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Medicinal Inorganic Chemistry
HO
H2N As As
As
OH
NH2
OH
NH2
HO
H2N
As As
As
HO
H2N
OH
NH2
As
As
HO
OH
NH2
NH2
Jaouen, G. Bioorganometallics, 2006, 1st Ed. pp. 1-32Orvig, C. Abrams, M.J. Chem. Rev. 1999, 99, 2201
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 medicineK[Au(CN)2] used for tuberculosis
Salvarsan for the treatment of syphilis
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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
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Thompson, K.H, Orvig, C.; Science, 2003, 300, 936
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medicinal inorganic chemistry
therapeutic agents (e.g. Li, Pt, Au, Bi)
radiopharmaceuticals diagnostic (e.g.99mTc) therapeutics (e.g. 186Re)
enzyme inhibitors
diagnostic agents MRI (e.g. Gd, Mn) x-ray (e.g. Ba, I)
essential elements mineral supplements (e.g. Cu, Zn, Se)
chelation
therapy
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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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
http://fr.wikipedia.orgCotton,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
Vitamin B12Heme
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Medicinal Inorganic chemistry: Chelation Therapy
Used for metal intoxication
1941: Citrate is used for acute lead intoxication
HO
OO-
O O-
O
-O
Since then, other chelating agents have come into clinical use:
DMSA
H2N NH
HN
NH2
TETAEDTA
COOHN
COOHNHOOC
HOOC HS
HS
OH
O
O
OH
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, 2219Wang et al. Bioconjugate Chem. 1996, 7, 56http://www.doemedicalsciences.org/Jaouen, G. Bioorganometallics, 2006, 1st Ed. pp. 1-32
OCH3
N N
O
TcOC
OC CO
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Medicinal Inorganic chemistry: Diagnostic Agents
Contrast agents:
- X-Ray:
I, Ba, BaSO4
Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512www.asrt.org/content/ThePublic/AboutRadiologicProcedures/ContrastAgents.aspxThompson, K.H, Orvig, C.; Science, 2003, 300, 936
MRI:
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Role of metals
Half life and energy of
isotopic decay
Behavior in magnetic field
Physical properties
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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medicinal inorganic chemistry
therapeutic agents (e.g. Li, Pt, Au, Bi)
radiopharmaceuticals diagnostic (e.g.99mTc) therapeutics (e.g. 186Re)
enzyme inhibitors
diagnostic agents MRI (e.g. Gd, Mn) x-ray (e.g. Ba, I)
essential elements mineral supplements (e.g. Cu, Zn, Se)
chelation
therapy
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
Metal is the structural scaffold
Pyridocarbazole ruthenium complexes
Bioactivity is related to reaction caused by the metal center
Tamoxifen
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Therapeutic Agents
Pharmaceutical industry usually dominated by organic drugs
Certain Inorganic drugs have proven their utility: Li, Bi
Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed. 1999, 38, 1512Fricker, S.P. Dalton Trans., 2007, 4903–4917 Alderden et al. Journal of Chemical Education 2006, 83
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 $
PtClH3N
H3N Cl
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Cisplatin
Classic synthesis in inorganic chemistry; pioneered by Dhara in 1970
Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed. 1999, 38, 1512Fricker, S.P Dalton Trans., 2007, 4903–4917 Alderden et al. J. of Chem. Educ. 2006, 83
K2 PtCl
Cl
Cl
ClK2 Pt
I
I
I
I
- 4 KClPt
NH3
I
I
NH3
K PtNH3
I
I
I
intermediate
- 2KI
2 NH3excess
KI
2 AgNO3
PtNH3
H2O
H2O
NH3(NO3)2
excessKCl
PtCl
Cl
H3N
NH3
Cisplatin- 2 KNO3
- AgI
PtNH3
Cl
Cl
NH3
Stereoselectivity
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Platinum is the reactive adduct for cisplatin (coordination chemistry)
Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed. 1999, 38, 1512Fricker, S.P. Dalton Trans., 2007, 4903–4917 Alderden et al. J. Chem. Educ. 2006, 83
PtClH3N
H3N Cl
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Cisplatin : Severe side effects (toxicity to kidneys and nervous system)
Resistance
PtOH3N
H3NO
O
O
Carboplatin
Widespread clinical use
Less toxic and fewer side effects
Bidentate ligand is more stable; slower reaction in the body
The Search Continues
NH2
NH2
Pt
O
O
O
O Oxaliplatin
Colon cancer N
PtNH3Cl
Cl
AMD473
Overcome resistance
Sterics govern activity
Alderden et al. J. Chem. Educ. 2006, 83
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Bioactivity is at the metal center
Cisplatin
Metal is the structural scaffold
Pyridocarbazole ruthenium complexes
Bioactivity is related to reaction caused by the metal center
Tamoxifen
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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
ON
ON
OH
[ox]
ON
Cl
ON
HO
ON
I
Toremifene Droloxifene Iodoxifene
S. Top et al. J. Organometal. Chem. 2001, 637, 500S. Top et al. Chem. Eur. J. 2003, 9, 5223
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Metal Based Approach
NH2
NH2
Pt
O
O
O
O
OH
O(CH2)2N(CH3)2
Jaouen and coworker:
Pt-N coordination bonds are too weak
- Hydrolyses too quickly
What other organometallic groups can be used?
NH2
NH2
Pt
O
O
O
O
Oxaliplatin
S. Top et al. J. Organometal. Chem. 2001, 637, 500
ON
OH
Hormonal vector
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Organometallic Approach: Metallocenes
S. Top et al. J. Organometal. Chem. 2001, 637, 500S. Top et al. Chem. Eur. J. 2003, 9, 5223
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
- Lipophilic
Fe
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FerroceneFenton reaction:
S. Top et al. J. Organometal. Chem. 2001, 637, 500Hillard et al. Angew. Chem. Int. Ed. 2006, 45, 285
genotoxic
FeFe
Fe2+
+ O2
Fe3+
+ O2
. -.
Fe
Fe2+
+ O2
. - 2H+
Fe
Fe3+
. + H2O2
Fe
Fe2+
+ H2O2
+
Fe
Fe3+
. + OH-+ OH
.
+
+
+
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ON
OH
Fe
Ferrocene
ON
OH
(Z)-4-Hydroxytamoxifen
Both effects coexist together: Anti-tumor and Anti-oestrogen propertiesS. Top et al. Chem. Comm. 1996, 955S. Top et al. J. Organometal. Chem. 1997, 541, 355
Jaouen and coworkers:
Fe
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Synthesis
McMurry coupling
S. Top et al. J. Organometal. Chem. 1997, 541, 355
Fe(EtCO)2O
(H3PO4)n80%
Fe O + O
R2
TiCl4/ZnTHF
66%
Fe
R1
1:R1 =OH,R2 =O(CH2)4Br
R1
2(Z+E) :R1 =OH, R2 =O(CH2)4Br
R2
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Synthesis
FeO
+ O
OMe
Ti(0) or Ti(II)
(Zn: reducing agent)
O
R1 R2
O
R4R3
O
R1R2
O
R4R3
O
R1R2
O
R4R3
O
R2R1
O
R4R3
O O+
Fe
OMe
FeOMe
+
Ti(0)
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Synthesis
Ferrocifens
S. Top et al. J. Organometal. Chem. 2001, 637, 500S. Top et al. Chem. Eur. J. 2003, 9, 5223
FeFe
OR
HH+H+
Fe
OR
OROH
OH
ZE
OH
Isomerization in protic solvents
HNMe2, HClEtOH, 80 C
autoclave
34%Fe
O
OH
N
3 (Z+E)
Fe
O
R2
Br
2 (Z+E)
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Ferrocifen
• 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
4-Hydroxytamoxifen
Fe
O
OH
N
3(Z+E)
OH
ON
(E+Z)
S. Top et al. J. Organometal. Chem. 2001, 637, 500S. 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
Fe
OH
Fe
OH
+
N
Fe
O
Fe
O
Fe
O
- e- -pyH+
- e-/- H+
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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
Fe
OH
O(CH2)nNMe2
O
OH
(Z)HO
O Fe OH
OH
(E+Z)
ReOC CO
CO
A. Nguyen et al. J. Organometal. Chem. 2007, 692, 1219
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Bioactivity is at the metal center
Cisplatin
Metal as a structural scaffold
Pyridocarbazole ruthenium complexes
Bioactivity is related to reaction caused by the metal center
Tamoxifen
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Structural DiversityNatural 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
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:
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
Protein Kinases
Blume-Jensen. P.; Hunter, T. Nature, 2002, 411, 355Fischer, P.M. Curr. Med. Chem. 2004, 11, 1583
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ATP Binding
N
N
NHN
N
H
H
Glu81
O
HN Leu83
N N
N O
O
O
NH
H
Glu81
O
HN Leu83
• 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
N
N
NN
N
H
H
Glu81
O
HN Leu83
Ribose-PPP
Fischer, P.M. Curr. Med. Chem. 2004, 11, 1583
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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
Omura, S. et al. J. Antibiotics, 1994, 48, 535M. Yang et al. Bioorg. Med. Chem. Lett. 2007, 17, 326
NN
N
H
O
O
OHMeO2C
EtSSEt
CEP-1347
N
N
H
O
OiPr
O
ON
CEP-7055
Derivatives with modulated specificities are in preclinical trials as anticancer drugs
N N
N O
H
O
O
NH
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Organometallic ChemistryMeggers and coworkers: coordinate a known bioligand (staurosporine) to an inert metal center
Bioligand Structural Specificity
M
C N
Y
NH
NHH
X
OCH2CH3
Inorganic compounds as structural scaffolds for the design of specific enzyme inhibitors
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A Metal for StructureMetals 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
MC B
D A
ME B
D C
A
ME B
D C
A
F
MB
C
A
D
E MG B
E C
A
D
F
Octahedral with 6 different substituents can form 30 different stereoisomers
C
CC
XC
D
A
BC
Meggers, E. Curr. Opin. Chem. Biol. 2007, 11, 287
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37
Ru(II)
Fricker, S.P. Dalton Trans., 2007, 4903–4917Taube, H. Chem. Rev. 1952, 50, 69
• hexavalent coordination sphere that cannot be easily obtained by any organic element
• kinetically inert coordinative bonds
• stabilities that are comparable to purely organic molecules
RuN
N
N
N
2+ NN
2ClO4-
not attacked by boiling conc. HCl or concentrated alkalis
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Meggers et al.
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, 521Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521Bregman, H, Caroll, P.J. Meggers, E. J. Am. Chem. Soc. 2006, 128, 877
Defined globular shape
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39
Synthetic Approach: 1.1 Ligand design
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521
NN
N
H
O
NN
NN
XN
H
L1
L2L3
L4
NH
NH
N
H
O
NH
O O
O
NN
NN
XN
H
O
(X=CO),(X=CH2)
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Synthesis
NN
NH
NH
NN
NN
N
TBDMS
O
1) NaH, DMF
2)
N
TBDMS
OO
Br Br
O
33 %
TBAF, DCM
71 %
NN
NN
N
H
OO
NN
NH
NH
NN
NN
N
Bn
O
1) NaH, DMF
2)
N
Bn
OO
Br Br
O
35 %
NaBH4, ETOH
90 %NN
NN
N
Bn
OHO
1) Reflux in Ac2O2) Zn, Reflux
89 %
NN
NN
N
Bn
O
TFA, H2SO4,Anisole, reflux
76 %
NN
NN
N
H
O
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521Woodward, R.B. Sondheimer, F. Taub, D. HEusler, K. McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223-4251.
4
5
6
7
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41
Attempts at Coordination
Crystal structure obtained
Proof that 4 can serve as a bidentate ligand
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521
Cis(Cl)trans(DMSO)
NN
NN
N
Bn
OO
+ cis-RuCl2(DMSO)4
Toluene, reflux
NN
NN
N
Bn
OO
Ru
Cl
SS OOCl
4
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42
NN
NN
NTBDMS
OO
TBAF, DCM
NN
NN
NH
OO
RuCl
ClS
S
O
O
Ru(COD)(CH3CN)2Cl2 NN
NN
NTBDMS
OO
Ru ClCl
NN
NN
HN O Ethanol, reflux
Ru(bpy)2(EtOH)22+
NN
NN
NH
OO
Ru ClCl
NN
NN
NH
O
Ru
N
N
N
N
2+
cis-RuCl2(DMSO)4
New Compounds
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521
1
2
3
5
6
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43
Stability
• 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
1 2 3
NN
NN
NH
O
Ru
N
N
N
N
2+NN
NN
NH
OO
Ru ClCl
NN
NN
NH
OO
RuCl
ClS
S
O
O
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44
compound Ab1 RSK1 Src PKCα ZAP70staurosporine 2 <1 <1 <1 <1
7 25 30 >100 >100 >1006 20 25 60 >100 501 10 8 30 >100 402 2 8 40 >100 303 5 8 30 50 40
Analysis of IC50 values
POTENCY and SPECIFICITY
Inhibition of some protein kinases with the various compounds (in μM)
NN
N
H
O
O
NH
O
NN
NN
N
H
OO
7 NN
NN
N
H
O
6
NN
NN
N
Bn
OO
RuCl
ClS
S
O
O
1
NN
NN
N
H
OO
RuClCl
2
NN
NN
N
H
O
Ru
N
N
N
N
2+
HH
3
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521
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45
Analysis
• The activity of compound 2 requires the entire assembly
NN
NN
N
H
OO
NN
NN
N
Bn
OO
RuClCl
• Potency is strongly reduced by 25
NN
NN
N
H
OO
RuClCl
Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521
Ru(COD)(CH3CN)2Cl2
2
Abl: chronic myeloid leukemia
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46
The team looked to different cores and a new compound was found:
New Core Structures
NN
NN
N
H
OO
NNH
N
H
OO
NN
N
H
OO
Ru
CO
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
Meggers, E. J. Am. Chem. Soc. 2004, 126, 13594
2 Synthetic approaches were used
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47
N
t-BuOK (3 equiv),DMF, 4 A M.S
50 %
SEM
O
O
O
NH
1) (COCl)2,Et2O
2) NaOMe,- 60oC
NH
O
O
O
93 %
1) NaH, THF
2) Me3Si(CH2)2OCH2Cl
82 %
N
O
H2N
+
hv, MeCN, Mg LampAir, I2 cat.
63 %
N
SEM
HN OO
NN
SEM
HN OO
N
N
SEM
HN
O
O
NO
HH
N
SEM
HN OHO
N
O
N
SEM
HN OO
N
HO H
p.t.
N
SEM
HN OO
N
t-BuOK
Faul. M et al. J. Org. Chem. 1998, 63, 6053Piers. E et al. Org. Chem. 2000, 65, 530-535Berlinck, R. G. S.; Britton, R.; Piers, E.; Lim, L.; Roberge, M.; Moreira da Roche, R.; Andersen, R. J. J. Org. Chem. 1998, 63, 9850Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521
1
Approach 1: Synthesis of pyridocarbazoles
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48
Photocyclization: electrocyclic reaction
Faul. M et al. J. Org. Chem. 1998, 63, 6053Piers. E et al. Org. Chem. 2000, 65, 530-535Berlinck, 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
N
HN OO
N
hvMeCN
heat
N
HN OO
N N
HN OO
NSEM
Air,I2 cat.
SEMSEM
HH
hv
hv
hv
heat
H
H
Pd/C cat.MeCN
N
N
NN
N
N
N
N
hv
SOMO
6 conrotatory
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Approach 1: Synthesis of pyridocarbazoles
Kita, Y.; Haruta, J.; Fujii, T.; Segwawa, J. Synthesis 1981, 451Bregman, H. Williams, G. S. Meggers, E. Synthesis, 2005, 9, 1521
LiBF4, MeCN-H2Oreflux
100 %NH
HN OO
NNH
N OO
N
TBDMS
MeCN, reflux
93 %N
SEM
HN OO
N
OOSi
tertbutyldimethylsilyloxymethoxyethene
No base is required, volatile side product
OOSi HN
O
O
N
O
OR
R
R
R
N
O
O
R
R
Si O
O+
OOSi
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Approach 2: Synthesis of Pyridocarbazoles
N
H
N
NHH2N
+
O
N
AcOH
HNN
NH
HNNH
NH
NH
N
NHH
NH2
N
NHH
HN
N NH
H
- H+
-NH3
Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521Thummel, R. P.; Hegde, V. J. Org. Chem. 1989, 54, 1720Caixach, J.; Capell, R.; Galvez, C.; Gonzalez, A.; Roca, N. J. Heterocycl. Chem. 1979, 16, 1631
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NH
N OO
N
TBS
Br
hvMeCN
heatNH
N OO
N
TBS
HBr
- HBr
NH
N OO
N
TBS
Approach 2: Synthesis of Pyridocarbazoles
NO O
BrBr
TBS
1) LiHMDS, THF-15oC
2) THF, -15oC to r.tNH
N OO
N
TBS
Br
68 %
NH
N OO
N
TBS
hv, pyrex filterMeCN
64 %N
H
N
Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521
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52
N
1)DIPEADMF,2) TBSOTf
71 %
NO O
BrBr
TBS
NH
N OO
N
TBS
Br
NH
N OO
N
TBS
O
+
O
HNNH2HCl
t-BuOHreflux
100%
O
NH
NN N
HN
HO
1)TMSpolyphosphate120oC63 %
2)BBr3, DCM87 %
NH
N
TBSO TBSO1)LiHMDS,THF,
2) THF,
TBSOhv, pyrex filterMeCN
78 %
58 %
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
NH
N OO
N
TBS1) [Ru(Cp)(CO)(MeCN)2]
+PF6-
K2CO3 (1 Eq)
2) TBAF, DCM NN
N
H
OO
Ru
CO
NH
N OO
N
TBS
Ru
CO
N
N
N OO
N
TBS
Ru
CO
H
K2CO3
-H+ N
N OO
N
TBS
Ru
CO
TBAF
Complex is pseudotetrahedral and possesses metal centered chirality
Stereoselectivity
Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521
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Potency
NN
N
H
OO
Ru
CO
NN
N
H
OO
Ru
CO
NN
N
H
OO
Ru
CO
HO
NN
N
H
OO
Ru
CO
HO
IC50’s against GSK-3a
10 nM 0.3 nM 80 nM
N N
N O
H
O
O
NH
50 nM
Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521
3 nM
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Glycogen Synthase Kinase 3 ( GSK-3)
NN
N
H
OO
Ru
CO
HO
IC50 of 0.3 nM
• GSK-3 plays a role in insulin signal transduction• potential importance for Alzheimer’s disease• potential for treating diabetes
N
NHNHN
N
HN
N
N
Cl
Cl
CHIR 99201
IC50 of 40 nM;
Bregman, H. Williams, G. S. Meggers, E.; Synthesis, 2005, 9, 1521 Cohen, P.; Goedert, M. Nat. Rev. Drug Discov. 2004, 3, 479
potent and selective
• compares to best published organic GSK-3 inhibitors
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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
NN
NTBS
OO
RuCl
UV-lightCH3CN
60 %NN
NTBS
OO
Ru NN
N Cl
TBAFCH3CN
90 %NN
NH
OO
Ru NN
N ClNH
N OO
N
TBS
[Ru(C6H6)Cl2]2CH3CN, K2CO3
69 %
Bregman, H.; Carroll, P.J.; Meggers, E. J. Am. Chem. Soc. 2006, 128, 879
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Bregman, H.; Carroll, P.J.; Meggers, E. J. Am. Chem. Soc. 2006, 128, 879
Rapid scanning of ligands: Searching for 3-D structures
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58
To the Future
Bregman, H.; Meggers, E. Org. Lett. 2006, 8, 5466
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59
Conclusion
• 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!!!)
THINK
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60
Acknowledgements
Prof. Keith FagnouMarc LafranceMegan ApSimonCatherine LebelMégan Bertrand-LaperleElisia VillemureNicole BlaquiereHo-Yan SunSophie RousseauxDaniel ShoreDerek SchipperDavid StuartDoris LeeDavid LapointeDaniel BlackBenoît LiegaultChris WhippMalcolm Huestis