Synthesis and reactivity of pelletierine-derived building blocks and pelletierine analogs

Lycopodium alkaloids are unique (and often impressive in terms of structures) polycyclic alkaloids that attract great interest from a biological point of view and that also provide ideal targets for total synthesis. Propylpiperidine units closely related to pelletierine are involved in the biosynthesis of these alkaloids. Therefore, stable pelletierine-like compounds, especially a (R)-phenylglycinol-based oxazolopiperidine analog, were prepared and their reactivity investigated. The compounds described in this work expand the tool-box of small building blocks in the piperidine series and pelletierine analogs and could be suitable for the synthesis of Lycopodium alkaloids following biosynthetically inspired strategies.     

Nature spermidine and spermine alkaloids: Occurrence and pharmacological effects

Spermidine and spermine are special polyamines in organisms, and produced in vivo by putrescine and S-adenosylmethionine catalyzed by a variety of enzymes. Spermidine and spermine possess multiple amino groups, and are closely related to cell division, growth and survival. Spermidine and spermine alkaloids are widely distributed in plants, bacteria and marine organisms, and can be divided into macrocyclic and open chain according to the skeletons. Spermidine and spermine alkaloids exhibited numerous pharmacological effects such as anti-inflammatory, antibiotics, anti-tumor, anti-Alzheimer and anti-virus. However, up to now, there are few systematic reviews on spermidine and spermine alkaloids. In this review, based on the number of atoms in the ring, we summarized the distributions and pharmacological effects of spermidine and spermine alkaloids. Spermidine and spermine alkaloids have special chemophenetic significances in the plant kingdom, especially the macrocyclic spermidine and spermine alkaloids. Spermidine alkaloids are much more abundant in nature than spermine alkaloids. The pharmacological activities of the open chain spermidine and spermine alkaloids are studied in depth. Polycyclic guanidine spermidine alkaloids, isolated from marine sponge, exhibit great potential in various cancer cells. However, pharmacological studies of macrocyclic spermidine and spermine alkaloids are scarce. Synthesis is an effective way to get more spermidine and spermine alkaloids and their analogues for further study.     

Functional polymers. II. Synthesis and properties of new polymeric cinchona alkaloids

New polymeric cinchona alkaloids having favorable structures and properties for asymmetric catalysts have been prepared by radical copolymerization of the alkaloids with acrylonitrile using azobisisobutyronitrile (AIBN) as an initiator. Of the many reaction solvents tried, dimethylformamide (DMF) was found to be the solvent of choice especially for a large-scale synthesis. Alkaloid monomers employed were free dalkaloids, such as quinine, quinidine, cinchonidine, and cinchonine, and modified ones including 9-O-ethoxycarbonylquinine and quinine salts. The copolymers were thermally stable powders, soluble in DMF and DMSO, and insoluble in common organic solvents. They were found to be converted into water-soluble polymeric alkaloids by hydrolysis with alkaline hydrogen peroxide.     

Studies on Atropo-Enantioselective Synthesis of the Natural Chiral Axial Biaryls

Ary-aryl bond formation plays an important role in modern organic synthesis. These bonds are very often occurred in natural products such as alkaloids as well as in numerous biologically active parts of pharmaceutical and agrochemical specialties. In addition, they are also the scaffolds of some of the most efficient and selective ligands for asymmetric catalysts, especially when atropisomery is possible. In this report, we report the structure and the enantioselective synthesis of some natura…     

The Lycopodium alkaloids

Lycopodium alkaloids are quinolizine, or pyridine and alpha-pyridone type alkaloids. Some Lycopodium alkaloids are potent inhibitors of acetylcholinesterase (AChE). Huperzine A (HupA) is reported to increase efficiency for learning and memory in animals, and it shows promise in the treatment of Alzheimer's disease (AD). 201 Lycopodium alkaloids from 54 species of Lycopodium (sensu lato) have been reported so far. This review is intended to to cover the chemical, pharmacological and clinical research on Lycopodium alkaloids reported in the literature from the spring of 1993 to August 2004. Structures of 81 new Lycopodium alkaloids are presented, classified and analyzed. The structural characters and biogenetic relationships of the four major Lycopodium alkaloid groups (lycopodine, lycodine, fawcettimine and miscellaneous) are discussed. Bioactivities of Lycopodium alkaloids, especially HupA, are summarized. In particular, the effect of HupA and other cholinesterase inhibitors (anti-AD drugs) on acetylcholine esterase (AChE) activity in the rat cortex and butylcholine esterase activity are compared. Structure-activity relationships and structure modifications of HupA and its analogs are described. Information on clinical trials with HupA and its derivative ZT-1 is presented. The state of HupA availability and recent advances in in vitro propagation of HupA producing plants are outlined. Finally, hypotheses about Lycopodium alkaloid biosynthetic pathways are discussed.     

Studies on the intestinal absorption of the alkaloids in the Gancaofuzi decoction in a Caco-2 cell culture system by UPLC–MS/MS analysis

In this study, the Caco-2 cell monolayer model was used to research the characteristic absorption and efflux of five diterpenoid alkaloids in Gancaofuzi decoction. An ultra performance liquid chromatography coupled with tandem mass spectrometry(UPLC–MS/MS) method was developed for the determination of the simulated intestinal transport of five diterpenoid alkaloids with reserpine as internal standard. The use of the apparent permeability coefficient(Papp) and efflux rate(Er) was instituted to evaluate the intestinal absorption of the alkaloids. Transport of the five alkaloids in Caco-2cell monolayer model was observed to better understand whether the intestinal absorption of alkaloids was influenced by the compatibility of four herbs in Gancaofuzi decoction. The results show that the Papp values of the five diterpenoid alkaloids were all more than 1 * 10~(-6)cm/s, confirming that the processes of permeability were valid. The flux of the alkaloids was time-dependent, and the intestinal absorption mechanism of the five alkaloids was mainly based on passive transport. The compatibility of Heishunpian, Baizhu, Guizhi and Gancao can reduce the intestinal absorption of alkaloids, especially the most toxic hypaconitine, and the attenuated effect of mixed herbal water extracts was better than that of different herbs' water extracts combination. The results prove that compatibility of four herbs in Gancaofuzi decoction is rational.     

Two New C19-Diterpenoid Alkaloids from Delphinium davidii Franch.

Two new C19-diterpenoid alkaloids, davidisines A (1) and B (2) along with thirteen known alkaloids were isolated from the whole herb of Delphinium davidii Franch. Their structures were established by spectral methods, especially 2D NMR techniques.     

Determination of caffeine and sympathomimetic alkaloids in weight loss supplements by high-performance liquid chromatography

Reversed-phase high-performance liquid chromatography utilizing photodiode array detection is used for the simultaneous determination of caffeine and nine alkaloids from Citrus aurantium (CA) and ephedra (EA) contained in dietary weight loss products. Since the Food and Drug Administration (FDA) ban of EA, manufacturers have substituted CA in their weight loss formulations, usually combined with high levels of caffeine. The alkaloids contained in CA have some physiological effects similar to those of the EA alkaloids and are, therefore, cause for concern. Caffeine has been shown to potentiate the toxicity of the EA alkaloids. Recently, a federal judge overturned the absolute ban and allowed marketing of low levels (<10 mg/day) of total EA alkaloids. To support an absolute ban, the FDA is now compelled to perform dose-dependent toxicology studies to determine the toxic dose(s) of EA. The toxicity of the CA compounds is largely unknown, especially in combination with caffeine. The described method enables quantitation over a wide range of product formulations. Recoveries range from 91% to 100% from a variety of fortified plant matrices.     

Alkaloids from Fruits of Daphniphyllum oldhamii

Seventeen Daphniphyllum alkaloids, including two new pentacyclic alkaloids, yuzuric acid ( 1 ) and daphnezomic acid ( 2 ), and 15 known ones, were isolated from the fruits of Daphniphyllum oldhamii. The structures and configuration of the two new alkaloids were determined on the basis of spectroscopic methods, especially 2D NMR techniques.     

Die Alkaloide aus Hedranthera barteri (Hook. f.) Pichon. 139. Mitteilung über Alkaloide

From the root bark of the apocynacea Hedranthera barteri (Hook. f.) Pichon were isolated the known indole alkaloids vobtusine ( 1 ), voacamine ( 2 ), callichiline ( 3 ), voacangine ( 4 ) and conoflorine ( 5 ), as well as the unknown plant bases amataine, goziline and owerreine, and also beninine and 1, 2-dehydrobeninine. The structures of the two last mentioned alkaloids were shown in an earlier publication to be 6 and 7 , respectively. Amataine, goziline and owerreine are bis-indole alkaloids, which on the basis of their chemical and spectroscopic (especially mass spectroscopic) properties have been assigned the structures 8 , 9 and 10 , respectively.     

Establishment of a search library about benzylisoquinoline alkaloids based on selective separation on the binaphthyl column and standard analysis on C18 column

A search library about benzylisoquinoline alkaloids was established based on preparation of alkaloid fractions from Rhizoma coptidis, Cortex phellodendri, and Rhizoma corydalis. In this work, two alkaloid fractions from each herbal medicine were first prepared based on selective separation on the “click” binaphthyl column. And then these alkaloid fractions were analyzed on C18 column by liquid chromatography coupled with tandem mass spectrometry. Many structure‐related compounds were included in these alkaloids fractions, which led to easy separation and good MS response in further work. Therefore, a search library of 52 benzylisoquinoline alkaloids was established, which included eight aporphine, 19 tetrahydroprotoberberine, two protopine, two benzyltetrahydroisoquinoline, and 21 protoberberine alkaloids. The information of the search library contained compound names, structures, retention times, accurate masses, fragmentation pathways of benzylisoquionline alkaloids, and their sources from three herbal medicines. Using such a library, the alkaloids, especially those trace and unknown components in some herbal medicine could be accurately and quickly identified. In addition, the distribution of benzylisoquinoline alkaloids in the herbal medicines could be also summarized by searching the source samples in the library.     

Lamellarin H(LMH)的研究进展

Lamellarin及其类似物是一类从海洋软体动物中分离出来的具有生物活性的吡咯生物碱,截至2008年已发现70多种,其中Lamellarin H(LMH)具有高效的抑制拓扑异构酶1,抑制HIV-1整合酶等活性,而且对各种肿瘤细胞特别是人类宫颈癌传代细胞(HeLa)具有很好的细胞毒性,从而在医学上有很大的价值.本文综述...     

Isoquinoline Alkaloid Contents in Macleaya cordata Extracts and Their Acetylcholinesterase and Butyrylcholinesterase Inhibition

An important strategy for treating neurodegenerative disorders is to maintain the levels of acetylcholine in the synaptic cleft by blocking the cholinesterases. Searching for new effective compounds with inhibited acetylcholinesterase and butyrylcholinesterase activity is one of the most significant challenges of the modern scientific research. The aim of this study was the optimization of the condition for cholinesterase activity determination by high-performance liquid chromatography coupled with diode array detector (HPLC-DAD) in terms of concentrations of enzymatic reaction mixture components, temperature of incubation, and incubation time. In vitro investigation of acetylcholinesterase and butyrylcholinesterase activity inhibition by some isoquinoline alkaloids and extracts obtained from the aerial part and roots of Macleaya cordata collected in May, July, and September. Acetylcholinesterase and butyrylcholinesterase activity inhibition of the extracts obtained from the plant had not been tested previously. The application of the HPLC method allowed eliminating absorption of interfering components, for example, alkaloids such as sanguinarine and berberine. The HPLC method was successfully applied for the evaluation of the acetylcholinesterase inhibitory activity in samples such as plant extracts, especially those containing colored components adsorbing at the same wavelength as the adsorption wavelength of 5-thio-2-nitro-benzoic acid, which is the product of the reaction between thiocholine (product of the hydrolysis of acetyl/butyrylthiocholine reaction) with Ellman’s reagent. Moreover, liquid chromatography coupled with a triple quadrupole mass spectrometer (LC–QqQ–ESI–MS/MS) analysis allowed evaluating the identification of relevant bioactive compounds in the obtained plant extracts. The investigated alkaloids, especially sanguinarine and chelerythrine, and all the Macleaya cordata extracts, especially the extract obtained from the aerial part collected in May, exhibited very high cholinesterase activity inhibition. HPLC-DAD was also applied for the kinetics study of the most active alkaloids sanguinarine and chelerythrine. Our investigations demonstrated that these plant extracts can be recommended for further in vivo experiments to confirm their cholinesterase inhibition activity.     

Electron ionization mass spectral study of oxo- and thio derivatives of minor tobacco alkaloids

The electron-ionization mass spectra (EI-MS) of oxo- and thio-derivatives of minor tobacco alkaloids and structurally similar piperidine alkaloids, i.e. thiocotinine (1), 2'-oxo-N-methylanabasine (2), 2'-thio-N- methylanabasine (3), 2'-oxoanabasamine (4) and 2'-thioanabasamine (5) are discussed and general fragmentation routes of their molecular cations are proposed. Comparison of the data obtained for 1 with the EI-MS data of metameric metabolites of nicotine: 3'-hydroxycotinine, (A) and 5'-hydroxycotinine, (B) allows a differentiation between these metamers. The data will be useful for the identification of metabolites of alkaloids of these types in biological matrices.     

Recent advances in the studies on luotonins

Luotonins are alkaloids from the aerial parts of Peganum nigellastrum Bunge. that display three major skeleton types. Luotonins A, B, and E are pyrroloquinazolino-quinoline alkaloids, luotonins C and D are canthin-6-one alkaloids, and luotonin F is a 4(3H)-quinazolinone alkaloid. All six luotonins have shown promising cytotoxicities towards selected human cancer cell lines, especially against leukemia P-388 cells. Luotonin A is the most active one, with its activity stemming from topoisomerase I-dependent DNA-cleavage. Such intriguing biological activities and unique structures have led not only to the development of synthetic methods for the efficient synthesis of these compounds, but also to interest in structural modifications for improving the biological properties. Recent progress in the study of luotonins is covered.     

A novel synthetic approach for the synthesis of pyridocarbazole alkaloids

The synthesis of 11‐methyl‐6H‐pyrido[4,3‐b]carbazole‐1(2H)‐one (5), which can be important for the synthesis of other pyridocarbazole alkaloids and especially 1‐substituted ellipticines, is described. Construction of the tetracyclic structure was achieved by a new route and two important precursor compounds (4a and 4b) for the synthesis of pyridocarbazole alkaloids and also many new tetrahydrocar‐bazole derivatives (7, 8, 9, 10, 11, 12, 13) were synthesized.     

Determination of Nicotine-Related Alkaloids in Tobacco and Cigarette Smoke by GC-FID

A simple and accurate method, gas chromatography (GC) with flame-ionization detection (FID) has been used for determination of the four main nicotine-related alkaloids in tobacco. Tobacco samples were treated with a small quantity of aqueous ammonia solution, to loosen the tobacco tissue and to convert all alkaloids to free bases, then extracted with 1:3 CH₃OH-CH₂Cl₂. A method for further simultaneous and comprehensive determination of six nicotine-related alkaloids in cigarette smoke was also developed. Because of the complexity of the cigarette smoke matrix and the small amounts of alkaloids, except nicotine, in cigarette smoke, the smoke extract was concentrated after removal of the acidic and neutral fractions. To reduce the adsorption and thermal degradation of alkaloids in the liner, especially for nornicotine, a suitable injector temperature was selected and pulsed injection mode was studied. Different cigarette smokes and tobaccos were analyzed for levels of nicotine-related alkaloids.Revised: 3 January and 21 March 2005     

Alkaloids and Colon Cancer: Molecular Mechanisms and Therapeutic Implications for Cell Cycle Arrest

Cancer is the second most fatal disease worldwide, with colon cancer being the third most prevalent and fatal form of cancer in several Western countries. The risk of acquisition of resistance to chemotherapy remains a significant hurdle in the management of various types of cancer, especially colon cancer. Therefore, it is essential to develop alternative treatment modalities. Naturally occurring alkaloids have been shown to regulate various mechanistic pathways linked to cell proliferation, cell cycle, and metastasis. This review aims to shed light on the potential of alkaloids as anti-colon-cancer chemotherapy agents that can modulate or arrest the cell cycle. Preclinical investigated alkaloids have shown anti-colon cancer activities and inhibition of cancer cell proliferation via cell cycle arrest at different stages, suggesting that alkaloids may have the potential to act as anticancer molecules.     

Novel Alkaloids from Stemona sessilifolia

Two new alkaloids, sessilifolines A ( 1 ) and B ( 2a ), were isolated from the stems of Stemona sessilifolia, together with three known alkaloids, tuberstemonine ( 3 ), sessilifoliamide A ( 4 ), and stemoninoamide ( 5 ). Their structures were established by mass‐spectrometric and spectroscopic methods, especially 2D‐NMR techniques.