Discovery of the Polyamine Conjugate with Benzo[ cd]indol-2(1 H)-one as a Lysosome-Targeted Antimetastatic Agent.

Polyamine derivatives have a promising prospect in dealing with disseminated tumor cells, a major obstacle in cancer therapy. To develop a bifunctional polyamine derivative that can serve as a fluorescent probe and an antimetastatic agent, three kinds of polyamine conjugates with benzo[ cd]indol-2(1 H)-one as a scaffold were designed and synthesized. Compound 5e was selected as a lead by in vitro screening. Two animal models demonstrated that 5e inhibited pulmonary metastasis and tumor growth. As a fluorescent probe, 5e might partially enter cells via a polyamine transporter and subsequently localize in the lysosome. Mechanistic investigations demonstrated the interdependence of 5e-triggered apoptosis and autophagy. Compound 5e modulated the expression of LC3-II, p62, cathepsins, and the expression of capases 3, caspase 8, Bcl-2, and p53. The SSAT-mediated Akt/ß-catenin pathways were also inhibited by 5e. The dual features of 5e make it a worthwhile lead compound for further structural optimization.

Novel aromatic-polyamine conjugates as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase.

Three types of aromatic-polyamine conjugates (6a-6s) were designed, synthesized and evaluated as potential inhibitors for cholinesterases (ChEs). The results showed that anthraquinone-polyamine conjugates (AQPCs) exhibited the most potent acetylcholinesterase (AChE) inhibitory activity with IC50 values from 1.50 to 11.13 µM. Anthracene-polyamine conjugates (APCs) showed a surprising selectivity (from 76- to 3125-fold) and were most potent at inhibiting butyrylcholinesterase (BChE), with IC50 values from 0.016 to 0.657 µM. A Lineweaver-Burk plot and molecular modeling studies indicated that the representative compounds, 6l and 6k, targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of ChEs. Furthermore, APCs did not affect HepG2 cell viability at the concentration of 100 µM. Consequently, these polyamine conjugates could be thoroughly and systematically studied for the treatment of AD.

Design, synthesis and evaluation of novel 4-dimethylamine flavonoid derivatives as potential multi-functional anti-Alzheimer agents.

A series of 4-dimethylamine flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents. The results showed that most of the synthesized compounds exhibited high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity at the micromolar range (IC50, 1.83-33.20 µM for AChE and 0.82-11.45 µM for BChE). A Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5j with AChE, and molecular modeling study showed that 5j targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, the derivatives showed potent self-induced Aß aggregation inhibitory activity at 20 µM with percentage from 25% to 48%. In addition, some compounds (5j-5q) showed potent oxygen radical absorbance capacity (ORAC) ranging from 1.5- to 2.6-fold of the Trolox value. These compounds should be further investigated as multi-potent agents for the treatment of Alzheimer's disease.

[Design, synthesis and evaluation of bis-nicotine derivatives as inhibitors of cholinesterases and beta-amyloid aggregation].

A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC50, 2.28-117.86 micromol x L(-1) for AChE and 1.67-125 micromol x L(-1) for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Abeta aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 micromol x L(-1).