Part I: Design, Synthesis and Biological Evaluation of C6-C8 Bridged Epothilone AnalogsPart II: Discovery of Small Molecule CXCR4 Antagonists Open Access

Zhan, Weiqiang (2008)

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In the first part of this dissertation, a series of conformationally restrained epothilone analogs with a short bridge between methyl groups at C6 and C8 were designed to mimic the binding pose determined for our recently reported EpoA-microtubule binding model. A versatile synthetic route to these bridged epothilone analogs has been successfully devised and implemented. The key stereochemistry within the bridged C6-C8 sector was controlled by asymmetric allylboration followed by hydroxy-directed epoxidation and regio-controlled epoxide opening with a Grignard reagent. The biological evaluation of these bridged epothilone analogs against A2780 human ovarian cancer cell line suggested that the introduction of a bridge between C6-C8 made these epothilones less potent by 55-1000 fold in comparison with Taxol. The biological results further confirmed the previous depicted structure-activity relationship (SAR) profile of epothilones, and provided significant SAR information arising from the C6-C8 sector.

The second part of this dissertation describes the discovery of novel small molecule CXCR4 antagonists. Compelling evidence is accumulating that the CXCR4/SDF-1 interaction and the resulting cell signaling cascade play a key role in metastasis by facilitating locomotion, chemoattraction, homing and adhesion of the metastatic cells to the defined organs, as well as supporting tumor growth and angiogenesis.In view of aspects of the molecular mechanism of the CXCR4 antagonist, AMD3100, we designed a template and identified G1 lead WZ13 by means of an affinity binding assay against the ligand-mimicking CXCR4 antagonist, TN14003. Following a structure-activity profile around WZ13,the design and synthesis of a series of novel small molecule CXCR4 antagonists led to the discovery of G2 lead WZ811, which shows subnanomolar potency in an affinity binding assay and in vivo function assays. Attempts to improve the pharmacokinetic profile of WZ811 resulted in the discovery of MSX-122 (WZ40). Preclinical studies indicated that MSX-122 is a novel, safe, and highly effective agent with oral bioavailability to block cancer metastasis and tumor angiogenesis by antagonizing CXCR4. MSX-122 is currently in phase I clinical trials.

Table of Contents

Part I: Design, Synthesis and Biological Evaluation of C6-C8 Bridged Epothilone Analogs 1.1. Introduction and Background 1.1.1 Microtubules: A Validated Target for Anti-Cancer Drugs 1.1.2 Epothilones: New Age for Anti-Cancer Drugs Targeting Microtubules 1.1.3 SAR Studies of Epothilones 1.1.4 Conformational and Modeling Studies of Epothilones 1.2. Design and Synthesis of C6-C8 Bridged Epothilones 1.2.1 Design Rationale 1.2.2 Initial Synthesis via Ring Closure Metathesis 1.2.3 Second Generation Synthesis via Suzuki Coupling 1.3. Biological Evaluation of Analogs 1.4. Conclusion 1.5. Experimental Section 1.5.1. Chemistry 1.5.2. Molecular Modeling and Docking 1.5.3. Cytotoxicity Assay 1.5.4. X-ray Crystallography data 1.6. References Part II: Discovery of Small Molecule CXCR4 Antagonists 2.1. Introduction and Background 2.1.1. CXCR4 Chemokine Receptor and Its Ligand SDF-1 2.1.2. AMD3100: A Potent CXCR4 Antagonist 2.2. Discovery of Small Molecule CXCR4 Antagonists 2.2.1 Design Rationale 2.2.2 Initial Screening to Identify the G1 Lead WZ13 2.2.3 SAR Study of WZ13 to Discover of G2 Lead WZ811 2.2.4 Functional Assays of WZ811 2.2.5 Discovery of MSX-122 2.2.6 Preclinical Study of MSX-122 2.3. Conclusion 2.4. Experimental Section 2.4.1 Biochemistry 2.4.2 Chemistry 2.5. References

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