Synthesis of alkyl analogues of 1,4-dihydropyridine for developing novel treatment against chemoresistance in prostate cancer Öffentlichkeit

Abstract

Prostate cancer is the leading cancer-related cause of death among male patients in the United States. The development of chemoresistance in prostate cancer calls for urgent emphasis in development of novel treatment to address this medical need. Recent studies have revealed that cancer cells are highly dependent on the EED-EZH2 signaling pathway as a mechanism of chemoresistance, and EED protein inhibition may be the key to target chemoresistance by disrupting EED-EZH2 protein-protein interaction. Nicardipine, among all of the existing known EED inhibitors, constitutes the most ideal candidate due to its advanced known drug profile. This thesis presents the synthesis and characterization of a novel class of analogues for screening and selecting optimal clinical candidates for cancer treatment development. Since the antihypertensive effect is undesirable and the nitrophenyl ring attached to the C4 position of nicardipine is suspected to be an active calcium channel-blocking component, the rational design consists of replacing the nitrophenyl ring with other substituents—specifically, cyclic and acyclic alkyl groups. Overall, the 1,4-dihydropyridine analogues were synthesized using the Hantzsch condensation, and most entries gave adequate overall yields of 30% to 40%. Significant effort was invested into optimizing the purification process to ensure substantial purity of all analogues for biological screening assay. All compounds were thoroughly characterized prior to biological testing for structural activity relationships, and future direction of synthesis were determined based on preliminary SAR results. We have successfully identified multiple candidates with optimal cellular activities with great potential to proceed into the clinical trials.

Table of Contents

Table of Contents

 

 

 

 

Introduction/Background                                                                                                1

 

Review of existing literature                                                                                           5

 

Methods                                                                                                                         10

 

Result and analysis

 

---General discussion of experimental outcome                                                      13          

 

---Spectroscopic analysis                                                                                              18

 

---SAR result and other aims                                                                                        24

 

Conclusion                                                                                                                      27

 

References                                                                                                                     29

 

Supporting information

 

---Experimental procedure                                                                                            32

 

---Mass spectrometry                                                                                                     36

 

---Nuclear magnetic resonance spectra                                                                     44

 

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic
Stichwort	Spectroscopic analysis Repurposing medication Medicinal chemistry Organic chemistry Synthetic chemistry
Committee Chair / Thesis Advisor	Frank McDonald, Emory University
Committee Members	Jose Soria, Emory University James Kindt, Emory University

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