Synthesis of amyloid-selective lysine acetylating agents, synthetic studies toward the total synthesis of (±)-caseabalansin A, and progress toward the total synthesis of (±)-isopalhinine A.

Abstract

Repulsive electrostatic forces between prion-like proteins limit the aggregation between them. In medicinal chemistry, a protein’s net electrostatic charge (Z) is an uncommon target and compounds that increase a prion’s Z are unreported. Our goal was to synthesize compounds that covalently and selectivity increase the negative charge of misfolded superoxide dismutase-1 (SOD1) by acetylating lysine-NH3+ in amyloid-SOD1. The active compounds mirror a “ball and chain” mace: a rigid amyloid-binding handle (benzothiazole, stilbene, or styrylpyridine); an aryl ester “ball”; and a flexible triethylene glycol chain which connects the handle and ball. When the compounds were employed in stoichiometric excess, acetylation up to 9 out of 11 lysine per misfolded subunit occurred and supercharged amyloid-SOD1 propagated more slowly than naturally charged amyloid-SOD1. These compounds are the first to selectively modify a protein in its amyloid state over its native state, and might give a clue as to how medicinal chemist can slow down prion propagation. In 2013, the Clerodane diterpenoid caseabalansin A was isolated from Casearia balansae along with its epimer 18-epicaseabalansin A. The natural products showed selective activity against PC3 tumor cells once O-acetylation was performed. Along with the compound’s modest biological activity, caseabalansin A has a number of interesting synthetic features including, a fused tetracyclic framework, a conjugated diene side chain, and eight stereocenters, two of which are quaternary centers. In devising a synthetic strategy, we envisioned constructing the core of the molecule using an intramolecular Diels-Alder reaction then completing the molecule by way of simple functional group interconversions. In 2013, Zhao and coworkers isolated isopalhinine A from Palhinhaea cernua. The compound is not known to possess any biological activity. Despite this, the compound does contain a variety of synthetically intriguing structural features including a 5/6/6/6/7 fused ring system containing an isotwistane and cycloheptane hemiaminal moieties. The key features of the synthesis include an allene Nazarov cyclization and a proposed late-stage titanium mediated 6-exo-trig cyclization/subsequent deoxygenation.