Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors.

Galantamine (GAL) and curcumin (CU) are alkaloids used to improve symptomatically neurodegenerative conditions like Alzheimer's disease (AD). GAL acts mainly as an inhibitor of the enzyme acetylcholinesterase (AChE). CU binds to amyloid-beta (Aß) oligomers and inhibits the formation of Aß plaques. Here, we combine GAL core with CU fragments and design a combinatorial library of GAL-CU hybrids as dual-site binding AChE inhibitors. The designed hybrids are screened for optimal ADME properties and BBB permeability and docked on AChE. The 14 best performing compounds are synthesized and tested in vitro for neurotoxicity and anti-AChE activity. Five of them are less toxic than GAL and CU and show activities between 41 and 186 times higher than GAL.

Catalytic Asymmetric Total Syntheses of (-)-Galanthamine and (-)-Lycoramine.

The catalytic asymmetric total syntheses of the biologically important and therapeutically valuable Amaryllidaceae alkaloids (-)-galanthamine and (-)-lycoramine have been divergently achieved from commercially available 3-butyn-1-ol. A newly developed spirocyclic pyrrolidine (SPD)-catalyzed enantioselective Robinson annulation rapidly constructs the key cis-hydrodibenzofuran core, which bears an all-carbon quaternary stereocenter of the target molecules with an excellent stereoselective control. Additionally, the current asymmetric synthetic strategy provides an alternative approach toward the syntheses of (-)-galanthamine and its analogues.

Design of Natural-Product-Inspired Multitarget Ligands by Machine Learning.

A virtual screening protocol based on machine learning models was used to identify mimetics of the natural product (-)-galantamine. This fully automated approach identified eight compounds with bioactivities on at least one of the macromolecular targets of (-)-galantamine, with different polypharmacological profiles. Two of the computer-generated hits possess an expanded spectrum of bioactivity on targets relevant to the treatment of Alzheimer's disease and are suitable for hit-to-lead expansion. These results advocate multitarget drug design by advanced virtual screening protocols based on chemically informed machine learning models.

An Overview of New Possible Treatments of Alzheimer's Disease, Based on Natural Products and Semi-Synthetic Compounds.

BACKGROUND: Dementias and all related neurodegenerative diseases of the Central Nervous System (CNS) are a current issue arousing a great deal of interest in the international scientific community. This is due to the increasing number of patients suffering from these diseases. These pathologies represent a serious problem, not only concerning the quality of life of the patient, but in addition, the enormous economic efforts that society has to do for their treatment. There are currently a few strategies that are available in order to prevent the progression or to mitigate symptoms of the aforementioned diseases. This consideration is particularly true if we consider the specific pathology of Alzheimer's Disease (AD). METHODS: We performed a literature search for peer-reviewed articles using different databases, such as PubMed or Scopus, and exploiting different keywords and different logical operators. RESULTS: Ninety-eight papers were included in the review. Four papers give an overview of the background of the dementias all over the world. The remaining papers are focused on new possibilities of treatment with natural and semi-synthetic compounds for AD. CONCLUSION: The aim of this review is to give an overview of new and promising natural products and semi-synthetic compounds which could represent a source of "lead compounds" for the development of new potential drugs that could be a valid therapeutic strategy for the treatment of this pathology.

The Synthesis of Certain Derivatives and Analogues of (-)- and (+)-Galanthamine and an Assessment of their Capacities to Inhibit Acetylcholine Esterase.

Syntheses of certain di- and mono-oxygenated derivatives (e.g., 2 and 3, respectively) and analogues (e.g., 4, a D-ring monoseco-analogue of 2) of both the (-)- and (+)-enantiomeric forms of the alkaloid galanthamine [(-)-1] are reported. All have been assessed for their capacities to inhibit acetylcholine esterase but, in contrast to the predictions from docking studies, none bind strongly to this enzyme.

Chemoenzymatic Total Synthesis of (+)-Galanthamine and (+)-Narwedine from Phenethyl Acetate.

The stereoselective total synthesis of unnatural (+)-galanthamine starting from phenethyl acetate is described. Chirality was introduced via microbial dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) to the corresponding cis-cyclohexadi-enediol, configuration of which provided the absolute stereochemistry of the ring C of (+)-galanthamine. Intramolecular Heck cyclization was used to form the quaternary carbon and dibenzofuran functionality. The synthesis of (+)-galanthamine was completed in a total of ten steps and an overall yield of 5.5 %. Experimental and spectral data are provided for all new compounds.

Rh-catalysed [5 + 1] cycloaddition of allenylcyclopropanes and CO: reaction development and application to the formal synthesis of (-)-galanthamine.

A Rh-catalysed [5 + 1] cycloaddition of allenylcyclopropanes and CO has been developed to synthesize functionalized 2-methylidene-3,4-cyclohexenones. The scope of this methodology has been investigated, showing that various functional groups can be tolerated. Both di- and tri-substituted allenylcyclopropanes can be applied to this cycloaddition and the [5 + 1] cycloadducts with the E configuration were obtained as the major products. In addition, the present [5 + 1] cycloaddition reaction has been utilized as a key step in the formal synthesis of the natural product (-)-galanthamine.

The Chemistry of Galanthamine. Classical Synthetic Methods and Comprehensive Study on its Analogues.

Galanthamine as an Amaryllidaceae alkaloid has an important role in the treatment of Alzheimer's disease. Some efforts were made to elaborate the total synthesis, and hundreds of its derivatives were prepared to find a more effective molecule with advantageous properties. Moreover, almost every part of the tetracycle was changed; in members of the rings, in the nature and position of the heteroatoms, and ring-opened analogues were also synthesized. In this review the basic synthetic works and the most important derivatives and analogues are overviewed.

Galantamine derivatives with indole moiety: Docking, design, synthesis and acetylcholinesterase inhibitory activity.

The inhibitors of acetylcholinesterase are the main therapy against Alzheimer's disease. Among them, galantamine is the best tolerated and the most prescribed drug. In the present study, 41 galantamine derivatives with known acetylcholinesterase inhibitory activities expressed as IC50 were selected from the literature and docked into a recombinant human acetylcholinesterase by GOLD. A linear relationship between GoldScores and pIC50 values was found and used to design and predict novel galantamine derivatives with indole moiety in the side chain. The four best predicted compounds were synthesized and tested for inhibitory activity. All of them were between 11 and 95 times more active than galantamine. The novel galantamine derivatives with indole moiety have dual site binding to the enzyme--the galantamine moiety binds to the catalytic anionic site and the indole moiety binds to peripheral anionic site. Additionally, the indole moiety of one of the novel inhibitors binds in a region, close to the peripheral anionic site of the enzyme, where the Ω-loop of amyloid beta peptide adheres to acetylcholinesterase. This compound emerges as a promising lead compound for multi-target anti-Alzheimer therapy not only because of the strong inhibitory activity, but also because it is able to block the amyloid beta deposition on acetylcholinesterase.

Synthesis of New Peptide Derivatives of Galanthamine Designed for Prevention and Treatment of Alzheimer's Disease.

New derivatives of galanthamine containing peptide fragments with ß-secretase inhibitor activity were synthesized. In position 6 of the galanthamine new shortened analogues of ß-secretase inhibitor OM 99-2 (Boc-Val-Asn-Leu-Ala-OH and Boc-Val-Asn-Leu-Ala-Val-OH) were included. The new derivatives of the galanthamine in position 11 including Boc and norgalanthamine in P3 or P4 positions, Val in P2' position and benzylamin in P3'-position were also synthesized. All new peptides were investigated on mice for acute toxicity. The test compounds were administered to mice via intraperitoneal (i.p.) route. They have low toxicity (LD50>1000 mg/kg) after i.p. The compound 11-N-demethyl-11-N-N-[Boc-Asp(Asp-Leu-Ala-Val-NH-Bzl)]-Galanthamine was investigated by two way active avoidance method. The compound has good influence on the conditioned reflexes, which improved the processes of learning and memory. Inhibition activity of newly synthesized compounds was monitored against BuChE and IC50 values are determined. All compounds show activity in micromolar concentration. Compounds 5 and 6 have around 10 times higher activity than galanthamine. Compounds 4 and 9 also show good activity. All newly synthesized compounds show low acute toxicity.

Catalytic asymmetric total synthesis of (-)-galanthamine and (-)-lycoramine.

The catalytic asymmetric total syntheses of (-)-galanthamine (1) and (-)-lycoramine (2) have been achieved by using a conceptually new strategy featuring two metal-catalyzed reactions as the key steps. A new method for the construction of 3,4-fused benzofurans has been developed through a palladium-catalyzed intramolecular Larock annulation reaction, which was successfully applied to the construction of the ABD tricyclic skeleton of 1 and 2. To achieve the asymmetric synthesis of 1 and 2, a Sc(III)/N,N'-dioxide complex was used to catalyze the enantioselective conjugate addition of 3-alkyl-substituted benzofuranone to methyl vinyl ketone for the construction of a chiral quaternary carbon center.

Formal synthesis of (±)-galanthamine and (±)-lycoramine using Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition of 1-ene-vinylcyclopropane and CO.

An efficient strategy using Rh(I)-catalyzed [(3 + 2) + 1] cycloaddition of 1-ene-vinylcyclopropane and CO as a key step to build the cis-hydrodibenzofuran skeleton has been developed and applied for the formal synthesis of (±)-galanthamine and (±)-lycoramine.

Synthesis of a D-ring isomer of galanthamine via a radical-based Smiles rearrangement reaction.

The 1,9-ethanoiminomethano-bridged tetrahydrodibenzo[b,d]-furan 2, a non-natural isomer of the alkaloid (-)-galanthamine (1) varying in the manner in which the D-ring is annulated to the ABC-core, has been prepared in racemic form. The synthetic sequence starts with the cyclopropane 3 and involves intramolecular Heck alkenylation and radical-based Smiles rearrangement reactions as key steps. Unlike natural product 1, but as predicted by docking studies, compound 2 is not a potent inhibitor of acetylcholine esterase.

Design, synthesis and biological evaluation of D-ring opened galantamine analogs as multifunctional anti-Alzheimer agents.

Facing the multifactorial nature of Alzheimer's disease, twelve dibenzofuran/carbazole derivatives, which can be considered as the D-ring opened analogs of galantamine, have been designed and synthesized as multifunctional anti-Alzheimer agents. In vitro tests revealed that compounds 3 and 5, which bear a nitrate moiety in the molecule, showed a potent inhibition activity towards AChE and compound 3 showed a good Aß42 aggregation inhibitory activity. Moreover, 3 and 5 could also release a relative low concentration of NO in vitro and they did not show toxicity to neuronal cells, while exerted a neuroprotective effect against the Aß-induced toxicity. More importantly, compound 3 showed a significant spatial memory improving effect in vivo, and a good safety in the ex vivo toxicity study.

Synthesis and evaluation of (-)- and (+)-[¹¹C]galanthamine as PET tracers for cerebral acetylcholinesterase imaging.

Improved radiopharmaceuticals for imaging cerebral acetylcholinesterase (AChE) are needed for the diagnosis of Alzheimer's disease (AD). Thus, (11)C-labeled (-)-galanthamine and its enantiomers were synthesized as novel agents for imaging the localization and activity of AChE by positron emission tomography (PET). C-11 was incorporated into (-)- and (+)-[(11)C]galanthamine by N-methylation of norgalanthamines with [(11)C]methyl triflate. Simple accumulation of (11)C in the brain was measured in an in vivo biodistribution study using mice, whilst donepezil was used as a blocking agent in analogous in vivo blocking studies. In vitro autoradiography of rat brain tissue was performed to investigate the distribution of (-)-[(11)C]galanthamine, and confirmed the results of PET studies in mice. The radiochemical yields of N-methylation of (-)- and (+)-norgalanthamines were 13.7% and 14.4%, respectively. The highest level of accumulation of (11)C in the brains of mice was observed at 10 min after administration (2.1% ID/g). Intravenous pretreatment with donepezil resulted in a 30% decrease in accumulation of (-)-[(11)C]galanthamine in the striatum; however, levels in the cerebellum were unchanged. In contrast, use of (+)-[(11)C]galanthamine led to accumulation of radioactivity in the striatum equal to that in the cerebellum, and these levels were unaffected by pretreatment with donepezil. In in vitro autoradiography of regional radioactive signals of brain sections showed that pretreatment with either (-)-galanthamine or donepezil blocked the binding of (-)-[(11)C]galanthamine to the striatum, while sagittal PET imaging revealed accumulation of (-)-[(11)C]galanthamine in the brain. These results indicate that (-)-[(11)C]galanthamine showed specific binding to AChE, whereas (+)-[(11)C]-galanthamine accumulated in brain tissue by non-specific binding. Thus, optically pure (-)-[(11)C]galanthamine could be a useful PET tracer for imaging cerebral AChE.

From nature to market: examples of natural products that became drugs.

Nature is an irrefutable source of inspiration for the modern man in many aspects. The observation and understanding of nature have allowed the development of new materials, new sources of energies, new drugs etc. Specifically, natural products provide a great contribution to the development of new agents for the treatment of infections and antitumor agents. However, obtaining natural products directly from animals, fungi, bacteria, plants etc has been considered not enough to attend the high demand by pharmaceutical industries. In this regard, various strategies based on biotechnological processes or synthetic approaches have been developed. In this scenario the total synthesis can be undoubtedly a useful and powerful tool for obtaining higher amounts of natural products and/or structural modifications thereof. Herein, we emphasize successful examples of total synthesis of galanthamine, morphine, paclitaxel and podophyllotoxin - natural products approved as pharmaceuticals.

Pd-catalyzed asymmetric allylic etherification using chiral biphenol-based diphosphinite ligands and its application for the formal total synthesis of (-)-galanthamine.

A library of novel chiral biphenol-based diphosphinite (BOP) ligands was designed and created. These BOP ligands were applied to a Pd-catalyzed intermolecular allylic etherification reaction, which provided a key intermediate for the formal total synthesis of (-)-galanthamine with 97% ee in 97% yield.

Total synthesis of (-)-galanthamine and (-)-lycoramine via catalytic asymmetric hydrogenation and intramolecular reductive Heck cyclization.

A synthetic strategy featuring efficient ruthenium-catalyzed asymmetric hydrogenation of racemic α-aryloxy cyclic ketone via dynamic kinetic resolution and palladium-catalyzed intramolecular reductive Heck cyclization has been developed for the asymmetric total synthesis of (-)-galanthamine (20.1%, 12 steps) and (-)-lycoramine (40.2%, 10 steps).

Kinetic study of the rearrangement of deuterium-labeled 4'-O-methylnorbelladine in Leucojum aestivum shoot cultures by mass spectrometry. Influence of precursor feeding on amaryllidaceae alkaloid accumulation.

Alkaloids from plants of the family Amaryllidaceae have important pharmacological properties and can be regarded as derivatives of the common precursor 4'-O-methylnorbelladine (6) via intramolecular oxidative phenol coupling. Their biosynthetic pathway, particularly in Leucojum aestivum, has not yet been totally elucidated. Therefore, shoot cultures of this plant were subcultured in medium containing the labeled precursor 4'-O-methyl-d(3)-norbelladine (3) at various concentrations (0.05, 0.10, and 0.20 g/L) and were incubated for various periods of time (15, 30, and 40 days). The aim of this work was to study the influence of this precursor on both labeled and native alkaloid accumulation. Biotransformation into galanthamine (1) and lycorine (2) in shoot cultures was demonstrated using HPLC coupled to mass spectrometry. A maximal amount of 0.16% of 1 referred to the dry weight was obtained at day 15 in shoots fed with 0.10 g/L of precursor. In addition, a 20.5% dry weight of 2 was reached after 40 days of feeding with 0.20 g/L of precursor.

Asymmetric synthesis of bioactive hydrodibenzofuran alkaloids: (-)-lycoramine, (-)-galanthamine, and (+)-lunarine.

Divergent route: a direct C-C bond-forming approach to the key aryl-substituted all-carbon quaternary stereogenic center present in bioactive hydrodibenzofuran alkaloids has been discovered. This approach involves an unprecedented organocatalytic enantioselective Michael addition of α-cyanoketones with acrylates and was used in a novel and divergent synthetic strategy for the title compounds in asymmetric fashion.