Imidazole-derived alkaloids

In the formation of certain imidazole-derived alkaloids (D 20) and of indole alkaloids of the barman type (D 21.3) the condensation takes place obviously via a stable amide. This amide is formed as described above from the amine and acyl Co A, in case of barman for instance from tryptamine and acetyl Co A ... 

For the most part, five-membered ring alkaloids tend to make one think of pyrrole- and imidazole-derived alkaloids. There are, however, also alkaloids that fall into this class that are, for example, derived from 1,2,4-thiadiazoles, for example, 19, the characterization of which is discussed Section 7.1.8. 

L-isoleucine L-leucine L-lysine Lysine-derived alkaloids Imidazole alkaloids Manzamine alkaloids True alkaloids... 

Aromatic azapentalenes have not been found naturally, though an imidazo[4,5-d]imidazole derivative has been implicated in the prebiotic synthesis of purines130 74 (see also Section III,A,l,d). Saturated derivatives occur fairly widely the Senecio alkaloids contain the reduced pyrrolol l,2-a]pyrrole (pyrrolizidine) skeleton,487 and the alkaloid withasomnine is a derivative of pyrrolo[ l,2-6]pyrazole.374,488 The mitomycin antibiotics mentioned earlier in this review (Sections III,B,l,f and III,B,5) contain the pyrrolol l,2-a]indole ring,166,331 and the recently reported fungal metabolite sporidesmin is a saturated derivative of pyrrolo[2,3-6]indole.489... 

Completely unrelated structures have appeared in the patent literature disclosed by Japanese inventors (Figure 9.33). The two imidazole derivatives 139 and 140 are micromolar PDE1 inhibitors [114]. More potent, and bearing some structural resemblance to the alkaloid papaverine, are the quinazolines 141 and 142 from... 

Dolichotheline (111) is a histamine-derived alkaloid produced by the cactus Dolichothele sphaerica Britton and Rose (Cactaceae) native to southern Texas and northern Mexico. The alkaloid was first isolated in 1969 by Rosenberg and Paul (160). Spectroscopic data suggested structure 111, 4(5)-(iV-isovalerylaminoethyl)imidazole or 7V -isovalerylhistamine. The structure was proved by synthesis. Refluxing of histamine with isovaleric anhydride yielded 111, identical to the natural product (160). In addition to the major alkaloid dolichotheline, five minor alkaloids have been isolated (161). These were identified as A-methylphenethylamine, /i-O-methylsyn-ephrine, vV-methyltyramine, synephrine, and / -0-ethylsynephrine by IR, NMR, and comparison to authentic materials / -0-ethylsynephrine was probably an artifact of synephrine, since it was not found in a second extraction attempt when no ethanol was used. 

The synthesis of C-4/C-10 cyclic bromopyrrole alkaloids has been intensively explored, and several approaches to their pyrrolo[2,3-c]azepin-8-one ring system (bearing an imidazole-derived ring at position 4) have been proposed [63-65]. 

A general review on the use of electrochemical methods for the synthesis of N-heterocycles and natural products includes a section on imidazole derivatives. Thin-layer chromatographic methods for the separation of imidazole alkaloids have been briefly reviewed. Pharmacological effects of pilocarpine (15) have been summarized as part of an excellent review on convulsant alkaloids. ... 

Benzimidazole-derived alkaloids are rare in nature, and only a few examples of these natural products can be found in the literature. On the other hand, the occurrence of the imidazole skeleton in various natural sources is quite common [47-49]. The benzimidazole alkaloid kealiiquinone (Fig. 3) has been isolated from a yellow button-like Micronesian sponge species of Leucetta [49]. 

In their ready oxidation by permanganate or hydrogen peroxide, their stability to chromic acid and their behavior on bromination (see Section 7a), and in their degradation and that of their quaternary salts by alkali, the alkaloids closely resemble known imidazole derivatives, and Pinner and Schwarz (40) consequently proposed structure XVI for pilocarpine. 

The imidazole molecule is incorporated into many biologically relevant molecules. For example, the amino acid histidine is present in proteins and enzymes, while histamine (its decarboxylated product) is important in the body s immune response system. The imidazole ring has been found in a number of natural products, particularly the oroidin-derived alkaloids. One of the structurally simple compounds in this class of natural products is girolline, containing a 2-amino-imidazole attached to a chlorohydrin moiety. ... 

Cyclooroidin (35), from Age las oroides [22], and its analogues agesamide (36) from Agelas sp. [40] and oxocyclostylidol (37) from Stylissa caribica [41] are N1/C9 derivatives (Figme 5). Cyclooroidin (35) could be envisaged as the precursor of the non-imidazole bromopyrrole alkaloids longamides (see below). 

Histamine possesses hormone activity in animals (E 3.1) and acts as a neurotransmitter (E 3.2). It is a plant feeding deterrent present, for instance, in nettle toxin (E 5.5.3). Also the alkaloid pilocarpine has strong physiological activity in vertebrates and deters potential predators (E 5.5.3). It is used as a cholinergic drug in medicine (F 2). Urocanic acid, hydantoin propionic acid, imidazoleacetic acid riboside, 1-methylhistidine, 1-methylimidazoleacetic acid and other imidazole derivatives are involved in the removal of L-histidine and histamine residues from the organism of animals. They are found in the urine. Urocanic acid is also a constituent of sweat (E 1). It is involved in the protection of skin to UV radiation (E 2.2). 

Ephedra spp. roots are known as major source of ephedrine and derivatives alkaloids, but this plant species also contains an imidazole derivative, feruloylhistamine (12), which was identified in methanolic extract of the drug in 1983 [19, 20]. After column chromatography and crystallization procedures, feruloylhistamine was characterized by and NMR and mass spectroscopy. A molecular ion peak was observed at miz 287 consistent to a C15H17N3O3 fragment, and the NMR spectrum revealed signals for aliphatic and aromatic carbons and also one carbonyl group. The synthetic derivative was also obtained and afforded the same physical data as the natural compound [19]. 

Two new imidazole alkaloids and a P-carboline-derived alkaloid hyrtioreticulin F (73) were isolated from the marine sponge H. reticulatus and subsequently characterized [75]. No data were reported for the imidazole alkaloids characterized in the study, but the authors did report... 

Xu, Y.Z., Yakushijin, K., and Horne, D.A. (1996) Transbromination of brominated pyrrole and imidazole derivatives Synthesis of the CuNs marine alkaloid stevensine. Tetrahedron Lett., 37, 8121-8124. 

One of the most significant developmental advances in the Jacobsen-Katsuki epoxidation reaction was the discovery that certain additives can have a profound and often beneficial effect on the reaction. Katsuki first discovered that iV-oxides were particularly beneficial additives. Since then it has become clear that the addition of iV-oxides such as 4-phenylpyridine-iV-oxide (4-PPNO) often increases catalyst turnovers, improves enantioselectivity, diastereoselectivity, and epoxides yields. Other additives that have been found to be especially beneficial under certain conditions are imidazole and cinchona alkaloid derived salts vide infra). 

Several purine derivatives are found in nature, e.g. xanthine, hypoxanthine and uric acid. The pharmacologically important (CNS-stimulant) xanthine alkaloids, e.g. caffeine, theobromine and theophylline, are found in tea leaves, coffee beans and coco. The actual biosynthesis of purines involves construction of a pyrimidine ring onto a pre-formed imidazole system. 

Mauritamide A (481), a taurine-containing metabolite, was isolated from the sponge Agelas mauritiana [411]. The taurine-containing alkaloids tauroacidins A (482) and B (483) were isolated from a Hymeniacidon sp. from Okinawa and are tyrosine kinase inhibitors [412]. An imidazole alkaloid, (9 )-clathridine 9-A-(2-sulfoethyl)-imine (484), a taurine derivative of clathridine, was isolated from the calcareous sponge... 

Lindel T, Hoffmann H, Hochgiirtel M, Pawlik JR (2000) Structure-Activity Relationship of Inhibition of Fish Feeding by Sponge-Derived and Synthetic Pyrrole-Imidazole Alkaloids. J Chem Ecol 26 1477... 

One could remark that histidine and its derivative histamine belong to the most widely distributed compounds containing the imidazole nucleus, but in spite of this broad occurrence, only a few alkaloids are known whose biogenesis can be attributed to histidine. 

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