Macrocyclic Alkaloids Research Articles

Phenol oxidative coupling in the biogenesis of the macrocyclic spermine alkaloids aphelandrine and orantine in Aphelandra sp.

A crucial step in the biosynthesis of the spermine alkaloid aphelandrine and its diastereoisomer orantine is an intramolecular cyclization of the intermediate (S)-dihydroxyverbacine. In order to elucidate this step of the biosynthetic pathway, microsomes from the roots of Aphelandra squarrosa Nees were incubated with unlabeled and (D8)-labeled (S)-dihydroxyverbacine. It was shown that the microsomal fraction catalyzes the intramolecular coupling of (S)-dihydroxyverbacine to aphelandrine. This was proven by microsomal transformation of (D8)-labeled (S)-dihydroxyverbacine to (D8)-labeled aphelandrine. The reaction absolutely requires NAPDH and O2. The underlying reaction mechanism is probably an oxidative phenol coupling catalyzed by an aphelandrine synthase. This enzyme is proposed to be a cytochrome P-450 oxidase. The intramolecular cyclization of (S)-dihydroxyverbacine represents an important point in the biogenesis of the aphelandrine-type alkaloids.

Complexation of dicarboxylates and phosphates by a semisynthetic alkaloid‐based cyclophane in water

AbstractDicationic N,N′‐dibenzylated cyclophane‐type derivative 1 of a bisisoquinoline macrocyclic alkaloid, S,S‐(+)‐tetrandrine, was prepared and characterized. In aqueous solution 1 undergoes dimerization, which was studied by the concentration dependence of its 1H NMR signals. The salt effect on the dimerization constant was analyzed by using different versions of Debye–Hückel‐type equations. 1H NMR titration of 1 by 10 dicarboxylate anions of different structures revealed strong peak binding selectivity for succinate in the series of α,ω‐dicarboxylates. Aromatic carboxylates have larger binding constants and for o‐phthalate the formation of both 1:1 and 1:2 host–guest complexes is observed. Binding of nucleotides (AMP, ADP and ATP) to 1 is surprisingly insensitive to the guest charge, indicating a major contribution of stacking interactions of the nucleobase with 1. Copyright © 2001 John Wiley & Sons, Ltd.

A Combinatorial Library of Macrocyclic Polyamines Produced by a Ladybird Beetle

The pupal defensive secretion of the coccinellid beetle Epilachna borealis is composed principally of a combinatorial library of several hundred macrocyclic polyamines. This new family of natural products is characterized by extremely large-ring monocyclic polylactones, which are derived from the oligomerization of three homologous (ω-1)-(2-hydroxyethylamino)alkanoic acids. The characterization and quantification of these novel macrocyclic alkaloids as well as of related open-chain oligomers are described. Via HPLC-MS analyses of suitable derivatives, macrocycles with ring sizes from 24 to over 150 members were characterized. Whereas the three building blocks appear to be randomly incorporated into these oligomers, comparison with other ladybird beetle species suggests that the spectrum of ring sizes produced is carefully regulated.

Macrocyclic Spermine Alkaloids fromVerbascum: Isolation, Structure Elucidation, and Syntheses of the (E/Z)-Isomeric Pairs (S)-Verbasikrine/(S)-Isoverbasikrine and (S)-Verbamekrine/(S)-Isoverbamekrine

The isolation and structure elucidation of the 17-membered macrocyclic spermine alkaloids (S)-verbasikrine (3), (S)-isoverbasikrine (6), (S)-verbamekrine (9), and (S)-isoverbamekrine (12) is presented. The syntheses of their racemates are described. The HPLC/APCI-MS analysis of the original total alkaloid extract of Verbascum pseudonobile is presented.

Molecular recognition by natural macrocycles. I. d-tubocurarine as a host molecule for organic anions.

The binding of 8-anilino-1-naphthalenesulfonate and 15 anions of substituted benzoic, aliphatic dicarboxylic, and N-acetyl-alpha-amino acids to a macrocyclic alkaloid d-tubocurarine in aqueous solution has been studied by fluorometry, conductometry, and 1H NMR. The binding constants vary from ca. 50 to 3300 M-1 depending on the guest structure, charge and hydrophobicity. The results of fluorescence and NMR studies show that the host-guest complexation of the anions of aromatic acids involves the formation of a salt bridge between the quaternary nitrogen of the alkaloid and the anionic group of the guest as well as hydrophobic/Van der Waals interactions between the guest and host aromatic moieties. The binding of dianions of aliphatic dicarboxylic acids most probably is purely electrostatic. In general, d-tubocurarine possesses binding ability comparable to that of synthetic cyclophanes. It binds enantiospecifically anions of N-acetyl-alpha-amino acids and discriminates between positional isomers of anions of hydroxy and carboxy substituted benzoic acids.

Molecular recognition by natural macrocycles. Part II. Esterolytic activity and chiral discrimination of amino acid derivatives by the zwitterionic form of (+)-tubocurarine †

The esterase and complexation properties of the zwitterionic form of a macrocyclic alkaloid (+)-tubocurarine possessing two phenolic nucleophilic groups are described. Cleavage of 4-nitrophenyl esters of N-protected phenylalanine enantiomers involves reaction paths with one and two alkaloid molecules. Substrate binding enantioselectivity is large and is opposite to the kinetic enantioselectivity, leading to the modest observed enantioselectivity of the reaction, which reaches a maximum (kL/kD ≈ 1.5) at ca. 0.002 mol dm–3 alkaloid concentration and practically disappears on going to 0.01 mol dm–3 alkaloid solution. Addition of boric acid initially enhances the reaction rate and enantiospecificity, but in more concentrated borate solutions the expected inhibition due to blocking of the phenolate groups is observed. For the first time reported for an alkaloid, the esterolytic activity of (+)-tubocurarine towards 4-nitrophenyl acetate falls on a common Bronsted plot together with cyclodextrins and some synthetic macrocycles. Binding of enantiomers of differently charged derivatives of alanine, phenylalanine and β-phenylethylamine to the zwitterionic form of (+)-tubocurarine in aqueous solution was studied by 1H NMR and fluorescence titration. The binding constants vary from <5 dm3 mol–1 for alanine to ca. 50 dm3 mol–1 for phenylalanine derivatives and the binding enantioselectivity varies from marginal for N-acetylphenylalanine enantiomers to a quite notable, three-fold differentiation between L- and D-phenylalanine. While the enantiospecificity depends primarily on electrostatic interactions, the overall stability is determined by guest hydrophobicity. This conclusion was confirmed by docking calculations for enantiomers of phenylalanine. Addition of amino acid derivatives to solutions containing (+)-tubocurarine and highly fluorescent 8-anilinonaphthalenesulfonate anion leads to enantioselective spectral responses which are indicative of formation of ternary complexes.

ChemInform Abstract: Misenine, a Novel Macrocyclic Alkaloid with an Unusual Skeleton from the Mediterranean Sponge Reniera sp.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Misenine, a novel macrocyclic alkaloid with an unusual skeleton from the Mediterranean sponge Reniera sp.

Misenine ( 1 1 a ), a new marine alkaloid possessing an unprecedented tetracyclic cage-like core with two macrocyclic rings, has been isolated from the Mediterranean sponge Reniera sp. and its structure was determined by extensive spectroscopic studies. A suggestion is made as to its biogenetic origin.

Absolute stereochemistry of isosaraine-1 and isosaraine-2

The absolute stereochemistry of the quinolizidone systems present in the marine macrocyclic alkaloids isosaraine-1 ( 3) and isosaraine-2 ( 4), minor metabolites of the Mediterranean sponge Reniera sarai, has been established by applying advanced Mosher's method to the alcohol derivatives ( 5 and 6).

Macrocyclic Budmunchiamine Alkaloids from Albizia lebbek

A MeOH extract of the seeds of Albizia lebbek gave three new macrocyclic alkaloids, named as budmunchiamines L4, L5, and L6 (1-3). The known budmunchiamines A, B, C, and F have also been found. The structures of 1-3 have been determined, by the use of spectroscopic methods and by comparison with budmunchiamines L1-L3, reported earlier from this plant.

Total synthesis of cyclostellettamine C, a bispyridinium macrocyclic alkaloid having muscarinic acetylcholine receptor antagonistic activity

Cyclostellettamine C (1), a bispyridinium macrocyclic compound having muscarinic acetylcholine receptor antagonistic activity, was synthesized by the stepwise ring closure method via 3-(13-hydroxytridecyl)-1-[13-(3-pyridyl)tridecyl]pyridinium trifluoromethanesulfonate (21). Through this study, the structure of naturally originating 1 was synthetically and biologically confirmed.

Molecular recognition by natural macrocycles. I. d-tubocurarine as a host molecule for organic anions

The binding of 8-anilino-1-naphthalenesulfonate and 15 anions of substituted benzoic, aliphatic dicarboxylic, and N-acetyl-α-amino acids to a macrocyclic alkaloid d-tubocurarine in aqueous solution has been studied by fluorometry, conductometry, and 1H NMR. The binding constants vary from ca. 50 to 3300 M−1 depending on the guest structure, charge and hydrophobicity. The results of fluorescence and NMR studies show that the host-guest complexation of the anions of aromatic acids involves the formation of a salt bridge between the quaternary nitrogen of the alkaloid and the anionic group of the guest as well as hydrophobic/Van der Waals interactions between the guest and host aromatic moieties. The binding of dianions of aliphatic dicarboxylic acids most probably is purely electrostatic. In general, d-tubocurarine possesses binding ability comparable to that of synthetic cyclophanes. It binds enantiospecifically anions of N-acetyl-α-amino acids and discriminates between positional isomers of anions of hydroxy and carboxy substituted benzoic acids.

Molecular Recognition by Natural Macrocycles. I. d‐Tubocurarine as a Host Molecule for Organic Anions

The binding of 8-anilino-1-naphthalenesulfonate and 15 anions of substituted benzoic, aliphatic dicarboxylic, and N-acetyl-α-amino acids to a macrocyclic alkaloid d-tubocurarine in aqueous solution has been studied by fluorometry, conductometry, and 1H NMR. The binding constants vary from ca. 50 to 3300 M−1 depending on the guest structure, charge and hydrophobicity. The results of fluorescence and NMR studies show that the host-guest complexation of the anions of aromatic acids involves the formation of a salt bridge between the quaternary nitrogen of the alkaloid and the anionic group of the guest as well as hydrophobic/Van der Waals interactions between the guest and host aromatic moieties. The binding of dianions of aliphatic dicarboxylic acids most probably is purely electrostatic. In general, d-tubocurarine possesses binding ability comparable to that of synthetic cyclophanes. It binds enantiospecifically anions of N-acetyl-α-amino acids and discriminates between positional isomers of anions of hydroxy and carboxy substituted benzoic acids.

Synthesis of the C2-Symmetric, Macrocyclic Alkaloid, (+)-Xestospongin A and Its C(9)-Epimer, (−)-Xestospongin C: Impact of Substrate Rigidity and Reaction Conditions on the Efficiency of the Macrocyclic Dimerization Reaction

Xestospongin A [also known as araguspongine D (1)], a C2-symmetric macrocyclic alkaloid isolated from the sponge Xestospongia exigua (Xestospongia sp.), and its C(9) epimer xestospongin C [also known as araguspongine E (2)] have been synthesized. The route capitalizes on the facile condensation between 5-halovaleraldehydes and 1,3-aminoalcohols to produce an oxaquinolizidine ring system in which all proper relative stereochemical relationships are controlled by equilibration. A linchpin synthesis was used to construct one key monomeric precursora 2,5-disubstituted thiophene derivative 26 [N≡CCH2CH(OH)-2-Th-5-CH2CH2CH(CH(OMe)2)CH2CH2CH2Cl]. A second precursor lacking the thiophene ring 38 [N≡CCH2CH(OH)(CH2)6CH(CH(OMe)2)CH2CH2CH2Cl] was assembled in a similar fashion. The carbinol center in each of these precursors was efficiently resolved enzymatically; lipase (PS-30) hydrolysis of the racemic acetate derivative of the thiophenemethanol derivative 26 and SP-435-catalyzed esterification of the β-hydroxynitr...

Marine Alkaloids. 18. Securamines and Securines, Halogenated Indole-Imidazole Alkaloids from the Marine Bryozoan Securiflustra securifrons1

Four halogenated indole-imidazole alkaloids, securamine A−D, have been isolated from the marine bryozoan Securiflustra securifrons and their structures determined by NMR and mass spectrometry. Securamine A and B are in equilibrium with two macrocyclic alkaloids, securine A and B, respectively.

Binding of organic anions to a macrocyclic alkaloid d-tubocurarine

An alkaloid d-tubocurarine in aqueous solution binds 8-anilino-1-naphthalenesulfonate and anions of substituted benzoic, aliphatic dicarboxylic, and N-acetyl-α-amino acids. The binding constants vary from ca. 50 to 3300 M −1 depending on the anion structure, charge and hydrophobicity. The binding of N-acetyl-α-amino acids is enantiospecific.

Pyrrolizidine alkaloids from Senecio mulgediifolius, two new 13-membered macrocyclic 7,9-diesters

The structure and absolute configuration of the new 13-membered macrocyclic alkaloids mulgediifoline and oxyretroisosenine were determined on the basis of chemical reactions and conventional spectral studies including differential nOe and 2D NMR techniques, COSY, HETCOR, COLOC, HMBC and NOESY. The absolute stereochemistry of the already known compounds retroisosenine and cis-nemorensic acid was assigned unambiguously.

Aplidites (A-G): Macrocyclic Orthonitrites From an Australian Tunicate, Aplidium sp.

An Australian marine tunicate Aplidium sp. collected from the Great Australian Bight has been found to contain seven macrocyclic alkaloids, identified as the novel marine metabolites aplidites A-G (1)-(7). Each aplidite incorporates a hitherto undescribed orthonitrite functionality. Structures for the aplidites were secured by detailed spectroscopic analysis, derivatization and degradation.

3-Alkyl 1,6-dihydropyridines from 3-alkyl 5,6-dihydro-pyridinium salts. Implications in the biosynthesis of some macrocyclic marine alkaloids

Additions of salts 1 and dihydropyridines 2 in an intramolecular manner have been invoked in the biosynthesis of some macrocyclic alkaloids such as manzamines, sarain A and halicyclamine A, recently isolated from sponges. We report conditions for the deprotonation of easily accessible salts 1, giving a regioselective entry to 3-alkyl 1,6-dihydropyridines 2. Also, we show that species 1 and 2 can be generated from a common intermediate such as 9. Dihydropyridines 2 are unstable at high temperatures giving isomeric 1,2- and 1,4-dihydropyridines, but were conveniently trapped by dienophiles to give synthetically useful isoquinuclidines such as 18 or 20.

Accumulation of tetrapeptide precursors of macrocyclic alkaloids by callus of Ceanothus americanus

Pulse-feeding of appropriate amino acids to rapidly-growing callus of Ceanothus americanus led to accumulation of novel tetrapeptides that were precursors of the macrocyclic alkaloids characteristic of the field-grown plant. Slow-growing pigmented callus lines maintained on a variety of media exhibited no detectable alkaloid metabolism but accumulated several flavonoids, some previously not reported in the plant.