TARGETING MIXED LINEAGE LEUKEMIA AS ANTICANCER THERAPY FOR INFANTILE ACUTE LYMPHOBLASTIC LEUKEMIA THROUGH THE SYNTHESIS OF NOVEL COMPOUNDS Open Access

Smentek, Matthew (2010)

Permanent URL: https://etd.library.emory.edu/concern/etds/8049g526h?locale=en
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Abstract

Abstract
TARGETING MIXED LINEAGE LEUKEMIA AS ANTICANCER THERAPY FOR INFANTILE ACUTE LYMPHOBLASTIC LEUKEMIA THROUGH THE SYNTHESIS OF NOVEL COMPOUNDS
By: Matthew G. Smentek

The synthesis of novel pharmaceutical compounds for anticancer therapy is a major focus for medicinal synthetic chemists. Recently, a novel compound (SM7) was discovered which could be used to develop a method to inhibit Acute Lymphoblastic Leukemia (ALL) translocation in the leukemia gene by targeting a variety of inhibitors for inducing cytotoxicity in a variety of MLL-leukemia cell lines. The biological evaluations for this compound may be specific for Mixed Lineage Leukemia (MLL) cell lines, but since the MLL transcription factor is found in 70-80% of infant ALL cases it may have clinical ramifications for the treatment of ALL.

The ultimate goal is to design a set of analogues of SM7 and have our collaborators test their biological efficacy. The chemistry used to synthesize these compounds has been well established and offers a simple pathway to establish molecular complexity rapidly. Nearly thirty different analogues were synthesized and tested for their biological efficacy. Of this small library of compounds, three showed promising levels of activity against MLL cell lines. These promising results suggest that the pursuit of further analogues may eventually yield an effective compound that may be used in future biological tests.

Another important series of analogues was also conceived which contained a heterocyclic moiety similar to that in compound SM7. Testing these molecules will be interesting because they offer an alternative molecular structure that bears a cyclopropyl moiety prevalent in a variety of biologically active compounds.

Table of Contents

TABLE OF CONTENTS

INTRODUCTION...1

Methods of Preparation for Analogues of SM7...5
Potentially Biologically Active Cyclopropyl Analogues...9
Summary...10

RESULTS AND DISCUSSION...12

Analogues Prepared from O-Alkylation...15
Analogues Prepared from Commercially Available Material...19
Cyclopropyl Analogues...24
Conclusions...28

EXPERIMENTAL...31
REFERENCES...71


LIST OF FIGURES

1. Lead Compound and General Structure of Initial Targets...1
2. Crucial Functionalities Within SM7...3
3. Method A: Condensation of Aldehydes with Hydantoin...6
4. Method B: Condensation of Aldehydes with N-Aryl Pseudothiohydantoin...7
5. Method C: Condensation of Aldehydes with 2-thioxo-thiazolidin-4-one...7
6. Method D: Condensation of Aldehydes with Various (Thio)Hydantoins...8
7. General Structure of the Cyclopropyl Target...9
8. Illustration of the Cyclopropanation of Vinyl Donor/Acceptor Carbenes...9
9. Synthesized Analogues of Lead Compound SM7...13
10. Condensation Reaction Between Vanillin and Hydantoin...14
11. O-Alkylation of Vanillin with Varying Reagents...15
12. Synthesized Analogues 4-11 and SM7...17
13. Biological Activity of Analogues 4-11 and SM7...18
14. Synthesized Analogues 12-15...19
15. Biological Activity of Analogues 12-15 and SM7...20
16. Synthesized Analogues 16-19...21
17. Biological Activity of Analogues 16-19 and SM7...22
18. Synthesized Analogues 20-33...23
19. Cyclopropyl Targets...24
20. Cyclopropanation of Electron-Rich Styrenes...25
21. LAH Reduction of Cyclopropyl Esters...26
22. Silyl Protection of the Primary Alcohol...26
23. Endgame of Cyclopropyl Analogue Synthesis...27
24. Biologically Active Compounds...29

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