Lycoramine

Cooperative hydrogen bonds and mobility of the non-aromatic ring as selectivity determinants for human acetylcholinesterase to similar anti-Alzheimer's galantaminics: a computational study.[Pubmed:29697300]

J Biomol Struct Dyn. 2019 Apr;37(7):1843-1856.

Galantamine (Gnt) is a natural alkaloid inhibitor of acetylcholinesterase and is presently one of the most used drugs in the treatment against Alzheimer's disease during both the initial and intermediate stages. Among several natural Gnt derivatives, sanguinine (Sng) and Lycoramine (Lyc) attract attention because of the way their subtle chemical differences from Gnt lead to drastic and opposite distinctions in inhibitory effects. However, to date, there is no solved structure for these natural derivatives. In the present study, we applied computational modeling and free energy calculation methods to better elucidate the molecular basis of the subtle distinctions between these derivatives and Gnt. The results showed that differences in the mobility of the non-aromatic ring carried by the Lyc-like sp(2)-sp(3) modification display drastic conformational, vibrational, and entropic penalties at binding compared to Gnt. Additionally, the establishment of a stronger hydrogen bond network added enthalpic advantages for the linkage of the Sng-like methoxy-hydroxy substituted ligands. These results, which suggest an affinity ranking in agreement with that found in the literature, provided insights that are helpful for future planning and development of new anti-Alzheimer's disease drugs.

Catalytic asymmetric total synthesis of (-)-galanthamine and (-)-lycoramine.[Pubmed:25847447]

Angew Chem Int Ed Engl. 2015 May 18;54(21):6255-9.

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.[Pubmed:25558884]

J Org Chem. 2015 Feb 6;80(3):1952-6.

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.

Alkaloid metabolite profiles by GC/MS and acetylcholinesterase inhibitory activities with binding-mode predictions of five Amaryllidaceae plants.[Pubmed:25305596]

J Pharm Biomed Anal. 2015 Jan;102:222-8.

Acetylcholinesterase (AChE) enzymatic inhibition is an important target for the management of Alzheimer disease (AD) and AChE inhibitors are the mainstay drugs for its treatment. In order to discover new sources of potent AChE inhibitors, a combined strategy is presented based on AChE-inhibitory activity and chemical profiles by GC/MS, together with in silico studies. The combined strategy was applied on alkaloid extracts of five Amaryllidaceae species that grow in Colombia. Fifty-seven alkaloids were detected using GC/MS, and 21 of them were identified by comparing their mass-spectral fragmentation patterns with standard reference spectra in commercial and private library databases. The alkaloid extracts of Zephyranthes carinata exhibited a high level of inhibitory activity (IC50 = 5.97 +/- 0.24 mug/mL). Molecular modeling, which was performed using the structures of some of the alkaloids present in this extract and the three-dimensional crystal structures of AChE derived from Torpedo californica, disclosed their binding configuration in the active site of this AChE. The results suggested that the alkaloids 3-epimacronine and Lycoramine might be of interest for AChE inhibition. Although the galanthamine group is known for its potential utility in treating AD, the tazettine-type alkaloids should be evaluated to find more selective compounds of potential benefit for AD.

[Effect of precursor on growth and accumulation of alkaloids of Lycoris radiata suspension cells].[Pubmed:24945053]

Sheng Wu Gong Cheng Xue Bao. 2014 Feb;30(2):247-54.

In order to investigate the effects of phenylalanine, tyrosine and tyramine on the growth of Lycoris radiata suspension cells and the accumulation of alkaloids, the growth quantity of the cells as well as the content of alkaloids in cells were determined, which were treated with above three kinds of precursors alone and phenylalanine combined with tyrosine respectively. The results indicate that the addition of phenylalanine alone and addition of phenylalanine on the basis of tyrosine at high concentration (200 micromol/L) had no significant effect on the growth of Lycoris radiata suspension cells and the content of alkaloids in cells; whereas tyrosine and tyramine promoted the growth of the cells and alkaloids accumulation. Treated with tyrosine at high concentration (200 micromol/L), the content of alkaloids of the cells was 2.56-fold higher than that of the control group, the amounts of Lycoramine (3.77 mg/g) and galanthamine (4.46 mg/g) were 6.61-fold and 6.97-fold higher than that of the control group, respectively. When treated with tyramine (200 micromol/L), the amount of alkaloids in Lycoris radiata suspension cells was 2.63-fold higher than that of the control group, and the amounts of Lycoramine (4.45 mg/g) and galanthamine (5.14 mg/g) were 9.08-fold and 9.18-fold higher than that of the control group, respectively. The above results demonstrate that adding tyrosine and tyramine in the media significantly promoted the growth of the Lycoris radiata suspension cells and alkaloids accumulation in the cells.

Four new compounds from the bulbs of Lycoris aurea with neuroprotective effects against CoCl(2) and H(2)O(2)-induced SH-SY5Y cell injuries.[Pubmed:23775477]

Arch Pharm Res. 2014 Mar;37(3):315-23.

Three new alkaloids, 2alpha-hydroxy-6-O-n-butyloduline, O-n-butyllycorenine, (-)-N-(chloromethyl)Lycoramine (1-3), and a new phenolic compound, ((7S)-7-(4-hydroxyphenyl)-7-hydroxypropyl)-2'-methylbenzene-3',6'-diol (14), along with ten known alkaloids (4-13), were isolated from the bulbs of Lycoris aurea collected from Huaihua County of Hunan Province, China. Their structures were elucidated by spectroscopic methods including HRESIMS, UV, IR, and NMR. All the isolated compounds were tested for their neuroprotective effects against CoCl2 and H2O2-induced SH-SY5Y cell death. Compounds 1-7 and 10 exhibited significant neuroprotective effects against CoCl2-induced SH-SY5Y cell injury, while compounds 1-5, 7, 10 and 12 showed obvious neuroprotective effects against H2O2-induced SH-SY5Y cell death.

Zephgrabetaine: a new betaine-type amaryllidaceae alkaloid from Zephyranthes grandiflora.[Pubmed:23513717]

Nat Prod Commun. 2013 Feb;8(2):161-4.

Zephgrabetaine (1), a new betaine type Amaryllidaceae alkaloid, along with seven known alkaloids, lycorine, galanthine, Lycoramine, hamayne, haemanthamine, tortuosine, and ungeremine were isolated from the bulbs of Zephyranthes grandiflora and their structures elucidated by spectroscopic data analysis. The isolated alkaloids were tested for in vitro cytotoxic activities against two cell lines, C-6 (rat glioma cells) and CHO-K1 (Chinese hamster ovary cells). A dose dependent cytotoxic effect was exhibited by all the alkaloids on these two cancer cell lines with prominent activity of lycorine and haemanthamine.

Nonaqueous CE ESI-IT-MS analysis of Amaryllidaceae alkaloids.[Pubmed:23436771]

J Sep Sci. 2013 Mar;36(6):1078-84.

The Amaryllidaceae are widely distributed medical plants. Lycorine, Lycoramine, lycoremine, and lycobetaine are the major active alkaloids in Amaryllidaceae plants. A nonaqueous CE ESI-IT-MS method for separation, identification, and quantification of the Amaryllidaceae alkaloids has been developed. The MS(1-3) behavior has been studied and the fragmentation pathways of main fragment ions have been proposed. The effects of several factors such as composition and concentration of buffer, applied voltage, composition, and flow rate of the sheath liquid, nebulizing gas pressure, flow rate, and temperature of drying gas were investigated. Under the optimal conditions, the linear concentration range of these compounds was wide with the correlation coefficient (R(2) ) >0.99. RSDs of migration time and peak areas were <10%. The LODs were <240 ng/mL. The proposed method can be successfully applied to the determination of the related alkaloids in the Lycoris radiata roots.

Simultaneous quantification of Amaryllidaceae alkaloids from Zephyranthes grandiflora by UPLC-DAD/ESI-MS/MS.[Pubmed:22939505]

J Pharm Biomed Anal. 2012 Dec;71:187-92.

A rapid, simple and sensitive ultra performance liquid chromatography-diode array detection method (UPLC-DAD) was developed and validated for quantification of four biologically important Amaryllidaceae alkaloids viz. Lycoramine, hamayne, haemanthamine and tortuosine in Zephyranthes grandiflora. The method employed BEH C(18) column (2.1mmx100mm, 1.7mum particle size) with linear gradient elution of acetonitrile and water (0.05% formic acid) in a flow rate of 0.3mL/min and at lambda(max) 280nm. Standard calibration curve for the analytes were linear (r(2)>/=0.9999), precise (intra-day RSDs<1.33% and inter-day RSDs<2.67%) and accurate (97.8-105.3%). The developed method was applied to the quality assessment of samples collected during different seasons and showed significant variation with an optimum amounts of these alkaloids in rainy season. The method was also applied for identification of Amaryllidaceae alkaloids in the plant and overall, seventeen Amaryllidaceae alkaloids of different structural types lycorine, haemanthamine, galanthamine, narciclasine were characterised. This study provides a qualitative and quantitative method for analysis of Amaryllidaceae alkaloids.

Total synthesis of (-)-galanthamine and (-)-lycoramine via catalytic asymmetric hydrogenation and intramolecular reductive Heck cyclization.[Pubmed:22612349]

Org Lett. 2012 Jun 1;14(11):2714-7.

A synthetic strategy featuring efficient ruthenium-catalyzed asymmetric hydrogenation of racemic alpha-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).

Asymmetric synthesis of bioactive hydrodibenzofuran alkaloids: (-)-lycoramine, (-)-galanthamine, and (+)-lunarine.[Pubmed:21748835]

Angew Chem Int Ed Engl. 2011 Aug 22;50(35):8161-6.

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 alpha-cyanoketones with acrylates and was used in a novel and divergent synthetic strategy for the title compounds in asymmetric fashion.

Alkaloid accumulation in different parts and ages of Lycoris chinensis.[Pubmed:20737914]

Z Naturforsch C. 2010 Jul-Aug;65(7-8):458-62.

The galanthamine, lycorine, and Lycoramine content of Lycoris chinensis was researched during development from young to old plants, i.e. in seeds, ten-day-old seedlings, three-month-old seedlings, one-year-old seedlings, and perennial seedlings. Notably the alkaloid level reduced to its lowest content 10 days after seed germinating. Then the accumulation of galanthamine tended to increase with age, reaching a higher value in perennial seedlings. The production pattern of lycorine and Lycoramine was found similar to that of galanthamine. Different plant organs were also evaluated for their galanthamine, lycorine, and Lycoramine contents. Mature seeds had the highest content of galanthamine (671.33 microg/g DW). Kernels, seed capsules, and root-hairs were the main repository sites for galanthamine, lycorine, and Lycoramine. The leaves were the least productive organs.

Domino double Michael-Claisen cyclizations: a powerful general tool for introducing quaternary stereocenters at C4 of cyclohexane-1,3-diones and total synthesis of diverse families of sterically congested alkaloids.[Pubmed:18781800]

J Org Chem. 2008 Oct 3;73(19):7498-508.

Reactions of substituted acetone derivatives with acrylic acid esters (>200 mol %) in the presence of t-BuOK (200 mol %) in t-BuOH-THF (1:1 by volume) turned out to proceed as a cascade process consisting of the first Michael addition, the second Michael addition, and the last Claisen reaction to afford 4,4-disubstituted cyclohexane-1,3-diones. Only more substituted enolates play the role of a Michael donor in this cascade process, and therefore the ketone took up two alkoxycarbonylethyl groups on the same carbon bearing more substituents. Such intermediates were followed by intramolecular Claisen reactions leading to cyclohexane-1,3-diones bearing quaternary stereogenic centers at C(4), which bears an alkoxycarbonylethyl group and the substituent of the starting acetone derivatives. Thus-obtained 4,4-disubstituted cyclohexane-1,3-diones were successfully employed for total syntheses of intricate alkaloids of biological interest such as (+)-aspidospermidine, (+/-)-galanthamine, (+/-)-Lycoramine, and (+/-)-mesembrine, all featuring quaternary stereogenic centers. DFT calculations provided us with clear-cut explanations for the observed chemoselectivity of the cascade process involving ketone-based enolates under thermodynamically controlled conditions.

The enantioselective synthesis of (-)-lycoramine with the Birch-Cope sequence.[Pubmed:17676911]

J Org Chem. 2007 Aug 31;72(18):6792-6.

The first enantioselective synthesis of (-)-Lycoramine has been achieved in 14 steps and 5% overall yield from the biaryl derivative 1. The synthesis applies the previously developed Birch-Cope sequence to create the key arylic quaternary stereocenter of (-)-Lycoramine with excellent enantioselective control. The product of the Birch-Cope sequence, a versatile 4,4-disubstituted-2-carboxamide-2-cyclohexen-1-one, was elaborated through an intramolecular conjugate addition of a phenol to create the dihydrofuran ring. Chemoselective elaboration of the allyl group into an amide followed by a modified Pictet-Spengler reaction generated the azepine ring.

Alkaloids of the flowers of Pancratium maritimum.[Pubmed:17253308]

Planta Med. 1998 Oct;64(7):669-70.

The defatted ethanolic extract of the fresh flowers of Pancratium maritimum L. yielded the four known alkaloids lycorine, maritidine, Lycoramine, and galanthamine. The structures of the isolated alkaloids were determined mainly through spectroscopic studies including one- and two-dimensional NMR (COSY, NOESY, DEPT, HETCOR, and HMBC) and CD techniques. Some spectral data are newly reported or revised.