Dissertation/Thesis Abstract

Synthesis of 7-Alkyl-3-Benzylcoumarins and Organophosphate-Coumarin Hybrids: Potential Implications in Cancer and Alzheimer's Disease
by Macklin, Lee Jared, M.S., California State University, Long Beach, 2020, 175; 28024501
Abstract (Summary)

Some new synthetic analogs of coumarin-based cannabinoid ligands (7-pentyl-3-benzylcoumarins) were synthesized and characterized by physical methods. A pipeline of these compounds based on the versatile 3-benzylcoumarin scaffold might lead to the identification of novel anti-tumor agents for certain cancers overexpressing the cannabinoid receptor subtype 2 (CB2R).

Furthermore, a small library of new organophosphorylated warfarins and 3-benzylcoumarins were synthesized and evaluated for in vitro cholinesterase inhibition by Ellman’s method. Most of the compounds were found to be selective for butyrylcholinesterase (BChE) over acetylcholinesterase (AChE), with IC50 values ranging from 0.363 μM to 53.0 μM determined after 15 seconds of enzyme exposure. Comparison of the most potent compound, 39c (3-benzyl-2-oxo-2H-1-benzopyran-5-yl diethyl phosphate) with its constitutional isomer 37c (diethyl 4-[(2-oxo-2H-1-benzopyran-3-yl) methyl] phenyl phosphate) revealed the high importance of phosphate positioning. Reversed selectivity and a 100-fold reduction of BChE inhibition was observed when the organophosphate was attached to the benzyl group instead of the coumarin core. Docking calculations suggest that 39c binds initially as a transition state mimic with near-optimal phosphate orientation relative to S198 and occupation of the oxyanion hole prior to phosphorylation.

Although many new reversible cholinesterase inhibitors are continually being described in the literature, we are unaware of any other reports describing irreversible BChE-selective coumaric inhibitors. Herein we have identified a new versatile coumarin scaffold as an efficient active-site director of covalent modifiers toward the esteratic site of BChE. The versatile lead scaffold 39c represents a proof of principle for a new class of irreversible coumarin-based inhibitors that are BChE-selective and are not limited to use of organophosphorus covalent modifiers These results might inspire the design of a new type of non-neuropathic and irreversible coumarin-based inhibitor against BChE, an important biomarker for Alzheimer’s disease progression.

Indexing (document details)
Advisor: Schwans, Jason P.
Commitee: Nakayama, Kensaku, Narayanaswami, Vasanthy
School: California State University, Long Beach
Department: Chemistry and Biochemistry
School Location: United States -- California
Source: MAI 82/4(E), Masters Abstracts International
Source Type: DISSERTATION
Subjects: Biochemistry, Medicine
Keywords: Alzheimer's disease, Butyrylcholinesterase, Coumarin, Organophosphate, Warfarin
Publication Number: 28024501
ISBN: 9798684652837
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