Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer’s disease

Abstract

The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal–Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.

Minor Structural Variations of Small Molecules Tune Regulatory Activities toward Pathological Factors in Alzheimer's Disease

“…[9d] As a way to compare 1–9 to other compounds, we also employed the commonly used the Trolox Equivalence Antioxidant Capacity (TEAC) assay (see below), directly correlated to the activity of Trolox. [5] Overall, our electrochemical studies are consistent with our calculation predictions that 2 and 7 are relatively more difficult to oxidize than 1 , 3–6 , 8 , and 9 ; thus, they are less likely to generate the radical form required for reactivity with metal-free Aβ and metal-bound Aβ species.…”

“…As summarized in Table 1, the compounds ( 5 , 6 , 8 , and 9 ) designed to undergo oxidation have similar or lower computed IPs to the previously determined values for 1 , [5] 3 , [5] 4 , [5] and L2-b [8] suggesting that 1 , 3–6 , 8 , and 9 can produce radicals to be necessary for activity. Furthermore, as expected, the computational studies indicate that 7 , along with 2 , are more difficult to be oxidized than the other compounds (Table 1).…”

“…In our initial studies of 1–4 (Table 1), the electron-donating properties of the aniline (in 1 ) and dimethylamine (in 3 ) groups were suggested to be important in the formation of their radical forms required for activity toward their targets. [5] In our complete chemical series, new compounds ( 5–9 ; Table 1) were included to contain electron-donating or electron-withdrawing groups to tune ionization potentials (IPs) of the basic framework affording distinct activities with targets: 1) a diethylamino (for 5 ) or 4-morpholino (for 6 ) group was installed in 5 and 6 , respectively, compared with the dimethylamino component of 8 , 9 , and L2-b ; 2) compound 7 , composed of an electron-withdrawing nitro moiety, was constructed to decrease the compound’s ability to oxidize similar to 2 , [5] which contains a 3,5-dimethoxybenzene moiety and is relatively stable even in the presence of Cu II . These compounds were relatively easily obtained and purified (see Supporting Information).…”

“…[1a–c,e–h,4] We recently reported the development of four small molecules ( 1–4 ; Table 1) which have different modes of action, despite being structurally similar, for targeting and controlling the aggregation of metal-free Aβ or metal-Aβ as well as the formation of ROS overall diminishing toxicity. [5] Herein, we report the overall investigations of the small molecules ( 1–9 ; Table 1) rationally designed to tune the reactivities with differing targets (i.e., metal ions, metal-free Aβ, metal-Aβ, ROS, free organic radicals) by performing slight structural modifications to a common structural framework. Through chemical, biochemical, biophysical, and computational studies, we demonstrate that 1–9 have structure-dependent capabilities to modulate the reactivities with their targets.…”

“…Through chemical, biochemical, biophysical, and computational studies, we demonstrate that 1–9 have structure-dependent capabilities to modulate the reactivities with their targets. The target specificity of these compounds (i.e., reactivity directed toward metal-free Aβ and/or metal-Aβ) have been indicated to be associated with their redox properties: [5] 1) The compounds that undergo oxidation relatively easily suppress the reactivity of metal-Aβ over metal-free Aβ ( 1 , 3 , 5 , 6 , 8 , and 9 ) or both metal-free and metal-bound Aβ ( 4 ); 2) the compounds ( 2 and 7 ) that are more difficult to oxidize indicate limited abilities to control the reactivity of Aβ in the absence and presence of metal ions. In addition, the activity of our small molecules toward metal [Cu II or Zn II ]-Aβ was indicated to be correlated to the formation of compound-metal-Aβ ternary complexes.…”