Indole carbazole alkaloid

Malbrancheamide (60) represents a novel type of CaM inhibitors although other natural indole alkaloids such as the unusual indole-carbazole alkaloids from a culture broth of a Nocardiopsis sp, namely K-252a-K252d, the brominated P-carbolines eudistomidins A and C, obtained... 

Staurosporine (36), an indole carbazol alkaloid isolated from Streptomyces staurosporeus was considered the most potent protein kinase inhibitor until the discovery of balanol. Staurosporine is not a selective inhibitor because it also inhibits PKA, PKG and tyrosine kinases at similar concentrations [1], This compound has significant cytotoxic and antiproliferative effects in vitro and several of its related analogues show antitumour activity in animal models. In addition, staurosporine and derivatives have been used to explore the role of PKC in cell functions. For instance, Jordan et al. [95] studied the ability of staurosporine and other PKC inhibitors to affect TNFa and interleukin-la (EL-la)-induced chemokine gene expression and protein production in synovial fibroblasts. In these circumstances, staurosporine enhanced IL-la-induced chemokine mRNA production. A possible explanation for this result is that the mechanisms of gene expression could be negatively regulated by different isoforms of PKC. [95]. Previously it had been observed that staurosporine... 

A new benzannulation methodology was developed in order to overcome the limitations of electrocyclic ring closure of divinylindoles. The cyclization is achieved via an allene-mediated electrocyclic reaction of 2,3-difunctionalized indoles. This method is more efficient for the synthesis of highly substituted 2-methyl carbazole alkaloids (559). The 3-alkenyl-2-propargylindole 557, a precursor for the allene intermediate, was prepared from 2-formylindole over several steps using simple functional group transformations (536,537) (Scheme 5.20). 

A. Simple indoles, carbazoles, carbolines, and physostygmine type alkaloids 106... 

It has also been proposed that the presence of endophytes can alter the usual suite of secondary metabolites of plants. For example, whilst Murraya spp. have been reported to produce indole and carbazole alkaloids, the Brazilian M. paniculata did not [25]. An endophytic Eupenicillium sp. was isolated from surface-sterilized leaf material of the Brazilian M. paniculata and subsequently cultured on white corn. The Eupenicillium sp. produced hydrophobic spiroquinazoline alkaloids that were separated using silica gel column chromatography and preparative gel-filtration... 

Of the more than 4500 known naturally occurring organohalogen compounds, a large fraction are alkaloids [1,3]. Most of these halogenated pyrroles, indoles, carbazoles, carbolines, tyrosines, and others have a marine origin. The present chapter surveys the occurrence, structure, and biosynthesis of these fascinating natural products. However, given their sheer number, this review focuses mainly on recent examples. 

Several investigators have developed the reductive cyclization of o-nitrostyrenes into an efficient synthesis of indoles. Thus, research by the groups of Watanabe [480], Soderberg [481], and Cenini [482] have established this reductive Pd-catalyzed TV-het-eroannulation reaction as a viable and powerful route to simple indoles and fused indoles (411) as shown below. In addition, Soderberg has shown the application of this method to carbazolones [481d], natural p-carbolines [481e], and the carbazole alkaloid murrayaquinone A [48If]. Ohta described the related Pd-catalyzed cyclization of o-aminophenethyl alcohol to indole in 78% yield [483]. 

Pityriazole (152) represents an unusual example of a 2-oxygenated carbazole alkaloid since it has an additional indol-3-yl substituent at C-1. This natural product was isolated along with other tryptophan metabolites by Steglich and co-workers from a culture of the human pathogenic yeast Malassezia furfur, which is believed to be responsible for the skin disease pit3riasis versicolor [177]. Due to the strucmral similarity of pityriazole (152) to mukonidine (149) and clausine L (148), we... 

Cycloaddition reactions continue to find application in the synthesis of natural products and related substances containing indole and carbazole rings. Moody has published a summary of syntheses of carbazole alkaloids in which cycloadditions of pyrano[3,4-b]indol-3-ones figure prominently. <94SL681>... 

Orf/io-quinodimethanes have been used in numerous S3mthetic applications for the construction of various polycyclic ring systems found in structurally complex target molecules, via [4+2] Diels-Alder type cycloadditions. In this context, indolo-2,3-quinodimethanes have become increasingly useful as synthetic precursors to a variety of interesting [6]annelated indoles, carbazoles, and alkaloids [111]. 

The most extensively used approach is route A (Scheme 1). Some of the more commonly employed indole syntheses, such as the Fischer, Bischler, Nenitzescu and the Gassman procedures, also fall into this category.Of these, the Fischer indole synthesis (Scheme 2) has been most widely applied. However, the requirement of properly substituted starting materials, which can often be difficult to fulfil, and/or the lack of regio-selectivity in the cyclizative step, limit its utility. An example of the use of the Fischer indole synthesis in the synthesis of a carbazole alkaloid is given in Scheme 3. 

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