Natural Quinazoline Compounds

The occurrence of the quinazoline skeleton in various natural sources as alkaloids, fungal metabolites, and marine natural products has generated interest of many groups on account of their useful biological properties and often very intriguing structures. For example, the unique novel structure of tetrodotoxin known as one of the most powerful non-protein neurotox-ins from the Japanese fugu (puffer fish), Sphoerdes rubripes and S. phyreus was finally elucidated as the labile complicated quinazoline derivative (8) (Fig. 2) in 1964 by Hirata et al., Tsuda et al., and Woodward et al., respectively [44-47]. It is of interest that the same toxin was also found in the Californian newt or salamander, Taricha torosa [48] and others [49,50]. Total synthesis of (±)-8 was achieved by Kishi in 1972 [51], and asymmetric synthesis of (-)-8 has been achieved by Isobe et al. [52], and also by Du Bois et al. [53] in 2003. Quinazoline alkaloids are continuously updated in Natural Product Reports [21-28], and comprehensive reviews are available [19,20,29-32]. Quinazoline alkaloids have been isolated from several families in the plant kingdom, as well as from bacteria and animal species, and many are biogenetically derived from anthranilic acid [54].

The first quinazoline alkaloid to be isolated was vasicine (peganine) (9) in 1888, produced by Indian medicinal tree Adhatoda vasica, and later isolated from other species along with the related pyrrolo[2,1-b]quinazoline alkaloids, vasicinone (10) and deoxyvasicinone (11), etc. [21,55,56]. A variety of other quinazoline natural products have been isolated, characterized and synthesized thereafter. Some of these examples including simple 2-substituted 4(3H)-quinazolinones such as 12 [57] and 13 (-)-chrysogenine [58,59] are shown in Fig. 2. N(3)-Substituted derivatives are also included as antimalar-ial (+)-febrifugine 14 and (+)-isofebrifugine 15 isolated as the active ingredient of Chinese medicinal plant Dichora febrifuga [24,25,60-63]. Unfortunately these are also toxic to man. This has led to extensive synthetic studies and biological screening of many quinazoline derivatives (see Sect. 3.6). Familiar quinazolin alkaloid rutaecarpine (16) [64,65] and evodiamine are known as the active compounds of Evodia rutaecarpa, used in


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