A Dual-Pronged Approach: A Ruthenium(III) Complex That Modulates Amyloid-β Aggregation and Disrupts Its Formed Aggregates

Abstract

Alzheimer's disease (AD) is a devastating neurological disorder for which soluble oligomers of the peptide amyloid-β (Aβ) are now recognized as the neurotoxic species. Metal-based therapeutics are uniquely suited to target Aβ, with ruthenium-based (Ru) complexes emerging as propitious candidates. Recently, azole-based Ru(III) complexes were observed to modulate the aggregation of Aβ in solution, where the inclusion of a primary amine proximal to the ligand coordination site improved the activity of the complexes. To advance these structure−activity relationships, a series of oxazole-based Ru complexes were prepared and evaluated for their ability to modulate Aβ aggregation. From these studies, a lead candidate, Oc, emerged that had superior activity relative to its azole predecessors in modulating the aggregation of soluble Aβ and diminishing its cytotoxicity. Further evaluation of Oc demonstrated its ability to disrupt formed Aβ aggregates, resulting in smaller amorphous species. Because altering both sides of the aggregation equilibrium for Aβ has not been previously suggested for metal-based complexes for AD, this work represents an exciting new avenue for improved therapeutic success.

Highly Efficient Singlet Oxygen Generation by BODIPY–Ruthenium(II) Complexes for Promoting Neurite Outgrowth and Suppressing Tau Protein Aggregation

“…Several other characteristics of ε-Cl that may play a role in its anti-tau ability include its structural similarity to KP1019 or PMRU20 and the ability to form hydrogen bonds with the peptides through the fluoride atoms on BODIPY . Nevertheless, insignificant anti-aggregation efficiency for cells treated without illumination suggests that singlet oxygen generation is the primary mechanism.…”

“…In the past decade, a series of Ru­(III) complexes bearing indazole, imidazole, or thiazole ligands containing four chlorido ligands (i.e., KP1019 and PMRU20) have been reported to modulate Aβ aggregation. ,, On the other hand, photoactivated Ru­(II) polypyridyl complexes have recently been shown to disrupt Aβ oligomerization or even photodissociate the aggregated amyloid platiques. , Even though numerous ruthenium complexes have been demonstrated as potential drugs to inhibt Aβ aggregation, ,− the other major hallmark of Alzheimer’s disease, tau protein aggregation, was rarely studied. We therefore thought that the highly efficient singlet oxygen generator ε-Cl might have the potential to inhibit NFT formation in living cells.…”

“…Several other characteristics of ε-Cl that may play a role in its anti-tau ability include its structural similarity to KP1019 or PMRU20 15 and the ability to form hydrogen bonds with the peptides through the fluoride atoms on BODIPY. 17 Nevertheless, insignificant anti-aggregation efficiency for cells treated without illumination suggests that singlet oxygen generation is the primary mechanism. Studies of singlet oxygen suppressing tau aggregation are elucidated with the mechanism of tau oxidation, where sulfhydryl groups in cysteine residues on tau protein are modified to sulfenic, sulfinic, and sulfunic acid and convert tau into aggregation incompetent conformation.…”

“…15,16 Numerous PMRU20 analogues have since been prepared and assessed for their ability to affect Aβ aggregation. 17,18 As a therapeutic strategy, photodynamic therapy (PDT) is attractive as it is a non-invasive process, with inherently low systemic toxicity, negligible drug resistance, and it allows for spatiotemporal selectivity by light activation. 19−22 Its use in the treatment of AD, however, is still in its infancy compared to the attention that has been paid for its use in the treatment of cancers.…”

“…Indeed, many ruthenium complexes targeting Aβ peptides have been developed as potential aggregation modulators for AD therapy. Among which are KP1019 and NAMI-A, the two most promising Ru­(III) complexes which had entered phase II clinical trials as anticancer drugs; , they have been shown to inhibit the aggregation of Aβ in vitro through a direct binding mechanism. , Another complex with a similar chemical structure, PMRU20, was found to exhibit a significantly greater impact in preventing Aβ aggregates and even disassembling the aggregated Aβ peptides. , Numerous PMRU20 analogues have since been prepared and assessed for their ability to affect Aβ aggregation. , …”