Pharmacophore-directed retrosynthesis applied to the ion channel inhibitor waixenicin A; multicomponent, enantioselective organocatalytic synthesis of tetrahydropyridazinones.

Kiledal, Sigrid Anne, 1995-

Pharmacophore-directed retrosynthesis applied to the ion channel inhibitor waixenicin A; multicomponent, enantioselective organocatalytic synthesis of tetrahydropyridazinones.

dc.contributor.advisor	Romo, Daniel.
dc.creator	Kiledal, Sigrid Anne, 1995-
dc.date.accessioned	2024-07-17T14:10:19Z
dc.date.available	2024-07-17T14:10:19Z
dc.date.created	2023-08
dc.date.issued	2023-08
dc.date.submitted	August 2023
dc.date.updated	2024-07-17T14:10:19Z
dc.description.abstract	Waixenicin A (waixA) is a xenicane molecule isolated from the marine coral Sarcothelia edmondsoni, and is a known selective inhibitor of the ion channel TRPM7, which mediates a lethal calcium cascade caused by hypoxic ischemic brain injury. This marine diterpene possesses a strained (E)-cyclononene trans-fused to a dihydropyran and a side-chain bearing a vinylogous bis-acetoxy acetal. In addition to its synthetic challenges, waixA is also of biological interest due to potent inhibitions of the ion channel transient receptor potential melastatin 7 (TRPM7), a divalent cation channel essential for maintaining magnesium homeostasis. In addition, this channel plays a critical role in the toxic calcium ion cascade induced by hypoxic-ischemic events. We thus set out to apply pharmacophore-directed retrosynthesis (PDR) to enable access to derivatives of varying complexity en route to the natural product to provide further SAR data for TRPM7 inhibition. In this work, we have accomplished the synthesis of several monocyclic derivatives containing both a simplified sidechain and that found in the natural product. The synthesis of these derivatives and further progress toward annulation of the cyclononene will be presented along with inhibition data toward TRPM7. Secondly, an enantioselective, multicomponent reaction was developed for the synthesis of tetrahydropyridazinones (THPZ), which are well-represented molecules within the realm of pharmaceuticals. This one-pot sequence utilized chiral acylammonium salts generated from tertiary amine catalysts, malonates, and azodicarboxylates in a nucleophile catalyzed-Michael-proton-transfer-lactamization. Subsequent derivatizations of these THPZs were also explored, which revealed unexpected ring-contractions and rearrangements and further displayed the utility of these substrates. Additionally, the use of allyl methyl malonate and a deallylative decarboxylation also enabled the formation of a second stereocenter.
dc.format.mimetype	application/pdf
dc.identifier.uri
dc.identifier.uri	https://hdl.handle.net/2104/12823
dc.language.iso	English
dc.rights.accessrights	No access – contact librarywebmaster@baylor.edu
dc.title	Pharmacophore-directed retrosynthesis applied to the ion channel inhibitor waixenicin A; multicomponent, enantioselective organocatalytic synthesis of tetrahydropyridazinones.
dc.type	Thesis
dc.type.material	text
local.embargo.lift	2028-08-01
local.embargo.terms	2028-08-01
thesis.degree.department	Baylor University. Dept. of Chemistry & Biochemistry.
thesis.degree.grantor	Baylor University
thesis.degree.name	Ph.D.
thesis.degree.program	Chemistry
thesis.degree.school	Baylor University