Pharmacophore-directed retrosynthesis (PDR) and Density functional theory studies applied to the potent ion channel inhibitor waixenicin A : synthetic studies toward a more stable salarin C congener, thia-salarin C, through the lens of PDR.

Waixenicin A (WaixA) exhibits potent (615 ± 121 nM) and highly selective inhibition of transient receptor melastatin 7 (TRPM7) over closely related ion channels. Thus, WaixA serves as a potential drug lead for the treatment of hypoxic-ischemic brain injury (HIBI) and a compelling target for synthetic efforts coupled to biological studies. We first performed conformational studies utilizing density functional theory (DFT) to gain insights into possible bioactive conformations of WaixA and information regarding the potential stabilizing interactions involved in the vinylogous acetal, which is the proposed pharmacophore. Pharmacophore-directed retrosynthesis (PDR) was also applied to WaixA leading to the design and synthesis of a series of monocyclic derivatives bearing the proposed pharmacophore. The ability of these highly simplified WaixA derivatives to exert inhibitory effects on TRPM7 was measured through patch clamp experiments by our collaborators (Hawaii Pacific University). Pharmacophore-directed retrosynthesis was also applied to the potent anti-cancer macrolide salarin C (SalC). SalC is one of ten congeners of this marine natural product family but shows the highest potency towards myeloid leukemia cells (IC50=5 nM) however, the mode of action is currently unknown, making it an ideal target for concurrent synthetic and biological studies. SalC also exhibits extreme instability towards singlet oxygen (1O2) through a Wasserman rearrangement, even concentrations present in ambient air, causing difficulties in both synthetic endeavors and manipulations during previous biological studies. This led us to hypothesize that replacing the endocyclic oxazole with a thiazole would reduce the rate of the Wasserman rearrangement, as previously shown in simpler systems, improving the stability while ideally not altering the potent anticancer activity given the minor change in conformation as determined by DFT. Previous researchers in our lab had incorrectly assigned the structure of a simplified thiazole containing macrolactone designed to test our hypothesis. We corrected these previous results and were able to show that introduction of the thiazole indeed prevents Wasserman rearrangement, however, alkene isomerization is observed when exposed to lab lighting over time. Furthermore, building on our now established route to the simplified thiazole-containing macrocycle, we were able to synthesize fragments required for the synthesis of thia-salarin C (thia-salC) that would involve fashioning the macrocycle followed by step-wise introduction of further functional arrays (e.g. epoxides and carbamate and side-chains) required for potent anticancer activity in a manner similar to tailoring biosynthetic enzymes. Our work begins with the synthesis of a triene fragment utilizing a cost-effective, enantiopure lactone with both stereocenters pre-installed as well as construction of the majority of the carbon skeleton through two, highly stereoselective, Julia-Kocienski olefinations.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Doctoral

Grantor

Baylor University.

Year dc:date.issued

2026

Author dc:creator

• Parris, Matthew Ray, 1997-

Advisor dc:contributor.advisor

• Romo, Daniel.

• Natural product synthesis.
• salarin C.
• Pharmacophore-directed retrosynthesis (PDR)
• Waixenicin A.

Statement dc:rights

• Baylor University works are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. Contact libraryquestions@baylor.edu for inquiries about permission.

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/2104/14792

OAI identifier oai:identifier

oai:baylor-ir.tdl.org:2104/14792