Index

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 . . .