
N
Ru(COD)(CH3CN)2Cl2
N
Cl
5
N
O
N
TBAF, DCM
N
Ru
H
N
N
Cl
Cl
O
N
Ru
N
Cl
2
H
N
O
N
N
N
N
H
N
Ethanol, reflux
Ru(bpy)2(EtOH)22+
6
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521
N
O
N
N 2+ N
Ru
N
N
N
N
3
42
Stability
H
N
O
N
N
O
S
O
N
Ru
N
Cl
Cl
S
H
N
H
N
O
O
N
N
N
N
Cl
Ru
N
N
Cl
O
N
2+ N
N Ru
N
N
N
O
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
43
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521
Analysis of IC50 values
Inhibition of some protein kinases with the various compounds (in μM)
compound
Ab1
RSK1
Src
PKCα
ZAP70
staurosporine
7
6
1
2
3
2
25
20
10
2
5
<1
30
25
8
8
8
<1
>100
60
30
40
30
<1
>100
>100
>100
>100
50
<1
>100
50
40
30
40
H
POTENCY and SPECIFICITY
H
N
H
O
Bn
N
O
O
N
O
H
O
N
N
O
N
N
H
N
N
N
O
O
NH
7
N
N
N
N
6
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521
O
N
N
O
N
N
O
N
Ru
S
S
O
N
N
N
N
O
N
N 2+
Ru
N
N
N
Cl
Cl
N
H
H
N
Cl
1
Ru
N
N
Cl
3
44
2
Analysis
Abl: chronic myeloid leukemia
H
H
N
O
N
N
N
O
O
O
N
N
Ru(COD)(CH3CN)2Cl2
N
• The activity of compound 2 requires
the entire assembly
N
Cl
N
N
Ru
Cl
2
Bn
• Potency is strongly reduced by 25
N
O
N
N
Cl
O
N
Ru
N
Cl
45
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521
New Core Structures
The team looked to different cores and a new compound was found:
H
H
H
N
O
N
O
N
O
O
N
O
N
N
N
O
N
N
H
N
N
Ru
O
C
Was identified from a screen of different Ru complexes against a panel of
protein kinases
2 Synthetic approaches were used
• IC50 is 3 nM for GSK-3a and 10 nM for GSK-3B
• high degree of selectivity
46
Meggers, E. J. Am. Chem. Soc. 2004, 126, 13594
Approach 1: Synthesis of
pyridocarbazoles
O
O
O
1) (COCl)2 ,
Et2 O
N
H
O
2) NaOMe,
- 60oC
H
O
H
N
O
HN
O
N
OH
p.t.
N
SEM
N
O
H
N
O
50 %
H
N
O
t-BuOK
O
H
N
SEM
O
H
N
HO
N
N
N
SEM
O
O
H
t-BuOK (3 equiv),
DMF, 4 A M.S
+
82 %
O
O
O
1) NaH, THF
2) Me 3Si(CH2 )2 OCH2 Cl
N
H
93 %
1
O
H 2N
N
N
SEM
SEM
hv, MeCN, Mg Lamp
Air, I2 cat.
N
H
N
O
O
63 %
N
N
SEM
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
N
N
SEM
47
Photocyclization: electrocyclic
reaction
N
H
hv
N
N
Pd/C cat.
MeCN
hv
N
hv
N
N
heat
H
N
N
SOMO
6
conrotatory
hv
O
H
N
O
hv
MeCN
H
N
O
SEM
N
Air,
I2 cat.
H
N
O
O
H H
heat
N
O
N
SEM
N
N
N
SEM
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
48
Approach 1: Synthesis of
pyridocarbazoles
H
N
O
O
H
N
O
TBDMS
O
N
93 %
N
H
SEM
O
MeCN, reflux
100 %
N
N
O
LiBF4 , MeCN-H 2O
reflux
N
Si
O
N
H
O
N
tertbutyldimethylsilyloxymethoxyethene
R
O
Si
O
O
R
O
HN
N
R
O
Si
O
N
O
R
O
O
R
Si
O
O
+
O
R
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
49
Approach 2: Synthesis of
Pyridocarbazoles
H2 N
O
NH
AcOH
+
N
N
N
H
-NH 3
H
N
H
N
HN
HN
NH
N
H
H
N
H
N
NH
H
N
H N
N
H
N
HN
NH 2
- H+
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
50
Approach 2: Synthesis of
Pyridocarbazoles
TBS
O
1) LiHMDS, THF
-15 oC
N
TBS
O
Br
N
H
2) THF,
N
-15 oC
to r.t
N
H
TBS
O
Br
N
O
N
N
H
hv, pyrex filter
MeCN
64 %
N
H
N
N
Br
TBS
O
Br
O
68 %
TBS
O
N
O
O
N
hv
MeCN
heat
N
TBS
O
Br
H
N
H
N
N
O
O
- HBr
N
H
N
51
Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521
Library of Analogues
1)TMSpolyphosphate
120oC
HO
63 %
O
+
N
O
t-BuOH
reflux
N
H
100%
O
N
N
2)BBr3 , DCM
87 %
HN
N
H
N
HCl NH2
TBS
1)DIPEA
DMF,
2) TBSOTf
O
1)LiHMDS,
THF,
TBSO
71 %
N
H
N
Br
2) THF, TBS
N
O
58 %
Br
N
O
TBSO
O
N
H
N
Br
TBS
N
O
hv, pyrex filter
MeCN
O
TBSO
78 %
N
H
N
Analogs with enhanced features
were used to test the affinity of
the pocket
52
Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521
Cyclometallation
O
N
O
TBS
N
H
O
O
1) [Ru(Cp)(CO)(MeCN)2 ]+PF6 K 2CO3 (1 Eq)
2) TBAF, DCM
N
N
Ru
N
H
N
O
C
Stereoselectivity
TBAF
TBS
N
O
TBS
O
N
O
TBS
O
N
O
O
K 2CO3
N
H
N
N
N
O
-H+
N
Ru
Ru
C
N
H
O
N
Ru
C
O
C
Complex is pseudotetrahedral and possesses metal centered chirality
Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521
53
Potency
IC50’s against GSK-3a
H
N
O
O
N
O
H
H
H
N
O
O
N
N
Ru
O
O
3 nM
N
N
N
N
C
O
C
O
0.3 nM
10 nM
N
Ru
Ru
Ru
C
O
HO
HO
N
N
O
O
C
80 nM
H
N
N
O
N
O
50 nM
O
NH
Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521
54
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
H
N
N
O
Cl
O
Cl
N
HO
N
HN
N
Ru
O
C
IC50 of 0.3 nM
N
H
N
N
N
HN
CHIR 99201
IC50 of 40 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
55
Diversity Oriented Synthesis
What about other targets?
Exploring small-molecule chemical space:
•
common precursor : less synthetic effort and more extended structural
options
TBS
N
O
O
TBS
N
O
O
[Ru(C6H6)Cl2]2
CH3CN, K2CO 3
N
69 %
N
Ru
60 %
Cl
O
H
N
O
TBAF
CH3CN
UV-light
CH3CN
N
N
H
O
TBS
N
O
N
N
N Ru N
N Cl
90 %
N
N
N Ru N
N Cl
•Purified by flash chromatography
•Four leaving groups
56
Bregman, H.; Carroll, P.J.; Meggers, E. J. Am. Chem. Soc. 2006, 128, 879
Rapid
scanning of
ligands:
Searching for
3-D structures
57
Bregman, H.; Carroll, P.J.; Meggers, E. J. Am. Chem. Soc. 2006, 128, 879
To the Future
Bregman, H.; Meggers, E. Org. Lett. 2006, 8, 5466
58
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!!!)
59
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
60