Modification of Tetrahydroisoquinoline-and-Mopholine-Containing CXCR4 Antagonists with Morpholine Analogs Restricted; Files Only

Wen, Yuming (Spring 2019)

Permanent URL: https://etd.library.emory.edu/concern/etds/x059c823j?locale=en
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Abstract

CXCR4 is a G-protein-coupled receptor that has only one natural ligand, CXCL12. Upon the binding of CXCL12, pathways downstream of CXCR4 such as pro-survival, proliferation, chemotaxis signaling, and transcription of immunosuppressive related genes are triggered. Cancer cells that overexpress CXCR4 can be attracted to CXCL12 rich niches and recruit immunosuppressive leukocytes. Inhibition of CXCR4 with small molecule antagonists can make the cancer cells more susceptible to chemotherapy drugs and the immune system and less likely to metastasize. EMU-000172 is one of a series of tetrahydroisoquinoline-based CXCR4 antagonists developed by Liotta group. It has a good predicted passive diffusion rate but still requires improvement in its off-target effect and metabolic stability. A series of morpholine analogs were chosen to replace the morpholine on EMU-000172. 11b and 12 were the first two to be synthesized. The approaches applied to synthesize 11b suffer from low conversion rates and a large amount of byproducts. However, with a Buchwald-Hartwig amination condition different from those previously used by other group members and a tailored TFA-mediated N-Boc deprotection, the effort to make 12 resulted in a good yield.

Table of Contents

Introduction                                                                                                                                     1

Result and discussion                                                                                                                      4

Future work                                                                                                                                    8

Conclusion                                                                                                                                      9

Experimental                                                                                                                                   9

References                                                                                                                                     18

Figures:

Figure 1. Small CXCR4 protagonists in the literature. Ψ indicates the ψ[-C(=NH)-NH-] substructure.

Nal stands for 3-(2-naphthyl)alanine.     2

Figure 2. TIQ-15 analogs synthesized previously by Liotta group.                                    3

Figure 3. Analogs of EMU-000034 previously synthesized by Liotta group.                    4

Figure 4. Morpholine analog candidates and the position of their oxygen relative to the original morpholine oxygen.

The angle was predicted with SMALL-MOLECULE DRUG DISCOVERY SUITE by Schrödinger. The 3D structure was drawn with PyMOL by Schrödinger.   5

Schemes:

           Scheme 1. Preparation of the key intermediate 10                                                        5

           Scheme 2. Preparation of 11a and 11b                                                                              6

           Scheme 3. N-Boc group deprotection of 11a with TFA     

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