Design, synthesis and anti-Alzheimer's disease activity evaluation of C-3 arylated huperzine A derivatives.

A series of C-3 arylated huperzine A (HPA) derivatives (1-30) were designed and synthesized in good yields via palladium-catalyzed Suzuki cross-coupling reaction. Cholinesterase inhibitory and neuroprotective activities of all 30 derivatives were evaluated. Cholinesterase inhibition results revealed that derivatives 2 and 15 exhibited dual inhibitory activity against both acetylcholinesterase (AChE inhibition: 2, IC = 1.

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

To design and synthesize a novel series of 1-aryldonepezil analogues. The 1-aryldonepezil analogues were synthesized through palladium/PCy-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. docking of the most effective compound was conducted.

Rethinking therapeutic strategies of dual-target drugs: An update on pharmacological small-molecule compounds in cancer.

Oncogenes and tumor suppressors are well-known to orchestrate several signaling cascades, regulate extracellular and intracellular stimuli, and ultimately control the fate of cancer cells. Accumulating evidence has recently revealed that perturbation of these key modulators by mutations or abnormal protein expressions are closely associated with drug resistance in cancer therapy; however, the inherent drug resistance or compensatory mechanism remains to be clarified for targeted drug discovery. Thus, dual-target drug development has been widely reported to be a promising therapeutic strategy for improving drug efficiency or overcoming resistance mechanisms.

Rapid Access to Tigliane, Ingenane, and Rhamnofolane Diterpenes from a Lathyrane Precursor via Biomimetic Skeleton Transformation Strategy.

Bioinspired skeleton transformation of a tricyclic lathyrane-type diterpene was conducted to efficiently construct a tetracyclic tigliane diterpene on a gram scale via a key aldol condensation. The tigliane diterpene was then respectively converted into naturally rare ingenane and rhamnofolane diterpenes through a semipinacol rearrangement and a visible-light-promoted regioselective cyclopropane ring-opening reaction. This work provides a concise strategy for high-efficiency access to diverse polycyclic diterpene skeletons from abundant lathyrane-type natural products and paves the way for biological activity investigation of naturally rare molecules.

Palladium-catalyzed synthesis and anti-AD biological activity evaluation of -aryl-debenzeyldonepezil analogues.

A series of novel -aryl-debenzeyldonepezil derivatives () were designed and synthesized as cholinesterase inhibitors by the modification of anti-Alzheimer's disease drug donepezil, using Palladium catalyzed Buchwald-Hartwig cross-coupling reaction as a key chemical synthesis strategy. cholinesterase inhibition studies demonstrated that the majority of synthesized compounds exhibited high selective inhibition of AChE. Among them, analogue possessing a quinoline functional group showed the most potent AChE inhibition effect and significant neuroprotective effect against HO-induced injury in SH-SY5Y cells.

Targeting autophagy with small-molecule activators for potential therapeutic purposes.

Autophagy is well-known to be a lysosome-mediated catabolic process for maintaining cellular and organismal homeostasis, which has been established with many links to a variety of human diseases. Compared with the therapeutic strategy for inhibiting autophagy, activating autophagy seems to be another promising therapeutic strategy in several contexts. Hitherto, mounting efforts have been made to discover potent and selective small-molecule activators of autophagy to potentially treat human diseases.

Palladium-catalyzed synthesis and acetylcholinesterase inhibitory activity evaluation of 1-arylhuperzine A derivatives.

A series of arylated huperzine A (HPA) derivatives (-) were efficiently synthesized in good yields (45-88% yields) through the late-stage modification of structurally complex natural anti-Alzheimer's disease (AD) drug huperzine A (HPA), using the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The acetylcholinesterase (AChE) inhibitory activity of all synthesized compounds was evaluated to screen the potential anti-AD bioactive molecules. The results showed that introducing the aryl groups to C-1 position of HPA resulted in the unsatisfactory AChE inhibitory activity.

Organocatalytic Asymmetric Morita-Baylis-Hillman Reaction of Isatins with Vinyl Sulfones.

The organocatalytic asymmetric Morita-Baylis-Hillman (MBH) reaction of isatin derivatives with various vinyl sulfones is disclosed. Chiral sulfone-containing 3-hydroxyoxindoles were produced in good to high yields and with good to high ee's. This report displays an unprecedented example to apply activated alkenes with sulfone moiety other than carbonyl groups in asymmetric MBH reactions and provides an efficient strategy to incorporate the sulfone functional group for the synthesis of chiral 3-hydroxyoxindoles.

Palladium-Catalyzed Synthesis, Acetylcholinesterase Inhibition, and Neuroprotective Activities of -Aryl Galantamine Analogues.

A series of new -aryl galantamine analogues (-) were designed and synthesized by modification of galantamine, using Pd-catalyzed Buchwald-Hartwig cross-coupling reaction in good to excellent yields. The cholinesterase inhibitory and neuroprotective activities of -aryl derivatives of galantamine were evaluated. Among the synthesized compounds, the 4-methoxylpyridine-galantamine derivative () (IC = 0.

Visible-Light-Promoted Tandem Thiol-Ene Click Reaction/Transannular Cyclization and Regioselective Cyclopropane Ring-Opening to Construct Sulfur-Containing Diterpenes.

The biorelevant sulfur-containing diterpenes with scarce 5/7/6/3 premyrsinane- and 5/7/6 myrsinane-type backbones were easily constructed from naturally abundant lathyrane-type factor L by visible-light-triggered tandem thiol-ene click reaction/transannular cyclization and regioselective cyclopropane ring-opening. The selenide diterpene was also successfully obtained to verify the system universality. This concise synthesis route gives an efficient strategy for obtaining structurally diverse diterpenes under very mild conditions and provides a promising anti-HIV bioactive premyrsinane diterpene .

Pd-Catalyzed Direct Modification of an Anti-Alzheimer's Disease Drug: Synthesis and Biological Evaluation of α-Aryl Donepezil Analogues.

Palladium/BuAdP efficiently catalyzed the direct α-arylation of ketone in the anti-Alzheimer's disease drug donepezil, leading to 15 aryldonepezil analogues exhibiting high selective inhibition of acetylcholinesterase (AChE). The cell-based assays revealed that the 3-methylpridinyl analogue () shows significantly lower toxicity compared to donepezil and remarkable neuroprotective activity against HO-induced damage in SH-SY5Y cells. Docking results of compound also interpreted the possible mechanism of the selective inhibition between AChE and butyrylcholinesterase (BuChE).

Pd-Catalyzed Direct Diversification of Natural Anti-Alzheimer's Disease Drug: Synthesis and Biological Evaluation of -Aryl Huperzine A Analogues.

The first systematic direct diversification of a complex natural product by metal-catalyzed N-H functionalization was carried out. A new series of -(hetero)aryl analogues (-) of the natural anti-Alzheimer's disease drug huperzine A (HPA) was prepared via palladium-catalyzed Buchwald-Hartwig cross-coupling reactions of HPA with various aryl bromides in good yields. Most of the -aryl-huperzine A (-aryl-HPA) analogues showed good acetylcholinesterase (AChE) inhibitory activity in experiments.

Iron-Catalyzed Skeletal Conversion of Lathyrane to Premyrsinane Diterpenes and Their Cytotoxic Activities.

Two new premyrsinane-type diterpenes ( and ) as diastereomers were synthesized from lathyrane-type diterpene euphorbia factor L () for the first time via an efficient Fe(acac)-catalyzed skeleton conversion process. This conversion features a biogenetically inspired strategy that relies on a concise reductive olefin coupling involving intramolecular Michael addition with free radicals. The structures of and were elucidated by a combination of the interpretation of their spectroscopic data and single-crystal X-ray diffraction analysis.

Late-Stage Modification of Medicine: Pd-Catalyzed Direct Synthesis and Biological Evaluation of -Aryltacrine Derivatives.

A new series of -aryltacrine derivatives were designed and synthesized as cholinesterase inhibitors by the late-stage modification of tacrine, using the palladium-catalyzed Buchwald-Hartwig cross-coupling reaction. In vitro inhibition assay against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) demonstrated that most of the synthesized compounds had potent AChE inhibitory activity with negative inhibition of BuChE. Among them, -(4-(trifluoromethyl)phenyl)-tacrine () and -(4-methoxypyridin-2-yl)-tacrine () showed the most potent activity against AChE (IC values of 1.

Isolation, Structure Elucidation, Semi-Synthesis, and Structural Modification of C-Diterpenoid Alkaloids from and Their Neuroprotective Activities.

Five new aconitine-type C-diterpenoid alkaloids, apetalrines A-E (-), were isolated from . Their structures were determined by analysis of 1D and 2D NMR, IR, and HRESIMS data. Semisynthesis of apetalrine B () from its parent compound aconorine was achieved to confirm the structure proposed.