Fused Heterocycles as Spinster Homolog 2 Inhibitors and Regio- and Stereoselective Copper-Catalyzed Borylation-Protodeboronation of 1,3-Diynes: Access to (Z)-1,3-Enynes
| dc.contributor.author | Burgio, Ariel Louise | en |
| dc.contributor.committeechair | Santos, Webster | en |
| dc.contributor.committeemember | Schulz, Michael | en |
| dc.contributor.committeemember | Lowell, Andrew Nesemann | en |
| dc.contributor.committeemember | Etzkorn, Felicia A. | en |
| dc.contributor.department | Chemistry | en |
| dc.date.accessioned | 2023-05-20T08:00:30Z | en |
| dc.date.available | 2023-05-20T08:00:30Z | en |
| dc.date.issued | 2023-05-15 | en |
| dc.description.abstract | Sphingosine 1-phosphate (S1P) is a lipid chemoattractant molecule. Once formed, S1P can be transported extracellularly by S1P transporters spinster homolog 2 (Spns2) or major facilitator domain containing 2B (mfsd2b). In the extracellular space, S1P can bind to S1P-specific G-protein coupled receptors (S1PR), which initiate many signaling pathways. A critical role of extracellular S1P is its ability to cause lymphocyte egress, which can have implications for inflammatory and autoimmune diseases. For this reason, there has been a growing interest in exploring potential spns2 inhibitors to further elucidate their therapeutic potential. Initial screenings confirmed that fused heterocycles, including phthalimide and benzoxazoles, demonstrated moderate inhibition of Spns2 using a HeLa cell assay. An extensive structure-activity relationship (SAR) study of these scaffolds was performed to analyze the impact of various amine head groups, regioisomers, and alkyl tails on performance. It was determined that 2-aminobenzoxazoles with secondary amines were potent inhibitors of the transporter. Additionally, the position of the lipophilic tail moiety played a large role in activity. From these modifications, SLB1122168 (2.44p) was found to be our lead compound. It was determined that (2.44p) had an IC50 of 94 ± 6 nM and was shown to be efficacious in decreasing lymphocyte count by 55% in a dose-dependent manner in both rat and mice models. The discovery of (2.44p) can serve as a novel chemical tool to investigate Spns2 biology and use it as a probe to determine the potential of Spns2 as a drug target. Organoboron compounds are useful synthetic intermediates in forming C-X, C-C, and C-H bonds. One way to synthesize these compounds is through copper catalysis. Copper is favorable to other transition metals because it is an Earth-abundant, low-cost metal that can be utilized in regio- and stereoselective reactions. Conjugated 1,3-enynes are important functional groups that iii are found in active natural products, organic synthetic intermediates, and materials. Previous methods used rare transition metals, designer ligands, or harsh acidic conditions to synthesize such compounds. In this dissertation, we developed a stereoselective one-pot copper-catalyzed semi-reduction of 1,3-diynes to produce (Z)-1,3-enynes. This method uses Cu(OAc)2, HBpin and Xantphos to successfully synthesize (Z)-1,3-enynes that were tolerated well over a broad substrate scope, including heterocyclic, alkyl, and aryl substituents. It was determined that this reaction went through a 2-boryl intermediate which was facilitated by a CuH species. | en |
| dc.description.abstractgeneral | Autoimmune diseases are caused by immune cells attacking healthy cells. The signaling lipid sphingosine-1-phosphate (S1P) plays a major role in trafficking immune cells, in which immune cells follow the S1P gradient from low concentrations (secondary lymphoid tissues) to high concentrations (lymph). In the case of multiple sclerosis, immune cells can attack healthy neurons that cause a myriad of symptoms. Currently, there are four drugs approved by the Food and Drug Administration (FDA) targeting the S1P pathway for multiple sclerosis. In all cases, these drugs act as S1P-receptor (S1PR) functional antagonists, which decreases the amount of extracellular S1P, which in turn decreases the immune cells in the lymph that can attack healthy cells. Unfortunately, all four drugs exhibit on-target cardiovascular side effects. To circumvent the on-target side effects seen in current FDA-approved drugs, other nodes of the S1P pathway have been assessed for multiple sclerosis. One node of interest is spinster homolog 2 (Spns2), a transporter of S1P, whose inhibition has also been shown to decrease extracellular S1P. In this dissertation, we will be assessing various inhibitors for their in vitro and in vivo properties. 1,3-Enynes are a functional group found in medicinally relevant compounds and can be used as intermediates to make more complex compounds. Current methods to make this functional group use expensive rare metals or harsh acidic conditions. We developed new methods that utilized copper, an abundant metal, and boron, an atom whose empty p orbital allows for unique reactivity. Utilizing a copper-hydride species allowed us to semi-reduce 1,3-diynes to (Z)-1,3-enynes, where water was used instead of acid to allow for the semi-reduction to occur. This reaction was shown to tolerate a wide range of substrates and gave good to excellent yield. | en |
| dc.description.degree | Doctor of Philosophy | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:37302 | en |
| dc.identifier.uri | http://hdl.handle.net/10919/115126 | en |
| dc.language.iso | en | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | Sphingosine-1-phosphate | en |
| dc.subject | S1P | en |
| dc.subject | Spns2 | en |
| dc.subject | lymphopenia | en |
| dc.subject | transporter inhibitor | en |
| dc.subject | copper catalysis | en |
| dc.subject | copper-hydride intermediate | en |
| dc.title | Fused Heterocycles as Spinster Homolog 2 Inhibitors and Regio- and Stereoselective Copper-Catalyzed Borylation-Protodeboronation of 1,3-Diynes: Access to (Z)-1,3-Enynes | en |
| dc.type | Dissertation | en |
| thesis.degree.discipline | Chemistry | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |