Alkaloids peptides

Excellent reviews dealing with only those alkaloids which incorporate a styrylamine unit have been provided by the leading researcher in this area. A further review is not readily accessible.  

Ogihara, Nagoya Shiritsu Daigaku Yakugakubu Kenkyu Nempo, 1974, 22, 1. 

A number of new 14-membered-ring alkaloids incorporating the p-hydroxy-styrylamine and j8-hydroxyphenylalanine structural features have been isolated and structurally elucidated, mainly by application of high-resolution mass spectrometry. Cre natine A (55) has been obtained from Discaria crenata while alkaloid A, (feretine) (56) and alkaloid A2 (57) have been isolated from Feretia apondanthera. In addition to four known alkaloids, the root bark of Zizyphus nummularia has yielded nummularine-D (58) and nummularine-E (59).  

Nummularine-F (60) and zizyphine-G (61), elaborated by Z. nummularia and Z. oenoplia respectively, represent the only new additions to the 14-membered-ring alkaloid class which exhibit the p-hydroxystyrylamine and 3-hydroxyproline units as characteristic features. The known cyclopeptide mauritine-A, together with minor amounts of amphibines-A, -E, and -F, and mauritine-C have been isolated from Z. spinachristi of Nigerian origin.  

Zizyphine-F (62 R = H), isolated from Z. oenoplia, is the first example of a cyclopeptide alkaloid bearing a phenolic hydroxy-group as part of the styrylamine unit. Its structure is based upon spectral data and conversion into the known 

The majority of alkaloids produced from ergot fungi are peptides of lysergic acid. Upon hydrolysis they decompose to give lysergic acid, two 

This alkaloid, which hitherto has not been found in nature, was, however, recently produced synthetically (169) (see Section V, B). 

The a-keto acids are not present as such in the alkaloids as no free keto group can be detected. It was thus assumed that an a-hydroxy-a-amino acid group was present in the alkaloids, which would decompose to the corresponding a-keto acid and 1 equivalent of NH3 (82, 86). 

Cleavage Products Resulting from Hydrolytic Degradation of Ergot Alkaloids of the Peptide Type 

Even more informative were the results of (1) the reduction with lithium aluminum hydride and (2) the thermocleavage. These results are depicted by formulas XLI-XLVII (89). 

Partial H relaxed spectra of frangulanine (23) have been used to assign the overlapping resonance lines, and the conformation of the alkaloid in CHCI3 has been deduced by and n.m.r., to show that a hydrogen bond exists, in the form of a 7 loop, between the isoleucine side-chain and the NH at position 6. Several examples of fourteen-membered, para-bridged ring systems (24) that are related to the peptide alkaloids have been synthesized all bind univalent (L ) 

The macrocyclic spermidine alkaloid pleurostyline, isolated from the leaves of Pleurostylia africana, has structure (26). Aphelandrine, obtained from the roots of Aphelandra squarrosa, has been assigned structure (27 R = H). It is present in eight other species of Aphelandra and also in Encephalosphaera lasiandra its O-methyl ether (27 R = Me) was isolated only from Aphelandra sinclairianOy however. 

A cyclic hexapeptide, bouvardin (28), isolated from Bouvardia temifolia, shows high cytotoxic properties through inhibiting the division of hamster ovary cells. 

Daetwyler, H. Bosshardt, H. O. Bernhard, M. Hesse, and S. Johne, Helv. Chim. Acta, 1978,61, 2646. 

Bosshardt, A. Guggisberg, S. Johne, and M. Hesse, Pharm. Acta Helv., 1978,53, 355. 

The occurrence of severine palmitate in the fruits of Atalantia monophylla and Hesperethusa crenulata,9 as well as its previous report in other citrus plants, has enabled a re-examination of its n.m.r. and mass spectra to be made, with the consequent revision of its structure to (12). 

The isobutylamide (13 R = CH2CH2CHMe2) has been isolated from the epigeal parts of Ottonia ovata,10 and it is thought to arise biogenetically by the 

Mivasaka. K. Kawabata. S. Takao. and E. Fujita. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu. 22nd.. 1979. 554 (Chem. Abstr.. 1980. 93. 204 909). 

Sharma s group has also synthesized guineensine, which is the alkaloid produced by both Piper guineense and P. officinarum.14 The isolation of trans- and cis-(—)-clovamides and their deoxy-analogues from the bark of Dalbergia 

Two brominated linear peptides that are found in the sponge Cliona celata, celenamide A (21 R = CH2CHMe2) and celenamide B (21 R = CHMe2), bear close structural relationships to the cyclic peptides integerrin and lasiodine A that occur in plants.16 A I3C n.m.r. analysis of cyclic peptide alkaloids has been reported and the chemical shifts of most of the carbon atoms in discarines A and B, lasiodines A and B, pandamine, pandaminine, and hymenocardine have been assigned.17 

A revised structure for the catecholamide spermidine siderophore obtained from Paracoccus denitrificans has been proposed the new structure contains a centrally located oxazole ring (6).3 The soft coral Sinularia brongersmai contains two spermidine derivatives, i.e. (7) and its 10,11-dehydro-derivative [(lOi )], both of which show cytotoxic activity.4 The hypotensive principle of the root bark of Lycium chinense has been isolated as an amorphous alkaloid called kukoamine A.5 Acid hydrolysis of the alkaloid produced only spermine and dihydrocaffeic acid, which, in association with its n.m.r. spectrum, indicated the structure (8). Another hypotensive principle, ephedradine B (9), has been obtained from Ephedra roots.6 

The four new cyclopeptide alkaloids (19a)—(19d) isolated from the shrub Ceanothus integerrimus contain a para-bridged fourteen-membered-ring nucleus (19), for which the name phencyclopeptine has been proposed.16 The crude alkaloidal extract from Ceanothus sanguineus17 showed the presence of five major components on composite field-desorption mass spectrometry. H.p.l.c., however, yielded six alkaloids, two of which were isomeric and one of which was a new alkaloid (20). The bark of Scutia buxifolia contains five scutianine alkaloids (B, C, D, E, and H) H is new, and is (21).18 Two new cyclopeptides, sativanines A and B, have been identified as (22) and (23) by m.s.-n.m.r. study.19 

The first and second papers in a series on medicinal plants of Pakistan report the presence of thirteen-membered cyclopeptide alkaloids in the leaves of Cocculus villosus20 and in their stems.21 A study on the cyclization of ansapep-tides , e.g. (24), has shown that the fourteen-membered ring was not obtained from (24 R = H) but that fifteen-, sixteen-, and seventeen-membered rings were produced from (24 R = COCH2NH2).22 

A potent toxin produced by Penicillium islandicum has been characterized23 by mass spectroscopy combined with partial acid hydrolysis, and shown to possess structure (25). Three alkaloids isolated from the Egyptian plant Cent-aurium spicatum (which is used for the treatment of hypertension) are (26 R R2 = O), its methoxy-acetal (26 R1 = OH, R2 = OMe), and spicatine.24 

A new Piperaceae amide, pipercide (27), obtained from the fruits of Piper nigrum, shows insecticidal activity against the adzuki bean weevil.25 New pungent compounds of the capsaicinoid group have been isolated from the fruits of Capsicum annuum var. annuum.26 

Simple amides continue to be isolated from the Piperaceae fcunily N-trans-feruloylpiperidine, feruperine (14), and its 4,5-dihydro-derivative have been isolated for the first time from natural sources (Piper nigrum).Isopiperlonguminine (15 Z,Z R = H), 

R = OAc) have been obtained from Ottonia corcovadensis, and (E,E) N-isobutyl-9-piperonyl-nona-2,4-dienoic amide (16) from Ottonia 

A short, convenient, stereoselective synthesis of pepper-derived alkaloids has been carried out by condensing piperonal with the ylide from methyl (E)-4-(diethylphosphono)-2-butenoate to give methyl (E,E)-5-(1,3-benzodioxol-5-yl)-2,4-pentadienoate, which on methoxide-catalysed aminolysis (piperidine, pyrrolidine, etc.) gave the required alkaloid. 

Tyramine in conjunction with cis ferulic acid gives the amide 

Brevigellin (29) has been isolated from the culture of Penicillium 29 

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A key step in the synthesis of 13-membered meta ansa and 14-membered para ansa peptide alkaloids involves catalytic hydrogenolysis of carbobenzyl-oxypeptide pentafluorophenyl esters. The most suitable solvent is dioxane with addition of a catalytic amount of pyrrolidinopyridine and 2% ethanol. Temperature should not exceed 90°C. The authors believe that after deblocking, the amino function remains on the surface until ring formation with the activated carboxylic function is accomplished (/5/). 

Das erste chemisch einheitliche und therapeutisch wirksame Alkaloid, das Ergotamin, ist 1918 von Stoll (79) isoliert worden. Die Mehrzahl der Peptid-Alkaloide ist erstmals in den Sandoz-Laboratorien in Basel aufgefunden worden. Die Entwicklung auf diesem Gebiet scheint mit der... 

Tabelle 2. Die beim hydrolytischen Abbau der Peptid-Alkaloide enlstehenden Spaltprodukte (in Anlehnung an Hofmann)... 

Gademann K, Budzikiewicz H (2004) The Peptide Alkaloid Anachelin NMR Spectroscopic Evidence for a (3-Tum Formation in Aqueous Solution. Chimia 58 212... 

Lewis, J. R. 2000. Amaryllidaceae, muscarine, imidazole, oxazole, thiazole, and peptide alkaloids, and other miscellaneous alkaloids. Natural Product Reports, 17 57-84. 

The teleocidins from terrestrial actinomycetales and the lyngbyatoxins from marine cyanobacteria (Chart 8.3.P) are peptide alkaloids well known for their tumor promoting ability. 

Several peptide alkaloids are either meta-(Zizyphine A, Mucronine, Maitansine) or paracyclophanes (Frangulanine) where n ranges from 10 to 19 70,b). They will not be included in this review. 

Two major families of compounds that incorporate the tetracyclic ergoline nucleus may be identified the amine alkaloids and the peptide alkaloids (Table 16-6). Drugs of therapeutic and toxicologic importance are found in both groups. 

The ergot alkaloids are extensively metabolized in the body. The primary metabolites are hydroxylated in the A ring, and peptide alkaloids are also modified in the peptide moiety. 

This methodology was used for the synthesis of the natural peptide alkaloid dihydrozizyhin G (4).3 The ring closure in this case proceeded in 67% yield. 

Numerous UCNMR investigations on alkaloids have been reported in the literature [598, 599]. In Table 5.13 the 13C chemical shifts and structures of representative alkaloids of different types are collected Pyrrolidine, piperidine and pyridine [600-602], tropane [600, 603-605], izidine [606-612], indole [600, 603, 613-633], isoquinoline [599, 630, 634-647], quinolinic [648-656], imidazole [657], yuzurimine alkaloids [658], alkaloids with exocyclic nitrogen [659, 660], diterpenoid [661-663], steroid [664-666] and peptide alkaloids [667-671], The complete signal assignment for the alkaloids given in Table 5.13 was achieved using the correlations between 13C NMR spectral parameters and structural properties and the 13C chemical shift values of model compounds described in Chapters 3 and 4 of this monograph. 

Fig. 5.3. Structure and complete 13C (dH in ppm) and H (V), in ppm) signal assignments of the peptide alkaloid franganinc, based on data from Fig. 5.4 and Table 5.14.

Certain strains of cyanobacteria produce toxins. These cyanobacterial toxins can be classified according to their chemical structure or their toxicity. Table 16.1 summarises the characteristics of the main cyanobacterial toxins. Depending on the chemical structure, there are cyclic peptides, alkaloids and lipopolysaccharides. According to the toxic effects, they are classified as ... 

Since the last review on ergot alkaloids, important new alkaloids from different sources, mostly from new ergot strains, have been discovered. Their proposed structure could in some cases be confirmed by synthesis. Some of them seem to be intermediates in the biogenetic pathway from tryptophan to the peptide alkaloids. Others are considered as end products of secondary plant metabolism. In any case we find many interesting structures among these recently discovered substances. 

Applying mild extraction methods to the mycelium of an ergo-cristine producing Claviceps purpurea strain, an unstable peptide alkaloid of a new type was recently detected (17). Its physical data and chemical transformations contributed to the elucidation of its structure. The fast methanolysis of the new alkaloid led to the well-known N-lysergyl-L-valine methyl ester (18) and L-phenylalanine-D-proline lactam. An amino acid analysis showed the presence of one mole each of valine, phenylalanine, and proline. Thus the new alkaloid has been characterized as iV-[AT-(d-lysergyl)-L-valyl]-L-phenylalanyl-D-proline lactam (18 C35H39N504 mp 235° [a]D +5° in chloroform). 

In this connection it is worth mentioning that the large-scale production of peptide alkaloids, by submerged culture techniques of selectively mutated Claviceps strains, is likely to succeed in the near future. This complex problem has been intensively studied in different laboratories for decades, but recent patents report on encouraging results (33). 

Since the publication of the synthesis of ergotamine (34) all naturally occurring peptide alkaloids have been synthesized by analogous routes. Moreover, it has been shown that they all have the same stereochemistry and differ from each other only in their L-amino acid units and the chain length of the a-hydroxy-a-amino acid moiety at the peptidic site. An X-ray study of a key intermediate has provided additional evidence for the correctness of the proposed absolute configuration of ergotamine (34a). 

The delicacy of the hitherto only synthetic pathway to the peptide alkaloids of lysergic acid is also underlined by the fact that other authors had failed to circumvent it (37). The main difficulty lies in the rapid epimerization of the L-proline containing intermediates to the d-proline isomers and the inherent instability of functionalized a-hydroxy-a-amino acid derivatives. 

The biosynthesis of the peptide alkaloids has not yet been studied to a great extent, mainly because of their rather complex structure. 

It would also be conceivable to regard d-lysergic acid amide as an intermediate for peptide alkaloids. Groger et al. (98) however showed this hypothesis to be improbable. In the same paper attention is drawn to another interesting fact. Some experiments were performed in which [14C,15N valine was introduced into C. purpurea strain Pepty 695, a fungus known to produce ergokryptine and ergocornine as the major alkaloids. 

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