t. w. schultz presented at the logan workshop march 23-24, 2010
TRANSCRIPT
![Page 1: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/1.jpg)
T. W. Schultz
Presented at the Logan Workshop
March 23-24, 2010
![Page 2: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/2.jpg)
Background Method & Data Base Reactions & Coverage What We are Currently Doing
![Page 3: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/3.jpg)
No consensus in number > 25 < 50 (40)Vary in preferred target moiety
Typically 45% -SH and 45% -NH2
Vary in structural domain Simple: isothiocyanate RN=C=S Complicated: Michael addition Complex: SNAr addition
![Page 4: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/4.jpg)
In order of increasing hardness include:
Thiol-group of cysteine S-atom of methionine Primary amino-group of lysine Secondary amino-group of histidine
![Page 5: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/5.jpg)
CH2=CH- k(thiol) K(amine) ______________________________________________________
C(=O)OMe 0.011 0.00076
C#N 0.0027 0.00020
C(=O)NH2 0.00046 0.000026
Different nucleophiles can differ in their absolute reactivity towards a given electrophile, but relative
reactivity is well correlated over a range of nucleophiles within the same mechanism.
![Page 6: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/6.jpg)
Use in a similar context to in vitro or in silicoQuantitative, rapid, inexpensive
experiments with model nucleophilesVerify reaction-based rules of reactivityDefine the chemical space of a reactionProvides a measure of relative potencyUseful in refining categories and modeling
![Page 7: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/7.jpg)
Full Kinetics- measured at several time intervals with several initial concentrations of electrophile (100 chemicals)
Partial Kinetics- measured at several time intervals with one initial concentrations of electrophile (O’Brien Assay)
Concentration giving 50% reaction in a fixed time- measured at one time with several initial concentrations of electrophile (1000 chemicals)
Extent of reaction after a fixed time- measured at one time with one initial concentrations of electrophile (Gerberick Assay)
![Page 8: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/8.jpg)
Quantitative with kinetics-linked endpointSimple, rapid, repeatable, and inexpensiveCysteine-based thiol targetDepletion-based (% free thiol) Analyses by
Concentration-Response (RC50)
Full kinetic
![Page 9: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/9.jpg)
![Page 10: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/10.jpg)
Readily availableConcentration can be analyzed by simple
methodsOdorless, non-hazardousWater soluble but NOT readily soluble in
organic solventsDoes not lead itself to HPLC
![Page 11: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/11.jpg)
Initial concentration of electrophile that gives a half-life of 120 minutes
Good if electrophile is in excess Adequate if concentrations of
electrophile and GSH are similar Poor if GSH is in excess; RC50 values are
then extrapolated
![Page 12: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/12.jpg)
> 2,600 individual assays≈ 1,000 separate structure> 25 different organic reactions (mechanisms)> 300 not reactive because of structure< 100 not reactive because of solubility< 50 not reactive because of color interference
![Page 13: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/13.jpg)
Highly relevant with multiple domains1) Michael Addition2) Nucleophilic substitution (N-sub) of
haloaliphatics3) N-sub of haloaromatics (SNAr)
![Page 14: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/14.jpg)
1) Michael Addition > 250 compounds (cpds)
2) Pre-Michael Addition > 50 cpds
3) N-sub of Haloaliphatics > 150 cpds
4) N-sub of Haloaromatics > 125 cpds
![Page 15: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/15.jpg)
Highly relevant with simple domains 1) disulfide exchange 2) O-heterocyclic ring opening 3) N-sub of alkyl sulfates & sulfonates 4) nitroso- & N-oxides 5) disulfide formation
![Page 16: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/16.jpg)
1) disulfide exchange, >10 cpds 2) O-heterocyclic ring opening, 20 cpds 3) N-sub of alkyl sulfates, 5 cpds 4) N-sub of alkyl sulfonates, >10 cpds 5) nitroso-compounds, >5 cpds 6) N-oxides, 10 cpds All demonstrate GSH reactivity &
are related to sensitization
![Page 17: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/17.jpg)
Less relevant 1) arenesulfinic acid substitution 2) azomethyne addition 3) thiocyanate addition 4) mercury thiolate formation 5) others
![Page 18: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/18.jpg)
Other chemical classes 1) unsaturated alcohols 2) secondary amines 3) dialkyl acetals 4) lactates 5) anhydrides (hydrolysis) 6) aldehydes (Schiff-base formers) 7) diones (cycloaddition to diamines)
![Page 19: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/19.jpg)
only ,-unsaturates are reactive
Compounds RC50 (mM) _______________________________________________ C=CC(O)Cn 25 - 50 C#CC(O)Cn 1.0 – 3.0 OCC=CCn 5.0 - 10.0 OCC#CCn 3.0 - 5.0
1-pentyn-3-ol 1.3, 1.7 4-CH3-1-pentyn-3-ol 16, 13 3,4-CH3-1-pentyn-3-ol NR at 50mM
![Page 20: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/20.jpg)
Base Structure and Special Features
R1C(X)YR2
Y = C6H5 > C#C > C=C, etc
X = I > Br > Cl > F
R1 = H > CnH(2n +1)
R2 no effect
![Page 21: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/21.jpg)
Base Structure and Special Features
XC6H3Y2
Y = NO2, > in-ring-N > CHO > CN
X = F > Cl > Br > IPosition of leaving group in relationship to activity groups effects potency
![Page 22: T. W. Schultz Presented at the Logan Workshop March 23-24, 2010](https://reader035.vdocuments.net/reader035/viewer/2022070411/56649f345503460f94c50cb8/html5/thumbnails/22.jpg)
Thank you