Due to the hugely important roles of neurotransmitter acetylcholine (ACh) and amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD), the development of multi-target directed ligands (MTDLs) focused on cholinesterase (ChE) and Aβ becomes one of the most attractive strategies for combating AD. To date, numerous preclinical studies toward multifunctional conjugates bearing ChE inhibition and anti-Aβ aggregation have been reported. Noteworthily, most of the reported multifunctional cholinesterase inhibitors are carbamate-based compounds due to the initial properties of carbamate moiety. However, because their easy hydrolysis in vivo and the instability of the compound-enzyme conjugate, the mechanism of action of these compounds is rare. Thus, non-carbamate compounds are of great need for developing novel cholinesterase inhibitors. Besides, given that Aβ accumulation begins to occur 10-15 years before AD onset, modulating Aβ is ineffective only in inhibiting its aggregation but not eliminate the already accumulated Aβ if treatment is started when the patient has been diagnosed as AD. Considering the limitation of current Aβ accumulation modulators in ameliorating cognitive deficits and ineffectiveness of ChE inhibitors in blocking disease progression, the development of a practically valuable strategy with multiple pharmaceutical properties including ChE inhibition and Aβ modulation for treating AD is indispensable. In this review, we focus on summarizing the scaffold characteristics of reported non-carbamate cholinesterase inhibitors with Aβ modulation since 2020, and understanding the ingenious multifunctional drug design ideas to accelerate the pace of obtaining more efficient anti-AD drugs in the future. 

Recent advance on pleiotropic cholinesterase inhibitors bearing amyloid modulation efficacy.

Introduction The brain functional network can describe the spontaneous activity of nerve cells and reveal the subtle abnormal changes associated with brain disease. It has been widely used for analyzing early Alzheimer's disease (AD) and exploring pathological mechanisms. However, the current methods of constructing functional connectivity networks from functional magnetic resonance imaging (fMRI) heavily depend on the software toolboxes, which may lead to errors in connection strength estimation and bad performance in disease analysis because of many subjective settings. Methods To solve this problem, in this paper, a novel Adversarial Temporal-Spatial Aligned Transformer (ATAT) model is proposed to automatically map 4D fMRI into functional connectivity network for early AD analysis. By incorporating the volume and location of anatomical brain regions, the region-guided feature learning network can roughly focus on local features for each brain region. Also, the spatial-temporal aligned transformer network is developed to adaptively adjust boundary features of adjacent regions and capture global functional connectivity patterns of distant regions. Furthermore, a multi-channel temporal discriminator is devised to distinguish the joint distributions of the multi-region time series from the generator and the real sample. Results Experimental results on the Alzheimer's Disease Neuroimaging Initiative (ADNI) proved the effectiveness and superior performance of the proposed model in early AD prediction and progression analysis. Discussion To verify the reliability of the proposed model, the detected important ROIs are compared with clinical studies and show partial consistency. Furthermore, the most significant altered connectivity reflects the main characteristics associated with AD. Conclusion Generally, the proposed ATAT provides a new perspective in constructing functional connectivity networks and is able to evaluate the disease-related changing characteristics at different stages for neuroscience exploration and clinical disease analysis.

/pdf/constructing-brain-functional-network-by-adversarial-1feokrc0.pdf

Constructing brain functional network by Adversarial Temporal-Spatial Aligned Transformer for early AD analysis

Efficient chemical synthesis is critical to satisfying future demands for medicines, materials, and agrochemicals. Retrosynthetic analysis of modestly complex molecules has been automated over the course of decades, but the combinatorial explosion of route possibilities has challenged computer hardware and software until only recently. Here, we explore a computational strategy that merges computer-aided synthesis planning with molecular graph editing to minimize the number of synthetic steps required to produce alkaloids. Our study culminated in an enantioselective three-step synthesis of (–)-stemoamide by leveraging high-impact key steps, which could be identified in computer-generated retrosynthesis plans using graph edit distances. Description Making the most of synthesis algorithms Software that predicts synthetic routes to complex molecules has been rapidly increasing in sophistication. The extent to which the algorithms replicate or complement human intuition nonetheless remains uncertain. Lin et al. challenged a commercial retrosynthesis program with an alkaloid for which more than 30 syntheses had been reported in the literature. The algorithm consistently proposed a Mannich reaction that no prior approach had featured, although drawbacks in the rest of the route benefited from human intervention. By devising a supplemental graph-based method of prioritizing key steps, the authors achieved the shortest synthesis of this target. —JSY Computer-aided retrosynthesis supplemented by graph-based step prioritization minimized step count in an alkaloid synthesis.

Computer-aided key step generation in alkaloid total synthesis

It is a well-known phenomenon that natural products can serve as powerful drug leads to generate new molecular entities with novel therapeutic utility. Evodiamine (Evo), a major alkaloid component in traditional Chinese medicine Evodiae Fructus, is considered a desirable lead scaffold as its multifunctional pharmacological properties. Although natural Evo has suboptimal biological activity, poor pharmacokinetics, low water solubility, and chemical instability, medicinal chemists have succeeded in producing synthetic analogs that overshadow the deficiency of Evo in terms of further clinical application. Recently, several reviews on the synthesis, structural modification, mechanism pharmacological actions, structure-activity relationship (SAR) of Evo have been published, while few reviews that incorporates intensive structural basis and extensive SAR are reported. The purpose of this article is to review the structural basis, anti-cancer activities, and mechanisms of Evo and its derivatives. Emphasis will be placed on the optimizing strategies to improve the anticancer activities, such as structural modifications, pharmacophore combination and drug delivery systems. The current review would benefit further structural modifications of Evo to discover novel anticancer drugs. 

Natural product evodiamine-inspired medicinal chemistry: Anticancer activity, structural optimization and structure-activity relationship.

Herein, a series of 11‐ or 12‐substituted benzophenanthridinone derivatives was designed and synthesized for the discovery of dual topoisomerase IB (TOP1) and tyrosyl‐DNA phosphodiesterase 1 (TDP1) inhibitors. Enzyme‐based assays indicated that two compounds 12 and 38 showed high TOP1 inhibitory potency (+++), and four compounds 35, 37, 39 and 43 showed good TDP1 inhibition with IC50 values ranging from 10 to 18 μM. 38 could induce cellular TOP1cc formation, resulting in the highest cytotoxicity against HCT‐116 cells (0.25 μM). The most potent TDP1 inhibitor 43 (10 μM) could induce cellular TDP1cc formation and enhance topotecan‐induced DNA damage and showed strong synergistic cytotoxicity with topotecan in both MCF‐7 and MCF‐7/TDP1 cells.

Synthesis and Biological Activities of 11‐ and 12‐Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB and Tyrosyl‐DNA Phosphodiesterase 1 Inhibitors

Alzheimer's disease (AD), as the fourth leading cause of death among the elderly worldwide, has brought enormous challenge to the society. Due to its extremely complex pathogeneses, the development of multi-target directed ligands (MTDLs) becomes the major strategy for combating AD. Carbamate moiety, as an essential building block in the development of MTDLs, exhibits structural similarity to neurotransmitter acetylcholine (ACh) and has piqued extensive attention in discovering multifunctional cholinesterase inhibitors. To date, numerous preclinical studies demonstrate that carbamate-based cholinesterase inhibitors can prominently increase the level of ACh and improve cognition impairments and behavioral deficits, providing a privileged strategy for the treatment of AD. Based on the recent research focus on the novel cholinesterase inhibitors with multiple biofunctions, this review aims at summarizing and discussing the most recent studies excavating the potential carbamate-based MTDLs with cholinesterase inhibition efficacy, to accelerate the pace of pleiotropic cholinesterase inhibitors for coping AD. 

Recent advance on carbamate-based cholinesterase inhibitors as potential multifunctional agents against Alzheimer's disease.

Natural product evodiamine is one of the most privileged scaffolds in drug discovery and is suitable for derivatization, which can be conducted quickly for structure optimization and structure-activity relationship research. In this work, a comprehensive SAR study on evodiamine scaffold with N14-3′-fluorophenyl substituted was completed, and compounds with high anti-tumor activity and good inhibitory effect on Top1 and Top2 were screened out. Tested evodiamine derivatives exhibited excellent broad-spectrum anti-tumor activity. Among them, compound 8b revealed 55.15% and 55.50% inhibition for Top1 and Top2 at 25 μM, as well as 0.16 and 0.13 μM IC 50 value for MGC-803 and SGC-7901 cells, respectively; compound 9a revealed 70.50% and 71.81% inhibition for Top1 and Top2 at 25 μM, as well as 0.22 and 0.27 μM IC 50 value for MGC-803 and SGC-7901 cells, respectively. The further biological evaluation showed that they could functionally induce apoptosis, significantly arrest the cell cycle at the G2/M phase, and markedly inhibit cell proliferation, migration and invasion. In addition, compound 9a performed a tumor inhibitory rate of 36.35% and showed no apparent toxicity in vivo . Overall, these optimized protocols will advance the progression of cancer chemotherapy and can be used to expand the options for screening therapeutic cancer drugs. • This study provided optimized protocols to modify evodiamine for expanding the options of screening therapeutic cancer drugs. • Compound 9a performed prominent anti-tumor efficacy and favorable both druggability in vitro and in vivo. • Compound 9a will play a key role in advancing the anticancer research of evodiamine analogs. 

Design, synthesis and bioactivity evaluation of favorable evodiamine derivative scaffold for developing cancer therapy.

The asymmetric total syntheses of five pyrrole-type Stemona alkaloids and two stereoisomers were accomplished, among which 3-n-butylneostemonine and bisdehydroneostemonine were synthesized for the first time, and the NMR data of...

Asymmetric Total Syntheses of Five Pyrrole-Type Stemona Alkaloids

Discovery of carbamate-based N-salicyloyl tryptamine derivatives as novel pleiotropic agents for the treatment of Alzheimer's disease.

Evodiamine has many biological activities. Herein, we synthesize 23 disubstituted derivatives of N14-phenyl or the E-ring of evodiamine and conduct systematic structure-activity relationship studies. In vitro antiproliferative activity indicated that compounds F-3 and F-4 dramatically inhibited the proliferation of Huh7 (IC50 = 0.05 or 0.04 μM, respectively) and SK-Hep-1 (IC50 = 0.07 or 0.06 μM, respectively) cells. Furthermore, compounds F-3 and F-4 could double inhibit topoisomerases I and II, inhibit invasion and migration, block the cell cycle to the G2/M stage, and induce apoptosis as well. Additionally, compounds F-3 and F-4 could also inhibit the activation of HSC-T6 and reduce the secretion of collagen type I to slow down the progression of liver fibrosis. Most importantly, compound F-4 (TGI = 60.36%) inhibited tumor growth more significantly than the positive drug sorafenib. To sum up, compound F-4 has excellent potential as a strong candidate for the therapy of hepatocellular carcinoma.

Yuqing Wang

Papers

Recent advance on carbamate-based cholinesterase inhibitors as potential multifunctional agents against Alzheimer's disease.

Design, synthesis and bioactivity evaluation of favorable evodiamine derivative scaffold for developing cancer therapy.

Asymmetric Total Syntheses of Five Pyrrole-Type Stemona Alkaloids

Discovery of carbamate-based N-salicyloyl tryptamine derivatives as novel pleiotropic agents for the treatment of Alzheimer's disease.

Design, Synthesis, and Biological Evaluation of Novel Evodiamine Derivatives as Potential Antihepatocellular Carcinoma Agents.