better science through synthesis: new medicinal … · of 11-desmethyl laulimalide, a highly potent...
TRANSCRIPT
WENDER GROUP - STANFORD UNIVERSITY
ISCHIA SEPTEMBER 2006 ROCHE LECTURE
BETTER SCIENCE THROUGH SYNTHESIS:
NEW MEDICINAL LEADS BASED ON PHARMACOPHORE TARGETING OFNEW REACTIONS AND ON NOVEL DRUG DELIVERY SYSTEMS
Dept. of Chemistry(H&S); Dept of Molecular Pharmacology(Medical School); Molecular & Genetic Medicine;
Cancer Biology; Clinical Oncology Quantitative ChemicalBiology; Neurobiology; Epithelial Biology; Imaging Institute
SOME RELEVANT LEAD REFERENCESPaul Wender, Nicole Deschamps, Robert Sun "Rh(I )-Catalyzed C-C Bond Activation: Seven-Membered Ring Synthesis bya [6+1] Carbonylative Ring Expansion Reaction of Allenylcyclobutanes " Angewandte Chemie Int. Ed. , 2006, 45(24), 3957.Wender, Croatt, Witulski, “New Reactions and Step Economy: The Total Synthesis of (±)-Salsolene Oxide Based on the TypeI I Transition Metal-Catalyzed Intramolecular [4+4] Cycloaddition” Tetrahedron 2006, 62, 7505-7511.Paul A. Wender,* Michael K. Hilinski, Nicolas Soldermann, Susan Mooberry “Total Synthesis and Biological Evaluationof 11-Desmethyl Laulimalide, a Highly Potent Simplified Laulimalide Analog” Organic Lett. 2006, 1507.Susan L. Mooberry, Deborah A. Randall-Hlubek, Rachel M. Leal, Sayee G. Hegde, Robert D. Hubbard, Lei Zhang and PaulA. Wender “Structure-Function Studies on a New Class of Microtubule Stabilizing Agents Based on Laulimalide” Proc.Natl. Acad. Sci. USA 2004, 101, 8803-8808.Erin A. Clark, Bradley S. Davidson, Paul A. Wender, Susan L. Mooberry “Laulimalide and Synthetic Laulimalide Analogsare Synergistic with Paclitaxel and 2-Methoxyestradiol” Molecular Pharmaceutics 2006, 457-467.Paul Wender, Mitchell P. Croatt, Nicole M. Deschamps "Metal-Catalyzed [2+2+1] Cycloadditions of 1,3-Dienes, Allenes, andCO" Angewandte Chemie Int. Ed. , 2006, 45(15), 2459-2462.Lisa Jones, Elena Goun, Rajesh Shinde, Jonathan Rothbard, C. Contag, P.Wender* “Releasable Luciferin-TransporterConjugates: Tools for the Real Time Analysis of Cellular Uptake and Release” J . Am. Chem. Soc. 2006, 128(20), 6526-6527.Elena Goun, Rajesh Shinde, Karen Dehnert, Angie Adams-Bond, Paul Wender, Chris H. Contag, Benjamin L. Franc“Intracellular Cargo Delivery by an Octaarginine Transporter Adapted to Target Prostrate Cancer Cells Though CellSurface Protease Activation” Bioconjugate Chem. 2006, 17(3), 787-796.Wender, Paul A.; Gamber, Gabriel G.; Williams, Travis J.; Rhodium(I )-Catalyzed [5+2], [5+2], and [5+2+1] Cycl;oadditions:New Reactions for Organic Synthesis in “Modern Rhodium-Catalyzed Organic Reactions” P. Andrew Evans Ed. Wiley-VCHVerlag Gmbh & Co. KgaA, Weinheim pp 263-299, 2005.Wender, P. A.; Gamber, G. G.; Hubbard, R. D.; Pham, S. M.; Zhang, L.; “Multicomponent Cycloadditions: The Four-Component [5+1+2+1] Cycloaddition of Vinylcyclopropanes, Alkynes, and CO” J . Am. Chem. Soc. 2005, 2836-2837.Jonathan B. Rothbard Theodore C. Jessop, Richard S. Lewis, Bryce A. Murray, Paul A. Wender “The Role of MembranePotential and Hydrogen Bonding in the Mechanism of Translocation of Guanidinium-Rich Peptides into Cells” J . Am.Chem. Soc. 2004, 9506-9507.Wender, Paul A.; Baryza, Jeremy L.; Brenner, Stacey E.; Clarke, Michael O.; Craske, Madeleine L.; Horan, Joshua C.; Meyer,Tobias “Function Oriented Synthesis: The Design, Synthesis, PKC Binding and Translocation Activity of a New BryostatinAnalogue” Current Drug Discovery Technologies 2004, 1, 1-11.Samuel, Hearn, Mack, Wender, Rothbard, Kirisits, Mui, Wernimont, Roberts, Muench, Rice, Prigge, Law, McLeod“Delivery of Antimicrobials into Parasites” Proc. Natl. Acad. Sci. USA , 2003, 100, 14281-14286.Paul A. Wender, Dennis J. Mitchell, Kanaka Pattabiraman, Erin Pelkey, Lawrence Steinman, Jonathan B. Rothbard"Molecular Transporters: The Design, Synthesis, and Evaluation of Molecules that Enable or Enhance Cellular Uptake"Proc. Natl. Acad. Sci. USA , 2000, 97, 13003-13008.Jonathan B. Rothbard, Sarah Garlington, Qun Lin, Thorsten Kirschberg, Erik Kreider, P. Leo McGrane, Paul A. Wenderand Paul A. Khavari, Conjugation of Arginine Oligomers to Cyclosporin A Facilitates Topical Delivery and Inhibition ofInflammation, Nature Medicine 2000, 6, 1253-1257.
OUTPUTNEW REACTIONS,
CATALYSTS, STRATEGIES
AS INSPIRATION FOR NEW REACTIONS, CATALYSTS, STRATEGIES
NEW THERAPEUTIC LEADSNEW MODES OF ACTION
NEW DRUG DELIVERY SYSTEMS
AS INSPIRATION FOR NEW THERAPEUTIC LEADS, MODES OF ACTION, MATERIALS
OUR RESEARCH FOCUSES ON…*NOVEL STRUCTURES…
INPUT
HO
RCO2 O2CR
H
OH
H
OOH
C
AB
D
PHORBOLO
HO OBz
OAcO OH
O
OAc
HPh
O
OH
NH
O
Ph CB
A D
TAXOL
O O
OOH
RO
E
E
ORH OH
H
OH
O
O
H
H
HO
B
C
A
BRYOSTATIN
H2N
HN
NH
HN
NH
HN
NH
HN
NH
X
O
O
O
O
O
O
O
O
O
HN
NH3
NH2
HN H2N O
H2N NH2
HN
H3N NH2
NH
H3N NH2
HN
H3N NH2
H3N NH2
NH
H3N NH2
HIV TAT 9-MER
O
O
HO
O
OMe
O
O
O
OO
O
MeO
HO
HO
HO
OMe
OH
OH
OH
OMe
HO
APOPTOLIDIN
O
H
O
O
OHO
O
O
OHMeO
B
A
C
RTX
*UNIQUE AND POTENT ACTIVITY, FUNCTION…
*INTEGRATION OF CHEM, BIO, MED
FUNCTION ORIENTED SYNTHESIS
Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Craske, M.L.; Horan, J.C.; Meyer, T. “ Function Oriented Synthesis:…” Current Drug Discovery Technologies, 2004, 1, 1-11.
•MEDICINAL AGENTS•MATERIALS•CATALYSTS•PROBES
•OVER 200 TOTAL SYNTHESES / YEAR IN ACS JOURNALS ALONE•MAKING MOLECULES IS NO LONGER THE BIGGEST CHALLENGEIN SYNTHESIS•THE MAJOR CHALLENGES NOW ARE TARGET DESIGN &SELECTION & ADVANCING SYNTHESIS TO MAKE SUCH TARGETS …
*Wender, Miller "Toward the Ideal Synthesis: Connectivity Analysis & Multi-Bond FormingProcesses" in Organic Synthesis: Theory and Applications T. Hudlicky (ed.), V. 2, 27, 1993, JAI Press.
Wender, Wright, Handy, "Toward the Ideal Synthesis" Chemistry & Industry, 1997, 765.
IN A PRACTICAL IF NOT IDEAL FASHION
TWO MAJOR PRIORITIES IN CHEMISTRY
•IMAGING TOOLS•DIAGNOSTICS•SENSORS•NANODEVICES
•ENERGY COLLECTION•ENERGY STORAGE•ENERGY CONVERSION•ENVIRONMENTAL
- ONE STEP, 100 % YIELD - READILY AVAILABLE STARTING MATERIALS
- OPERATIONALLY SIMPLE, SAFE AND ENVIRONMENTALLY SOUND - RESOURCE (COST, TIME, MATERIAL, PERSONNEL) EFFECTIVE
THE IDEAL SYNTHESIS AND STEP ECONOMY
*Wender, Miller, "Toward the Ideal Synthesis: Connectivity Analysis and Multi-Bond Forming Processes", in Organic Synthesis: Theory and Applications T. Hudlicky, ed., V. 2, pp 27-66, 1993, JAI Press.
Wender, Dennis Wright, Scott Handy, "Toward the Ideal Synthesis," Chemistry & Industry, 1997, 765.
WHY IS STEP ECONOMY SO IMPORTANT? A 70 step synthesis, even if 100% selective & efficient, is still a 70 step synthesis.70 steps take time, add cost, deplete resources, generate waste (solvent, etc)…
Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Craske, M.L.; Horan, J.C.; Meyer, T. “ Function Oriented Synthesis:…” Current Drug Discovery Technologies, 2004, 1, 1-11.
STEP ECONOMY:REDUCES LENGTH, WASTE (SOLVENT, ATOM LOSS!!!), ENVIRONMENTAL IMPACT,DEVELOPMENT & EXECUTION TIME, SEPARATION SCIENCE, EFFORT, COST;
IMPROVES YIELD, SPEED, SCIENTIFIC ADVANCEMENT, SAFETY, RETURN ONINVESTMENT, AND MOST IMPORTANTLY HUMAN ECONOMY
Louis Piaroulli…his cancer was spreading through his bonesand lymph nodes. Traditional chemotherapy hadfailed. Then, doctors tried again with the same chemotherapydrug, but they added bryostatin. Before adding bryostatin, Piaroulli's boneswere riddled with cancer.
"The response was exceptional and dramatic, and we would not have anticipated thisresponse from chemotherapy alone," says Schwartz (Memorial Sloan-Kettering).
BRYOSTATIN: NOVEL STRUCTURE, UNIQUE FUNCTION
Five months after the treatment, there was no trace of the disease.
Underwater TreasuresDoctors Searching for Potential Cancer Cures Beneath the SeaJohn McKenzie abc NEWS“A treasure chest of potential medicine lies in the sponges,algae and coral that live beneath the sea. And doctors thinksome of them may even help cure cancer…” O
O
O
O
O
OH
OH
O
HO
OAc
HO
CO2Me
MeO2C
O
B3
7
1330
19
21
26
11
34
5
2515
17
C
23
1
9A
BRYOSTATIN 1
OO
O
O
O
O
OH
OH
O
H
HO
CO2MeO
SIMPLER BUT FUNCTIONALLY SUPERIOR TARGETS=SHORTER (STEP ECONOMICAL) SYNTHESES
BRYOSTATIN
OO
O
O
O
OH
OH
O
HO
OAc
HO
CO2Me
MeO2C
O
AB
C
SPACER DOMAIN
RECOGNITION DOMAIN
BRYOLOG
A
C
B
Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Craske, M.L.; Horan, J.C.; Meyer, T. “ Function OrientedSynthesis:…” Current Drug Discovery Technologies, 2004, 1, 1-11.Wender, De Brabander, Harran, Jimenez, Koehler, Lippa, Park, Siedenbiedel, Pettit, Proc. Natl. Acad. Sci., 1998, 6624Wender, Baryza, Bennett, Bi, Brenner, Clarke, Horan, Kan, Lacote, Lippa, Nell, Turner J. Am. Chem. Soc. 2002, 13648
FOS:COMPUTER HOMOLOGYMODELING
RECOGNITION DOMAIN
SIMPLER SPACER DOMAIN
BEYOND NATURAL PRODUCTS: DESIGN A BETTER TARGET
TOWARD A PRACTICAL (MANUFACTURING) SYNTHESIS OF “BRYOLOGS”
O
O
O
O
O
O
OH
OH
O
H
HO
CO2Me
O
H
H
H
17
19
21
25
C
A
B
15
O
OPMB
O
OBn
TBSO
(made in 4 steps)
(5 steps from Me (R)-lactate)
19C
25
21
17
23
22
O
OPMB
OBn
25
23
O
TBSO
19
21
1722
O
20C RING
FORMATION
O
OPMB
OBn
TBSO OMe
O CO2Me
21
17
20
C•DEOXYGENATION•ALKYLIDINATION
7 LLS; 11 O 8 S
I II (19 STEPS)Wender, De Brabander, Harran, Jimenez, Koehler, Lippa, Park,Shiozaki, J . Am. Chem. Soc. , 1998, 4534. Proc. Natl. Acad. Sci.USA , 1998, 6624.
Wender, P. A.; Baryza, J.; Bennett, C.; Bi, C.; Brenner, S. E.; Clarke, M.; Horan, J.; Kan, C.; Lacote, E.; Lippa, Nell, P.; Turner, T. J. Am. Chem. Soc.; 2002, 124, 13648-13649.
(a) NaH, TBDMSCl, THF, rt; (b) (COCl)2, DMSO, Et3N, CH2Cl2, -78°C; (c) 4-chlorobutanol, MeMgCl, -78°C; Mg, THF, reflux; -78°C, THF; 75% 3 steps; (d)(COCl)2, DMSO, Et3N, CH2Cl2, - 78°C; 75%; (e) 5 mol% Ti(Oi-Pr)4, 10 mol% (R)-BINOL, B(OMe)3, allylSnBu3, 4 Å sieves, CH2Cl2, RT; 75%; (f) PTSA, 4 Åsieves, MePh; RT; 80% (g) MMPP, NaHCO3, CH2Cl2, MeOH, 0°C; 75%; (h) 0.1 eq. TPAP, 3 eq. NMO, 4 Å sieves, CH2Cl2, MeCN, 0°C - RT; 81%(i) K2CO3,MeOH, (MeO)(OH)CHCO2Me, - 78°C; 80%; (j) CeCl3∗7H2O, NaBH4, MeOH, -30 ∞C; (k) C7H15CO2H, DIC, DMAP, CH2Cl2, RT; 79% 2 steps; (l)HF/pyridine, THF, RT.; (m) Dess-Martin periodinane, NaHCO3, CH2Cl2, RT; 79% 2 steps; (n) (DHQD)2PYR, K2OsO2(OH)4, K2CO3, K3Fe(CN)6, t-BuOH, H2O,0°C; 90%; (o) TESCl, pyr, CH2Cl2, rt; (p) 1-Br, 2-EtO-ethene, t-BuLi, ZnMe2, -78°C; (q) HF, CH3CN, H2O, rt; (r) 1:3 TBSCl:imidazole, 9:1 CH2Cl2 : DMF;40% 4 steps.
OH OH OTBSO OHOHTBSO OH d,e f
g, h
a-c
17 19
OMgX
XMg
1719
20
20
23
23 23
O
TBSO
19C
25
21
17
23
20
O
TBSO
19C
21
17
20
OMe
O
6 OVERALL
I'
II' (9 STEPS)
O
TBSOOMe
O CO2Me
21
17
20
C
O
O
MeO
CO2Me
O
R
O
OTES
OTES O
O
MeO
CO2Me
O
R
OH
OTBS
OHC
4:1
i j-o p-rC C
2525
20
25
262617 17
15
19
21
$ 0.01 / gram
(18 STEPS)
3 steps, 75%kilogram scale
O
O
O
O
O
O
OH
OH
O
H
HO
CO2Me
O
H
H
H
17
19
21
25
C
A
B
15
TOWARD A PRACTICAL (MANUFACTURING) SYNTHESIS OF “BRYOLOGS”
O Cl
O O
O
O O O OBn
O
OBn
TBDPSO
O
OO O
OBn
TBDPSO
O
OO O
OH
TBDPSO
OO O
O
TBDPSO OH
a b-d e,f
g-i j
O OBn
$
$ OO
O
$
11
1
1
1
1
4
455 3
3
3
5
9
9
9
5
9
5
11
11 11
11
7
6
54
3 2 1
A
10 steps, 25% overall yield
Paul A. Wender, Alexander V. M. Mayweg, Christopher L. VanDeusen Organic Lett. 2003, 277-279
>95:5 es
>95:5 ds >99:1 ds
•LATE STAGE CONVERGENCY•MILD MACROACETALIZATION•COMBINATORIAL SYNTHESIS
2,4,6-Cl3ArCOCl,Et3N, rt, DMAP
81%
1.Amberlyst resin2. cat. Pd(OH)2/C,
H2
88%
Wender, Baryza, Bennett, Bi, Brenner, Clarke, Horan, Kan, Lacote, Lippa, Nell, Turner, J . Am. Chem. Soc.; 2002, 124, 13648.Wender, De Brabander, Harran, Jimenez, Koehler, Lippa, Park, Shiozaki, J . Am. Chem. Soc. , 1998, 4534.Wender, De Brabander, Harran, Jimenez, Koehler, Lippa, Park, Siedenbiedel, Pettit, Proc. Natl. Acad. Sci. USA , 1998, 6624.Wender, Hinkle, Koehler, Lippa, Medicinal Research Reviews, 1999, 388.
A PRACTICAL (MANUFACTURING) SYNTHESIS OF DESIGNED TARGET
BRYOSTATIN
Scale up in progress2nd gen. Synthesis J. Am. Chem. Soc. 2002
BRYOLOG ~ 25 STEPS(BRYOSTATIN > 70 STEPS)
SPACER DOMAIN
RECOGNITION DOMAIN
O O
OOH
O
CO2Me
MeO2COAc
H OH
H
OH
O
O
H
H
HO
O
R
O O O
OOH
O
CO2Me
H H
OBn
H
H
R'
O
R
O O O
OOH
O
CO2Me
H H
H
OH
OH
H
R'
O
R
CHO
OH
R R
OH
O O O
OOH
O
CO2Me
H H
OBn
O
H
H
R'
O
R
CHO
O
R R
O
O
3
3
3
25
25
25
15
15
11
11
3
1
19
26
1
1
AB
C
AB
C
AB
C
AB
C
N
C
NC
Ca2+RACK
Inactive(cytosol) Active
(membrane)
translocation releasespseudosubstrate andactivates protein
C1a C1bC2 PS Kinase GFP
488 nM
508 nM
plasmid
transfection expressionactivation/
translocation
1. encode plasmid for each isozyme
2. express each plasmid independently
REAL TIME EVALUATION OF PKC TRANSLOCATION
J. Baryza, S. Brenner, M. Craske, T. Meyer, P.WenderChemistry & Biology 2004, 1261.
Newton, Chem. Rev. 2001
membrane
B
Cell Sensitivity
MDA-MB-435
MOLT-4
NCI-H460
HCC-2998
K-562
COLO
A549/ATCC
SF-295
SK-MEL-5
CCRF-CEM
SN12C
MDA-MB-231/ATCC
ACHN
LOX
U251
PC-3
EKVX
786-0
HT29
MCF7
HL-60(TB)
KM12
UACC-257
HCT-116
SF-268
SK-MEL-2
T-47D
UACC-62
OVCAR-3
OVCAR-4
SW-620
IGROVI
SNB-75
UO-31
NCI-H322M
-2
-1
0
1
2
3pico-bryo
nano-bryo
log
(bry
oG
I 50)
- lo
g(a
nalo
gG
I 50)
GROWTH INHIBITION IN HUMAN CANCER CELL LINESStanford / National Cancer Institute USA (Ven Narayanan)
SOME ANALOGS 102-3 BETTER
FUNCTION ORIENTED SYNTHESIS: BETTER, AVAILABLE LEADS
•BRYOLOG AND BRYOSTATIN HAVE SIMILARVIRTUAL STRUCTURES, SOLUTION STRUCTURES, PKC AFFINITIES
•BRYOLOGS ARE GENERALLY MORE POTENT (10-100 FOLD) THAN BRYOSTATIN IN HUMAN CANCER CELL GROWTH INHIBITION
•BRYOLOGS ARE COMPARABLE OR BETTER THAN BRYOSTATIN IN ANIMAL ASSAYS•PICOLOG SYNTHESIS < 30 STEPS, ~ $3K/gm (BRYO $2.3M/ gm); NOW IN SCALE UP
J. Am. Chem. Soc. 2002, 13648•PRE-CLINICAL DEVELOPMENT CANDIDATE
O
O
O
O
O
OH
OH
O
HO
OAc
HO
CO2Me
MeO2C
O
B3
7
1330
19
21
26
11
34
5
2515
17
C
23
1
9A
<30 STEPS>70 STEPS
O
O
O
O
R
O
O
OH
OH
O
H
HO
CO2Me
3
7
13
19
21
26
11
34
5
2515
1723
1
9
O
B
C
A
FOS
Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Craske, M.L.; Horan, J.C.; Meyer, T.“ FOS” Current Drug Discovery Technologies, 2004, 1, 1-11. Chemistry & Biology 2004, 1261.
STEP ECONOMY
PRACTICAL IMPRACTICALIDEAL
TARGETCOMPLEXITY
[VALUE]
# OF STEPS
STEP ECONOMY AND FUNCTION ORIENTED SYNTHESIS:Wender, Brabander, Harran, Jimenez, Koehler, Lippa, Park, Siedenbiedel, Pettit Proc. Natl. Acad. Sci. USA 1998, 6624;Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Craske, M.L.; Horan, J.C.; Meyer, T. “ Function OrientedSynthesis” Current Drug Discovery Technologies, 2004, 1, 1-11
FOSDESIGNED
FUNCTIONALANALOG
NEW RXNSTARGET
N
O
13 steps
1-2%
Willstätter & Waser 1911 Reppe & Toepel 1940
Ni (0) cat
70%
H
H
NOW…COMBINE NEW REACTIONS AND FOS…INVENT NEW FUNCTIONAL TARGETS WITH NEW RXNS
PHARMACOPHORE TARGETING WITH NEW REACTIONS
SELECTIVEINHIBITORS
ASMEDICINAL
LEADS
OUTPUTINPUT
DESIGNHIGH
THROUGHPUT IN SILICO
SYNTHESISCOMBI CHEM
FUNCTIONH-T
SCREENS
New reactionsnovel structures
The virtual medicinal chemist
Real time cell &animal assays
•STEP ECONOMY TOKNOWN SCAFFOLDS•STEP ECONOMY TONEW SCAFFOLDS
O
O
O
O
O
OH
OH
O
HO
OAc
HO
CO2Me
MeO2C
O
B3
7
1330
19
21
26
11
34
5
2515
17
C
23
1
9A
O
O
O
O
R
O
O
OH
OH
O
H
HO
CO2Me
3
7
13
19
21
26
11
34
5
2515
1723
1
9
O
B
C
A
>70 steps <25 steps
FOSFOS
NEXTLEVEL?
NEWRXNS SIMPLER
FASTER
N
O
OO
H
R'
CANCER CHEMOTHERAPEUTIC LEADPICOMOLAR ACTIVITY
NEUROPATHIC PAINFEMTOMOLAR ACTIVITY
DESIGNING NEW REACTIONS FOR UNMET NEEDS
TUMOR PROMOTERNANOMOLAR ACTIVITY
OH
OR
H
H
OR'
OHO
OH
O
O
O
H
HO
OH
OH
BzO OH
O
BzO
O
O
O
H
HO OO
O
OMe
OH
R
R
R
R2C/2e
+
4C/4e
6!
THE DIELS-ALDER CYCLOADDITION: A POWERFUL PROCESS FOR 6-MEMBERED RINGS
4+2
Sarel, Breuer J. Am. Chem. Soc. 1959, 6522: Thermal reaction; VCP to CP 51.7kcal/M; Herges in "Chemical Structures”Springer-Verlag, 1988: "vinylcyclopropanes do not react even with the strongest dienophiles..."; Chem. Ber. 1986, 829
XR
R
7+
R
R 2C 5C
DESIGNING NEW REACTIONS: A HOMOLOG OF A [4+2] TO 6 IS A [5+2] TO 7
HEAT ALONE
X
THERMAL REACTION DOES NOT WORK*
DESIGNING NEW REACTIONS: THE [5+2] CYCLOADDITION
THEREFORE, SELECT SUITABLE METAL TO MEDIATE ∏-SYSTEM ACTIVATION(MANY METALS REACT WITH CPs and / or VCPs; must suppress 2+2+2, VCP to CP)
M
H
H H
Ln
M
MLnS
Z
MLn
LnCP 1st
HH
H H
*
MLn
H
H
H
ca. 0°
CP 2nd
Wender, Takahashi, Witulski J. Am. Chem. Soc. 1995, 4720; J. Am. Chem. Soc. 1998, 1940
Rh(CO)Cl
R
R
R
Rh(CO)Cl
(CO)ClRh
R
Cl(OC)Rh
R
Rh(CO)Cl
R
RPATHWAY 1
DFT calculations: Zhi-Xiang Yu,Paul Wender, Ken Houk
J. Am. Chem. Soc. 2004, 9154
Ea > 50 kcal/mol
A NEW REACTION: TRANSITION METAL CATALYZED [5+2] CYCLOADDITIONS
O
R
O
R
* ALKYNES (Wender, Takahashi, Witulski J. Am. Chem. Soc. 1995, 4720; J. Am. Chem. Soc, 1998, 10976)
1-10 mol % Rh(PPh3)3Cl
R= H, Me, CO2Me, TMS, Ph 7
80-95 %
5
1-10 mol % AgOTf
t-Bu
E
E
H
E
E
•
92% ee
H
91% ee
t-Bu
1 mol % CAT
PhCH3, 100 °C
3 hH 5 7
96%, only cis
* ALLENES (Wender; Glorius; Husfeld; Langkopf; Love J. Am. Chem. Soc., 1999, 5348; Organic Lett. 2000, 2323)
MeO2C
MeO2CMeO2C
MeO2C
1.0M, PhMe, 110°C, 17h
86-91%, only cis
* ALKENES (J. Am. Chem. Soc. 2001, 123, 179; J. Am. Chem. Soc. 1998, 1940; Tetrahedron 1998, 7203)
0.1 mol % RhCl(PPh3)3
0.1 mol% AgOTf
5R
R= H, Me
7
H
R
(exo selective)
INTERMOLECULAR TRANSITION METAL CATALYZED [5+2] CYCLOADDITIONS
CO2Me
CO2Me
OTBS
MeO2C
MeO2C
O
CO2Me
CH3H3C
MeO2C
O
*ALKYNYL ESTERS
93 %
* HH
O
+
92 % 88 %H
O
IT IS REMARKABLY GENERAL (1-3hr @ 25-40°C for most alkynes)
CAT.; H+
INTERNAL AND TERMINAL ALKYNES
*
79 %
H
H H
H
OCAT.; H+ CAT.; H+
EVEN ACETYLENE*
5 mol % [Rh (CO)2Cl]2,
CDCl3, 40 °C; H+
88 %
ALKYNYL KETONES
OO
2 hr
Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem. Soc, 1998, 10976.
*LnRh OTBS
POSSIBLE RESTING STATE OF CATALYST*
CAT.; H+
1.5 hr, 40°C
2.5 hr, 40°C
1.5 hr, 40°C
6 hr, 40°C
OMe OMe
ONE MOLE SCALE
CC ACTIVATION: FROM VCPs to VCBs & A NEW REACTION
Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am. Chem. Soc. 2000, 122, 7815.
R1=R2=HR1=H, R2=Me
95%
78%
A, 3hB, 20h
10 mol % RhCl(PPh3)3, 10 mol % AgOTf
10 mol % RhCl(CO)(PPh3)2, 10 mol % AgOTf
NO
R1
R2
Ts
O
TsN
R1
R2
110°C, tol
catalyst
FIRST [6+2] CYCLOADDITIONS
NEW REACTIONS INSPIRING OTHER NEW REACTIONS:
E
E
O
H
H
E
EH
OH
H
E
E
H
5 mol % [Rh(CO)2Cl]2, 10 mol % P(n-Bu)3,
10 mol % AgOTf
OH
H
E
E
M
86%
8%
-CO
Mechanism: Wender; Correa; Sato; Sun J. Am. Chem. Soc. 2000, 7815:
A NEW THREE COMPONENT CYCLOADDITION:TRANSITION METAL CATALYZED [5+2+1] CYCLOADDITIONS
O
RhLn
O
RhLn
O
+ CO- CO
[5+2] CYCLOADDUCT
[6+2]
THUS FAR, [4+4], [4+2], [5+2], AND [6+2] CYCLOADDITIONS, OVERALL [M+N] CYCLOADDITIONS.COULD A 3rd COMPONENT OF 1, 2, etc ATOMS BE ADDED TO ACHIEVE [M+N+O] CYCLOADDITIONS?
7
8
[5+2]
[6+2] CYCLOADDUCT
[5+2+1] CYCLOADDUCT
[6+2-1] CYCLOADDUCT
NEW REACTIONS BEGET OTHER NEW REACTIONS
A NEW, THREE COMPONENT CYCLOADDITION:TRANSITION METAL CATALYZED [5+2+1] CYCLOADDITIONS
INTRAMOLECULAR [5+2] CYCLOADDITIONS: Wender, Takahashi, W itulski, J. Am. Chem. Soc. 1995 117, 4720.INTERMOLECULAR [5+2] CYCLOADDITIONS: Wender, Rieck, Fuji, J. Am. Chem. Soc, 1998, 120, 10976.
[6+2] CYCLOADDITIONS: Wender, Correa, Sato, Sun, J. Am. Chem. Soc. 2000, 122, 7815. [5+2+1] CYCLOADDITIONS: Wender, Gamber, Zhang, Hubbard, J. Am. Chem. Soc. 2002, 2876.
1-5 mol% [Rh(CO)2Cl]2, dioxane, 60°C, 1-2 atm CO, conc. up to 0.5M; Works with esters, amides, aldehydes, ketones; yields good to excellent; high regioselectivity
1 mol% [Rh(I) cat.
CO
O
OH
+
O
OR 99%
OO
O
OOMe
H+
1 mol% [Rh(I) cat.
CO
O
OH
+H2N
H2N
H2N
O
OR 96%
OO
O
OOMe
H+
NEW SCAFFOLDS
Aldrich
Aldrich
Aldrich
Intramolecular [4+4] cycloaddition of bis dienes (1986)Intramolecular [4+2] cycloaddition of diene-ynes (1989)
Intramolecular [5+2] cycloaddition of VCPs & pi-systems (1995)Intermolecular [5+2] cycloaddition of VCPs & alkynes (1998)Intermolecular [6+2] cycloaddition of VCBs & pi-systems (2000)
Intermolecular [5+2+1] cycloaddition of VCPs, alkynes, CO (2002)
Intermolecular [5+1+2+1] cycloaddition of VCPs, alkynes, 2 CO (2005)
Intramolecular [2+2+1] cycloaddition of alkynes, dienes, CO (Dienyl PK) (2003)
Hetero [5+2] cycloaddition of cyclopropyl imines (2002)
Intramolecular [4+2+1] cycloaddition of dienes, alkynes, CO (2004)
Carbonylative ring expansion [4+2+1]/[6+1] of allenylcyclobutanes (2006)
Intra/intermolecular [5+2]/[4+2] cycloadditions (2001)
Intramolecular [2+2+1] cycloaddition of alkenes, dienes, CO (2004)
The allenyl Pauson-Khand [2+2+1] cycloaddition of bis-alkenes, CO (2006)
NEW REACTIONS, THE IDEAL SYNTHESIS, STEP ECONOMY, PHARMACOPHORE TARGETING
Representative New TM Catalyzed Reactions…New Strategies…New Structures…
Intermolecular [3+2] cycloadditions (unpub)Intermolecular [4+2+2] cycloadditions of dienes, alkenes, alkynes (2006)
Intermolecular [2+2+1] cycloaddition of alkenes, dienes, CO (2004)
Intramolecular [4+2] cycloaddition of diene-allenes (1995)
Intramolecular [4+2+2] cycloadditions of dienes, alkenes, alkynes (2006)
Can we exploit thesenew reactions to rapidlyassemble new or novel
FUNCTIONAL molecules
GRAND CHALLENGES: THE BARRIER PROBLEM•Genomics (blueprint)•Proteomics (targets)•Systems Biology (pathways)•Chemogenomics (ligands)
A CHALLENGE AHEAD…
TISSUEBARRIERS
CELLBARRIERS
THERAPY DEPENDS ON BREACHING BARRIERS…
DRUG / PROBE
TARGET
XTRANSPORTER
Varmus, Klausner, et al. “Grand Challenges in Global Health” Science, 2003, 398-399.Jain, R.K. “The Next Frontier of Molecular Medicine: Delivery of Therapeutics” Nature Med. 1998,
“The bilayer provides the basic structure of the membrane and serves as a relativelyimpermeable barrier to the flow of water soluble molecules” …most standard textbooks
BREACHING BIOLOGICAL BARRIERS
TOO POLAR(LIPID BILAYER PROBLEMS)
e.g., RNAi
THE PROBLEM: MOST DRUGS MUST BE BOTH WATER & LIPID SOLUBLE FOR PASSIVE DIFFUSION INTO TISSUES AND CELLS
TOO NON-POLAR(WATER SOLUBILITY PROBLEMS)
e.g., TAXOL
•WATER SOLUBLE•MEMBRANE
IMPERMEABLE
•WATER SOLUBILITY PROBLEMS•MEMBRANE
LOCALIZATION
MANYPOTENTIAL DRUGS
ANDBIOCHEMICAL PROBES
HAVE UPTAKE/SELECTIVITYPROBLEMS
THINKING OUT OF THE log P BOX AND PHYSICAL PROPERTY HOMOGENEITY
Wender, P.; Mitchell, D.; Pattab iraman, K.; Pelkey, E.; Steinman, L.; Rothbard, J. Proc. Natl. Acad. Sci. USA, 2000, 13003Rothbard, Garlington, Lin, Kirschberg, Kreider, McGrane, Wender, Khavari, Nature Medicine 2000, 1253
CELLX
JUST RIGHT
THE LOG P BOX
X
T-D/P
THERAPY DEPENDS ON BREACHING BARRIERS
BARRIER PROBLEMS ARE A MAJOR CAUSE OF HIT-TO-LAUNCH ATTRITIONA POTENTIAL FIX: MOLECULAR TRANSPORTERS
*HIV tat and Antennapedia are transcription factors that cross biological membranes
MEPVDPRLEPWKHPGSQPKTACTTCYCKKCCFHCQVCFTTKALGISYGRKKRRQRRRPPQGSQTHQVSLSKQPTSQPRGDPTGPKE*KKKVERETETDPFD
NATURAL CHEMICAL CODES FOR FACILITATED CELLULAR UPTAKE
*Evolutionary pressures have produced mechanisms to prevent and promote uptake
*This works for the HIV tat protein, the “gold standard” in research - it would have limited use in therapy (cost of goods, metabolism, etc) and - it is not necessarily an optimized system*Design a better transporter; what’s required in tat? Stanford (Engleman, Fathman, Kiley, Rothbard, Wender) -> CellGate
*HIV tat 49-57 is required for translocation (Frankel, Pabo 1988)SIGNIFICANTLY, IT IS CHARGED BUT EXHIBITS FACILITATED UPTAKE
arginine-lysine-lysine-arginine-arginine-glutamine-arginine-arginine-arginine
49 57H2N
HN
NH
HN
NH
HN
NH
HN
NH
X
O
O
O
O
O
O
O
O
O
HN
NH3
NH3
HN H2N O
H2N NH2
HN
H2N NH2
NH
H2N NH2
HN
H2N NH2
H2N NH2
NH
H2N NH2
CHEMICAL CODES FOR CELLULAR UPTAKE
Uptake of Peptide & Peptoid-aca-FITC conjugates into Human Jurkat T Cells
Wender, Mitchell, Pattabiraman, Pelkey, Steinman, Rothbard Proc. Natl. Acad. Sci. USA , 2000, 97, 13003;Rothbard, Garlington, Lin, Kirschberg, Kreider, McGrane, Wender, Khavari, Nature Medicine 2000, 6, 1253-1257;Mitchell, Kim, Steinman, Fathman, Rothbard, J . Pept. Res. 2000, 56(5), 318-325. ; J . Med. Chem. 2002, 3612-3618.* Wender, Jessop, Pattabiraman, Pelkey, VanDeusen Organic Letters 2001, 322
R5 R6 R7 R8 R15 R20 R25 R30R9
CONFOCAL ANALYSISHEAD GROUP TYPE &
TRANSPORTER LENGTH
NN
NN
N
O
O
O
O
O
NO
O
ORN
O
NH
NH
S
O
O
HO
COOHn
HN
H2N NH2
n
HN
H2N NH2
n
HN
H2N NH2
n
HN
H2N NH2
n
HN
H2N NH2
n
HN
H2N NH2
n
HN
H2N NH2
PEPTOID TRANSPORTER
N-hex7
N-hex8
N-hex9
SUPERIOR SYSTEMS
AND
COST OF GOODS*
Mea
nFl
uore
scen
ce
0
1000
K9
NOT SIMPLYCHARGE
Tat49-57
UPTAKE
BACKBONE STEREOCHEMISTRY& POSITION (PEPTOIDS)
Tat49-57
R7 R9 r7 r9
Mea
nFl
uore
scen
ce
0
L
DUPTAKE
STEP ECONOMY THROUGH SYNTHESIS AND FUNCTION GUIDED DESIGN
LINEAR: TARGET OF n UNITS REQUIRES 2n STEPS; THUS EVERY 2 STEPS ADD 1 UNIT
Repeat:7. Make acid8. Make amine9. Couple
XNHRCO[NHRCONHRCO] 6NHCO2Bn9 OPERATIONS OVERALL
NO RESIN, SOLN. SCALABLECOST SAVINGS >100FOLD;
GMP SCALED IN US PHARMA
1. Activate 2. Couple repeat 16 OPERATIONS OVERALL
SEGMENT DOUBLING: A TARGET OF 2n UNITS REQUIRES 3n STEPS THUS AN 8-MER (n=3) REQUIRES ONLY 9 STEPS; THUS EVERY 3 STEPS DOUBLE THE SIZE!
BocNHRCO2H
HCl•NH2RCO2Bn
BocNHRCHCONHRCHCO2Bn3
$
$
1
2
4
5
BocNHRCONHRCO2H
HCl•NH2RCONHRCO2Bn
BocNHRCONHRCONHRCONHRCO2Bn6
G G -G2G -G2 -G3 -G4 -G5 -G6 -G7 -G8 G -G2 -G3 -G4 -G5 -G6 -G7-G8
Wender, Jessop, Pattabiraman, Pelkey, VanDeusen Organic Letters 2001, 3229.Wender, Mitchell, Pattabiraman, PelkeySteinman, Rothbard Proc. Natl. Acad. Sci. USA , 2000, 13003
MOLECULAR TRANSPORTERS FOR CELLULAR UPTAKE
NN
NN
N
O
O
O
O
O
NO
O
ORN
O
NH
NH
S
O
O
HO
COOHn
HN
H2N NH2
n
HN
H2N NH2
n
HN
H2N NH2
n
HN
H2N NH2
n
HN
H2N NH2
n
HN
H2N NH2
n
HN
H2N NH2
PEPTOID TRANSPORTERS
Proc. Natl. Acad. Sci. USA , 2000, 13003
RXRXRXRXRXRXRSPACED
ARG-TRANSPORTERSJ. Med. Chem. 2002, 3612
OLIGOARGININE TRANSPORTERS
Nature Medicine 2000,1253
NH2O
O
NH
NH
n
TFA
NHH2N
R
OLIGOCARBAMATE TRANSPORTERS
J. Am. Chem. Soc. 2002 13382
nX
NH
O
S
NH
HN
OO
NH
4
ARBOREAL DENDRIMER TRANSPORTERS
Organic Lett. 2005, 4815
SW NANOTUBE TRANSPORTERS
J. Am. Chem. Soc. 2004, 6850
AND OTHERS…
DRUG--LINKER--HN
NH
HN
NH
HN
NH
HN
NH
XO
O
O
O
O
O
O
O
HN
HN
H2N NH2
NH
H2N NH2HN
H2N NH2
H2N NH2
NH
H2N NH2
HN
H2N NH2
HN
H2N NH
HN
H2N NH2
THE MEMBRANE BARRIERSinger-Nicolson (Science 1972) fluid mosaic modelVereb, Damjanovich, et al. (PNAS 2003) Dynamically structured mosaic model
“The bilayer provides the basic structure of the membrane and serves asa relatively impermeable barrier to the flow of water soluble molecules” …
Variations of this statement are found in most standard textbooks
WHY ARGININE AND NOT LYSINE?
ARGININE
0
200
400
600
800
mean
flu
orescen
ce
DiMe-R8Me-R8
R8
ARE HYDROGEN BONDSTHAT IMPORTANT?
Rothbard, Jessop, Lewis, Murray, Wender J. Am. Chem. Soc. 2004, 9506-9507.
HN
H2N
O
N
N N
8
NH
O
R"
R"
5NH
S
Fluorescein
H
H
H
TFA
O
P
O
O O
R R' MEMBRANE
OP
O
O
O
R
R'
REPLACE "H"
WITH METHYL
A
B
N
H H
N
N
HH
R H
NON-POLAR MEMBRANE NON-POLAR MEMBRANE
EXTRACELLULAR
POLAR MILIEU
POLAR
GROUP
POLAR
GROUP
LESS
POLAR
COMPLEX
O
P
O
O O
R R'
N
H H
N
O
P
O
N
O O
R R'
HH
R H
LYSINEN
R H
EXTRACELLULAR
POLAR MILIEU
POLAR
GROUP
POLAR
GROUP
LESS
STABLE
COMPLEX
H H
NON-POLAR MEMBRANENON-POLAR MEMBRANE
O
P
O
O O
R R'
N
R H
H H
O
P
O
O O
R R'
TRANSPORTER-PEPTIDE CARGO UPTAKE INTO HEART TISSUE
PEPTIDE DELIVERY TO PREVENT ISCHEMIC DAMAGE
PRECONDITIONING : BRIEF EPISODES OF ISCHEMIA DECREASE NECROSIS DURING PROLONGED ISCHEMIARACK PEPTIDES SIMULATE PRECONDITIONING WHEN INJECTED INTO CELLS BUT CANNOT ENTER BY DIFFUSION
HO2C-DYGIPDAHC-SS-CR7-CONH2RACK-TRANSPORTER CONJUGATE
HO2C-DYGIPDAHC-SHRACK PEPTIDE
(“DRUG”)
HS-CR7-CONH2TRANSPORTER
+
•THE RACK PEPTIDE ITSELFMUST BE MICROINJECTEDINTO CELLS•TRANSPORTER RACKCONJUGATE WORKSWITHOUT INJECTION
RACKCS-
SCTat
RACKCS-
SCR7
50%
78%
NO
TRMT
CREATINE
PHOSPHOKINASE
RELEASE
DAMAGE
PROTECTION
BASIS FOR NEWCOMPANY, 2003
L. Chen, L. Wright, C-H. Chen, S. F. Oliver, P. A. Wender,* D. Mochly-Rosen*CHEMISTRY & BIOLOGY, 2001, 1123
TRANSPORTER ENABLED DRUG UPTAKE IN HUMAN SKINPaul Wender, Dennis Mitchell, Kanaka Pattabiraman, Erin Pelkey, Lawrence Steinman, Jonathan RothbardProc. Natl. Acad. Sci. USA , 2000, 13003-13008; Jonathan Rothbard, Sarah Garlington, Qun Lin, ThorstenKirschberg, Erik Kreider, P. Leo McGrane, Paul Wender, Paul Khavari, Nature Medicine 2000, 1253-1257
HUMAN TRIALS ESTABLISHED SAFETY AND THERAPEUTIC LEVELS OF CONJUGATE: T-L-CsA -> T-L + CsA (pH based release)
ASSAY NEEDED TO QUANTIFY RELEASE IN ANIMALS
UPTAKE OF BIOTINYLATED CYCLOSPORIN (A) AND BIOTINYLATED CYCLOSPORIN TRANSPORTER CONJUGATE(C) IN HUMAN SKIN GRAFTED ON IMMUNE DEFICIENT MICE. PANELS B AND D ARE CONTROLS USING PROPIDIUMIODIDE TO VISUALIZE ALL CELLS.
REAL TIME QUANTIFICATION OF TISSUE PENETRATION, CELL UPTAKE,RELEASE & INTRACELLULAR FUNCTION IN TRANSGENIC MICE
Rothbard, Garlington, Lin, Kirschberg, Kreider, McGrane, Wender, Khavari Nature Medicine 2000, 1253.L. Jones, E. Goun, R. Shinde, J. Rothbard, C. Contag, P. Wender* J. Am. Chem. Soc. 2006, 128(20), 6526.
Luc-RL-Trans (Luciferin-Releasable Linker-Transporter)
Luc-RL-Trans
Stratum corneum
Luc-RL-Trans
Cell membrane
Luc + RL + Trans
Intracellrelease
luciferase
Light
Animalscan be re-used!
STRATUM CORNEUM
area of application
EPIDERMIS
DERMIS
DESIGN STRATEGY FOR REAL TIME DERMAL UPTAKE
S
N
S
N
O
COOH
O
O
SS
NHAc
O
N
H
H2N
O
NH
NH2
H2N
8
F3C
O
O
Conjugate Vehicle: propylene glycol, ethanol,buffered water
GSH(mM)
GSH(mM)
GSH(mM)
GSH(mM)
GSH(mM)
GSH(mM)
GSH(mM)
GSH(mM)
GSH(µM)
S
N
S
N
HO
COOH
Conjugate
GSH103> in cell
S
O O
S
N
S
N
O
COOH
O
O
SH
L L L L
LLLL
L hv•Comp radiolabeling
LIGHT
L. Jones, E. Goun, R. Shinde, J. Rothbard, C. Contag, P. Wender* J. Am. Chem. Soc. 2006, 128(20), 6526.
SYNTHESIS OF NEW BIO-RELEASABLE CONJUGATES
R8-CARBONATE 5 SYNTHESIS: 3 STEPS, OVERALL YIELD 40%
1. 2-aldrithiol, MeOH, 97%; 2. i) Phosgene,pyr, tol, ii) Luciferin, NaOH, H2O, 70%; 3.AcHN-Cys-arg8-CONH2, DMF, 59%
SH
O
O
S S
NN
S
N
S
O
OS S
N
S
N
S
NHAc
O
NH
r8 CONH2O O
+ 8 TFA
HO1-2 3
HO2C HO2C
•C67 H124 N36 O15 S4
•NO PROTECTING GROUPS•GENERAL AND SCALABLE
L. Jones, E. Goun, R. Shinde, J. Rothbard, C. Contag, P. Wender* J. Am. Chem. Soc. 2006, 128(20), 6526.
March 25 all buffers 37oC
5 minute pulsewells seeded with 30,000 cells/well pH 6.9/7.4
0
250,000
500,000
750,000
1,000,000
1,250,000
1,500,000
1,750,000
2,000,000
2,250,000
2,500,000
2,750,000
3,000,000
0 200 400 600 800 1000 1200 1400 1600 1800 2000
time (seconds)
Flu
x (
ph
oto
ns/s
eco
nd
)
50mM r8 carbonate 6 HBS
25mM r8 carbonate 6 HBS
50mM r8 carbonate 6 K+HBS
25mM r8 carbonate 6 K+HBSLuc-RL(SS)-Trans
Luc + RLSH + HS-Trans
GSH (in cell)
REAL TIME QUANTIFICATION OF CELL UPTAKE IN TRANSFECTED PC3M CELLS
Luc-RL(SS)-Trans
Cell Entry
Light
Luciferase
Phot
ons/s
ec
March 25
0
250,000
500,000
750,000
1,000,000
1,250,000
1,500,000
1,750,000
2,000,000
2,250,000
2,500,000
2,750,000
3,000,000
3,250,000
3,500,000
3,750,000
4,000,000
0 200 400 600 800 1000 1200 1400 1600 1800 2000
time (seconds)
Flu
x (
photo
ns/s
econd)
50mM luciferin HBS 1 minute
50mM luciferin HBS 2 minute
50mM luciferin HBS 5 minute
50mM luciferin K+HBS 1 minute
50mM luciferin K+HBS 2 minute
50mM luciferin K+HBS 5 minute
POINTS OF IMPORTANCE:•UPTAKE & RELEASE ARE RAPID•UPTAKE/RELEASE DOSE DEPENDENT•UPTAKE IS INHIBITED BY K+•UPTAKE/RELEASE MAX. IN MINUTES•SIGNAL FROM CONJUGATE IS ~ ALLFROM BIORELEASE•UPTAKE/RELEASE IS REPRODUCIBLE•UPTAKE OF LUCIFERIN SHOWSDIFFERENT KINETICS
Phot
ons/s
ec
Time (seconds)
Luciferin
Luciferin-RL(SS)-conjugate
K+ inhibition
uptake
L. Jones, E. Goun, R. Shinde, J. Rothbard, C. Contag, P.Wender* J. Am. Chem. Soc. 2006, 128(20), 6526.
FUNCTION ORIENTED SYNTHESIS
Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Craske, M.L.; Horan, J.C.; Meyer, T. “ Function Oriented Synthesis:…” Current Drug Discovery Technologies, 2004, 1, 1-11.
•MEDICINAL AGENTS•MATERIALS•CATALYSTS•PROBES
•OVER 200 TOTAL SYNTHESES / YEAR IN ACS JOURNALS ALONE•MAKING MOLECULES IS NO LONGER THE BIGGEST CHALLENGEIN SYNTHESIS•THE MAJOR CHALLENGES NOW ARE TARGET DESIGN &SELECTION & ADVANCING SYNTHESIS TO MAKE SUCH TARGETS …
*Wender, Miller "Toward the Ideal Synthesis: Connectivity Analysis & Multi-Bond FormingProcesses" in Organic Synthesis: Theory and Applications T. Hudlicky (ed.), V. 2, 27, 1993, JAI Press.
Wender, Wright, Handy, "Toward the Ideal Synthesis" Chemistry & Industry, 1997, 765.
IN A PRACTICAL IF NOT IDEAL FASHION
TWO MAJOR PRIORITIES IN CHEMISTRY
•IMAGING TOOLS•DIAGNOSTICS•SENSORS•NANODEVICES
•ENERGY COLLECTION•ENERGY STORAGE•ENERGY CONVERSION•ENVIRONMENTAL