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Introduction Experiment Results Conclusion
Introduction
2004 Summer San Francisco State University Dr. Clifford Berkman’s lab Research Purpose: To make the medicinal dr
ug for prostate cancer.
Introduction
Prostate cancer is one of the most frequently diagnosed cancers among men and the second most common cause of cancer-related deaths in American (second to lung cancer).
About 200,000 men are diagnosed each year.
Reference: Prostate.com
Introduction: Prostate Cancer
Benign or Malignant
Malignant cancer Cells Spread from the prostate to nearby lymph nodes, bones or other organs.
Introduction: PSMA
When A man has prostate cancer, an enzyme called PSMA is located on the surface of the cancer cell
PSMA: Prostate Specific Membrane Antigen
Enzyme is a Protein used to catalyze biological reactions The Enzyme PSMA
What’s going on at the Surface
Domain E is responsible for the catalytic activity of the enzyme.
The other Domains has no enzyme activity
E: Catalytic activity
A model for the organization of the PSMA.
Prostate Cancer Cell
Introduction: Inhibitors
The Medicinal Drugs we were trying to make this summer are called inhibitors
Inhibitors are compounds that stop the growth of cancer cells
Preliminary Studies done by Dr. Berkman suggest that compounds that look like the one in figure 1, can decrease cancer growth
Figure 1
Introduction
X = 4-Cl, 4-OMe, 4-Me, 3,4-Cl2, 4-OPh 3-Cl, 4-tBu, 4-CF3, 4-Br, 3-CF3-4-Cl, 3-Me, 4-N(Me)2, 3-N(Me)2, 3-CF3, 2,4-Cl2, 4-NO2, 3-CF3-4-NO2, 4-NH2, 4-OH, 3-Ome, 4-OiPr, 2-Cl, 2-Me, 2-OMe, 4-F, 3,5-Cl2, 3-NO2, 4-OCH2Ph,
Figure 1
X could be those following molecules.
The following molecule looks like the drug we are trying to design for prostate cancer.
Introduction
In order to make the compound in Figure 1, the first step is to make the compound in Figure 2.
Figure 2
Figure 1
Wanted and Unwanted Compound
PO
O
O
PO
O
O
Wanted Compound Unwanted Compound
During the course of the summer, my responsibility was to make the desired molecule above. But we had a lot of problems with the chemistry. Our Desired compound kept isomerizing into the unwanted compound above.
The Experimental
The next couple of slides details how the Wanted and Unwanted compounds were
made
Experimental: Experiment 1 Reaction Scheme
PO
O
O
H
Br
CH3
SiN
SiCH3CH3CH3
CH3CH3
PO
O
O
PO
O
O
PO
O
O CH3
SiNH
SiCH3CH3CH3
CH3CH3+ K+(-)Toluene
0oC : (-) K+
+
Neat
Various Temperature
Step 1
Step 2
+
Unwanted CompoundWanted Compound
Phosphonate Salt
Side Product
Allyl Bromide
DibenzylphosphonatePotassium Hexamethyl
disilazane
Experiment
Step 1 Add Dibenzylphosphite to a round bottom flask with
a magnetic stir bar. Set this flask on an Ice Bath Add Potassium hexamethyl disilazane ( KHMDS) dr
op wise and stir for 1hour
Step 2 Remove the Ice Bath Add allyl bromide drop wise and stir overnight At this point the heat conditions will be employed
Experiment 1
Experiment
Experiment 2…Resaction Scheme
PO
O
O
H
BrP
O
O
O
PO
O
O
PO
O
OO
OH+
+
Unwanted Compound Wanted Compound
THF or DMSO
Room Temperature
:(-) K+
+
Neat
Room Temperature
K+: (-)
Step 1
Step 2
Dibenzylphosphite
Side Product
Allylbromide
PhosphonateSalt
Potassium tert-Butoxide
Experiment
Step 1 Add Dibenzylphosphite to a round bottom flask wi
th a magnetic stir bar. Set this flask at room temperature
Add Potassium tert-Butoxide (powder) and stir for 1 hour
Step 2 Add Allyl Bromide drop wise and stir overnight At this point the heat conditions will be employed
Experiment 2
Experiment
Using a Separatory Funnel, the reaction mixture inside Add Ethyl Acetate (EtOAc) Add water
There were two layers present. organic was at the top aqueous was at the bottom
Shake the separotory funnel and release aqueous layer Wash with 10% HCl and shake and release aqueous layer Wash with NaHCO3 and shake and release aqueous layer Wash with Sat. NaCl and shake and release aqueous layer Dry the reaction with Na2SO4
Filter Na2SO4 and evaporate the solvent
Work up Procedure
(For Both Experiments)
Experiment
Once the solvent is evaporated, Run a TLC using 10% Isopropanol in Hexane 3% Methanol in Dicholoromethane
Run a Crude NMR Purification with 3% Methanol in Dichloromethane Run a Pure NMR Get the graphs of NMR tests.
Test Procedure
Results
Experiment 1 gave both wanted and unwanted product.
Experiment 2 gave only the desired product.
Comparison
The Wanted CompoundAllylphosphonate
The UnwantedVinylphosphonate
PO
O
O
PO
O
O
Results
Experiment 1 % Yields
Temperature oC
Major Compound Starting Materials
Wanted Compound
Unwanted Compound
0 Unwanted Product 0% 8% 92%
25 Unwanted Product 0% 14% 86%
40 Unwanted Product 0% 10% 90%
The results of the experiment 1 gave the unwanted compound and a small amount of the wanted compound.
Experiment 1
ResultsExperiment 2
The results of the experiment 2 gave the majority of the wanted compound and a small amount of the starting material. No unwanted product was present.
Experiment 2 % YieldsTemperature Resulting
CompoundStarting
MaterialsWanted
CompoundUnwanted Compound
25 Wanted Product
25% 75% 0%
Results
The reason why I tried experiment 1 under three different conditions is at each temperature condition the major product was the unwanted compound.
By changing the condition we thought that we could produce the wanted compound. We tried experiment 2 only one time and received the wanted compound with the first attempt.
NMR Results
The next couple of slides Characterize the Compound found in Experiment 2
PO
O
O
CH
2
CH2CH
CH
CH
CH
CH
CH
2
CH
CH2
CH
CH
CHCH
CH
(a)
(b)
Ethyl Acetate
Hb Ha
This a crude NMR
•The Crude NMR is shown to show that the reaction did not produce any of the unwanted compound
•There is some allylbromide present. And some EtOAc present but we know that the wanted compound is present because of the Ha and Hb Peaks.
Benzene RingRegion
Proton NMR test result of an experiment after experiment 2
ResultsPhosphorus NMR test result of an experiment after experiment 2
This test looks like we get the wanted compound.
25.09 ppm indicates our wanted compound.
PO
O
O
CH
2
CH2CH
CH
CH
CH
CH
CH
2
CH
CH2
CH
CH
CHCH
CH
Conclusion
The wanted compound may not be stable when using the conditions from Experiment 1, because we saw it isomerizing to the unwanted compound.
The wanted compound was formed when we tried Experiment 2. This experiment will be done to conform the results.
Other chemical methods will be used for making the allylphosphonate.
Special Thanks
Dr. BerkmanDr. BerkmanThanks for helping and teachingThanks for helping and teaching
Mentor: Nichole ColemanMentor: Nichole ColemanThanks for helping and teaching me patiently.Thanks for helping and teaching me patiently.
Ms. Elaine Yamaguchi & Mr. Glann Fuller & Wally YokoyamaMs. Elaine Yamaguchi & Mr. Glann Fuller & Wally Yokoyama American Chemical SocietyAmerican Chemical Society Mr. MatsumotoMr. Matsumoto Project Seed MentorsProject Seed Mentors
Thanks for helping me.Thanks for helping me.
Project Seed StudentsProject Seed StudentsThanks for having lunch with me.^-^Thanks for having lunch with me.^-^
A n d . . .
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