Quinoline and Acridine Alkaloids

Claisen reaction malonate chain extension of anthraniloyl starter 

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Figure 13. L-anthranilic acid is a precursor of quinazoline, quinoline and acridine alkaloids.

The polyketide synthases responsible for chain extension of cinnamoyl-CoA starter units leading to flavonoids and stilbenes, and of anthraniloyl-CoA leading to quinoline and acridine alkaloids (see page 377) do not fall into either of the above categories and have now been termed Type TTT PKSs. These enzymes differ from the other examples in that they are homodimeric proteins, they utilize coenzyme A esters rather than acyl carrier proteins, and they employ a single active site to perform a series of decarboxylation, condensation, cyclization, and aromatization reactions. 

Reviews of quinoline and acridine alkaloids are now available in the second edition of Rodd . The synthesis of quinazolones has been reviewed. ... 

FIGURE 1.13 L-anthranilic add Is a precursor of qulnazoline, quinoline, and acridine alkaloids. 

Alkaloid biosynthesis needs the substrate. Substrates are derivatives of the secondary metabolism building blocks the acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid and 1-deoxyxylulose 5-phosphate (Figure 21). The synthesis of alkaloids starts from the acetate, shikimate, mevalonate and deoxyxylulose pathways. The acetyl coenzyme A pathway (acetate pathway) is the source of some alkaloids and their precursors (e.g., piperidine alkaloids or anthraniUc acid as aromatized CoA ester (antraniloyl-CoA)). Shikimic acid is a product of the glycolytic and pentose phosphate pathways, a construction facilitated by parts of phosphoenolpyruvate and erythrose 4-phosphate (Figure 21). The shikimic acid pathway is the source of such alkaloids as quinazoline, quinoline and acridine. 

The stereoselective synthesis of Af-heterocycles like quinolines [1] and acridines [2] is of great interest because many of these compounds can be used for the synthesis of alkaloids. In addition, compounds with the quinoline and acridine skeletons frequently exhibit pharmaceutically interesting properties [3]. 

Klingsberg, E. and Newkome, G.R., Eds., Pyridine and Its Derivatives, Interscience, New York, 1960 Schoefield, K., Heteroaromatic Nitrogen Compounds Pyrroles and Pyridines, Butterworths, London, 1967 Hurst, D.T., An Introduction to the Chemistry and Biochemistry and Pyrimidines, Purines, and Ptreridines, J. Wiley, Chichester, UK, 1980 Plunkett, A.O., Pyrrole, pyrrolidine, pyridine, piperidine, and azepine alkaloids, Nat. Prod. Rep. 11, 581-590, 1994 Kaiser, J.P., Feng, Y., and Bollag, J.M., Microbial metabolism of pyridine, quinoline, acridine, and their derivatives under aerobic and anaerobic conditions, Microbiol. Rev. 60, 483-498, 1996. 

It has generally been considered that the quinoline alkaloids of the Rutaceae, together with the acridine and quinazoline alkaloids which often occur alongside them, are all derived from an anthranilic acid... 

Biosynthesis In plants the quinoline system can be formed by several different biogenetic routes (biochemical convergence). In the Cinchona alkaloids tryptophan acts as the precursor while simple quinolines, furoquinolines, and acridines originate from an-thranilic acid. The second biosynthetic parmer is often a hemiterpene (for furoquinolines) or an iridoid monoterpene (secologanin, see secoiridoids) for Cinchona alkaloids. 

Although probably not significant, it is interesting that the first applications of inverse-detected 2D NMR techniques in the study of marine alkaloids were applied to quinoline-based alkaloids. There have also been a sizeable number of isoquinoline and acridine-derived marine alkaloids reported. Thus, we will begin our survey of marine alkaloids with these groups. 

Rutaceae alkaloids aUetdoids from common rue Rusa graveolens L.) and other members of the Rutaceae. They include quinoline, furanoquinoline, pyra-noquinoline and acridine compounds, all biosynthesized from anthranilic add. The furanoquinolines have spasmolytic activity, and the drugs are sometimes used therapeutically. 

Quinoline, acridine and benzodiazepine alkaloids (D 8.4.2) Nonprotein amino acids (D 9.1)... 

Dehydroquinic acid, shikimic acid, and chorismic acid are carboxylated compounds containing a six-membered carbocyclic ring with one or two double bonds (Fig. 143). The secondary products derived from these substances either still contain the ring and the C -side chain of the acids (see the structure of the benzoic acid derivatives, of anthranilic and 3-hydroxyanthranilic esters, D 8, D 8.2, D 8.4 and D 8.4.1) or have additional rings (see the formulae of naphthoquinones and anthraquinones, D 8.1, of quinoline, acridine, and benzodiazepine alkaloids, D 8.3.2). The carbon skeletons may be substituted by isoprenoid side chains (see the structure of ubiquinones, D 8.3) and may carry different functional groups, e.g., hydroxy, carboxy, methoxy, and amino groups. 

Quinoline, acridine and benzodiazepine alkaloids are formed in microorganisms, e.g., pseudans in Pseudomonas and benzodiazepines in Penicillium as well as in higher plants, e.g., Rutaceae and Compositae. 

The chemistry of thienoquinolines has been explored to a limited degree. Two types (378,379) will be described in this subsection. The pharmacological interest in thieno[2,3-Z>]quinoline (378) and derivatives thereof stems from their isosteric and isoelectronic resemblance to acridine furthermore, (378) constitutes the sulfur analog of furoquinoline (Section 3.17.2.1.5), which is the parent system of a number of alkaloids. Thieno[3,4-6]quinoline (379) is an o-quinonoidal heterocycle which is of interest both for theoretical reasons compared with its isoconjugate analogues and as a synthon in Diels-Alder reactions for the preparation of other condensed heterocycles. 

T r y p t"o p h a n, 3-hydroxyanthranilic acid, quinoline, acridine and benzodi azepine alkaloids... 

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