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Staurosporine 26 targets the active site of the adenosine-binding pocket of most protein kinases. Together with several related analogues, 26 displays significant cytotoxic and antiproliferative effects [19]. Figure 3: Staurosporine 26 bound to the adenosine-binding pocket [19] from pdb1stc. Due to the key role of protein kinases in cellular signaling and their association with cancer, a tremendous effort in the development of selective protein kinase inhibitors was undertaken. Midostaurin 35 , a semisynthetic derivative of staurosporine 26 , is currently in clinical trials for the treatment of acute myeloid leukemia [20].

Figure 4: Structure of imatinib 34 and midostaurin Although rebeccamycin 28 and its congeners only differ in the lack of the second glycosidic linkage, a completely different mode of action is effective. By stabilizing the topoisomerase I DNA-cleavable complex they prevent the replication of DNA and act as efficient antitumor compounds [21]. The extraordinary bioactivity of indolocarbazoles has drawn a lot of attention from chemists and biologists.

Biosynthetically, the indolocarbazole scaffold is derived from two fused tryptophan molecules, whereas the sugar moiety originates from glucose and methionine [23]. In , Steglich isolated lycogalic acid A 38 , also known as chromopyrolic acid, along with staurosporinone 30 and traces of arcyriaflavin A 31 from the extracts of Lycogala epidendrum [24].

Chapter1_040115 - Textbook Paul M Dewick Medicinal Natural...

This finding and results from Hoshino, which demonstrated that 38 is derived from L-tryptophan 36 [25] , indicate a close biosynthetic relationship between these alkaloids. After additional experiments, the authors concluded that lycogalic acid A 38 is the biosynthetic key intermediate for the biogenesis of indolocarbazoles.

This hypothesis was verified through gene disruption studies and the isolation of putative intermediates []. The formation of the isoindole framework is initiated by the oxidation of L-tryptophan 36 to imino indolepyruvic acid 37 , a process, which is catalyzed through the enzyme StaO. The subsequent condensation of two molecules of imine 37 is catalyzed by the oxidase StaD and gives lycogalic acid A 38 [].

StaP and StaC convert 38 into staurosporinone 30 via an intramolecular aryl—aryl coupling and an oxidative decarboxylation [29,30]. Scheme 3: Biosynthesis of staurosporine As already mentioned before, indolocarbazoles are characterized by their excellent biological activities and unusual architecture and hence drawing an enormous interest from the synthetic organic chemistry community. This led to several syntheses of the natural occurring aglycone staurosporinone 30 [] and culminated in the first total synthesis of staurosporine 26 by Danishefsky in [36].

Based on their previous results [38] , the common intermediate 48 was recognized as an ideal branching point.

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With eleven synthetic operations and a longest linear sequence of only seven steps, this route is highly convergent and employs a novel Rh-carbenoid-mediated formation of 30 as its key step. Further reduction and Moffat oxidation gave 47 , which was believed to be the direct precursor for the common intermediate Lewis acid catalyzed Tiffenau—Demjanov-type ring expansion of 47 gave 48 as a single product.

During their attempts to methylate 48 , an unprecedented benzilic acid-type rearrangement ring contraction was discovered. Staurosporine 26 could be synthesized in five steps from 48 and in a longest linear sequence of 19 steps.

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Scheme 5: Synthesis of 26 , 27 , 49 and 50 diverging from the common intermediate Macrocyclic polyketides: The first cytochalasan alkaloids, cytochalasin A 51 and B 52 , originally named phomins [39] , were isolated in []. Since then, the number of natural products belonging to this family has increased to over Cyctochalasan alkaloids display a wide range of biological properties, such as cytotoxic, antimicrobial, antiviral and phytotoxic activities and were reviewed in detail by Hertweck in [44].

Structurally, they consist of one amino acid and a highly substituted hydroisoindolone moiety fused to a macrocyclic ring ring size 9— In certain cases, the ring system can be oxidized to an unusual cyclic carbonate as observed for cytochalasin E Depending on the amino acid incorporated in the isoindolone moiety, the cytochalasans can be further subdivided into cytochalasins [41] phenylalanine , chaetoglobosins [45,46] tryptophan , aspochalasins [47] leucine , pyrichalasins [48] tyrosine or alachalasins [49,50] alanine.

Figure 5: Selected members of the cytochalasan alkaloid family. The biosynthesis of cytochalasans was established on the basis of various isotope labeling experiments using cytochalasin B 52 as a model system []. The stepwise assembly of the nonaketide 61 is realized from activated tryptophan 36 , one acetyl-CoA 59 starter and eight malonyl-CoA extender 60 units. The remaining methyl groups are believed to be installed by S -adenosyl methionine SAM.

Recently, gene disruption studies of Chaetomium globosum revealed the enzymes involved in the final oxidative transformations leading to chaetoglobosin A 57 [57].


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Scheme 6: Biosynthesis of chaetoglobosin A 57 [56]. The diverse biological activities and unique molecular architecture of the cytochalasan alkaloids have made them a famous synthetic target. In line with the focus on the construction of the isoindole component, one can identify the Diels—Alder reaction as the most popular strategy.

A linear, biomimetic synthesis using a late stage intramolecular Diels—Alder reaction was implemented in the Stork synthesis of cytochalasin B 52 [59] and the Thomas synthesis of cytochalasin H, D, G and O []. An intermolecular reaction was reported for the synthesis of aspochalasin B 58 by Trost and Vedejs []. The intermediate 67 , which contains all of the carbon atoms of the natural product, was synthesized in eight steps starting from the advanced building blocks 64 , 65 and Selective deprotonation and trapping the so-formed enolate with phenylselenyl chloride gave an intermediate selenide.

Oxidation and elimination of the corresponding selenoxide at elevated temperature generated the necessary dienophile, which directly underwent an intramolecular endo -Diels—Alder reaction to give the isoindolinone For the synthesis of 69 another ten steps were necessary to discriminate between the three remaining double bonds, functionalize the full carbon skeleton and set the remaining stereocenters.

Five steps, including the exchange of protecting groups and one oxidation, completed the synthesis of cytochalasin D Scheme 7: Synthesis of cytochalasin D 70 by Thomas [63]. In comparison to the syntheses mentioned before Stork, Thomas, Trost, Vedejs , the convergent approach reported by Myers allows a modular entry to diverse members of the cytochalasin alkaloid family [68]. Strategic bond disconnections revealed the common isoindolinone precursor The synthesis of the latter commenced from N , N -dibenzylphenylalanine 71 to afford the Diels—Alder substrate 72 in four steps.

The envisioned intramolecular Diels—Alder cyclization of the silyl enol ether 72 provided the depicted endo -diastereomer in good yield.

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Exchange of the N -benzyl for a Boc-protecting group and cleavage of the silyl enol ether gave the corresponding ketone, which was first converted to an enol-triflate and then to the tricyclic alkene At this stage, the syntheses of cytochalasin B 52 and cytochalasin L, 78 diverged. For 78 , another five steps were necessary to form the isoindolinone After oxidation of the primary alcohol with Dess—Martin periodinane, the obtained aldehyde was coupled with the readily available N -phenyltetrazole sulfone 75 via a Julia—Kocienski olefination. Installation of the phosphonate and desilylation gave 76 , which, after oxidation, reacted in the presence of sodium 2,2,2-trifluoroethanol NaOTFE in 2,2,2-trifluoroethanol TFE via an intramolecular Horner—Wadsworth—Emmons reaction to Cytochalasin L, 78 was obtained from 77 via reduction, acetylation and a magnesium sulfate induced rearrangement of the epoxide to the allylic alcohol.

The synthesis of cytochalasin B 52 15 steps from 73 proceeded in a similar fashion and was highlighted in detail by Hertweck [44]. The authors state that this approach is highly diversifiable and allows for a rapid access to a variety of members of the cytochalasin alkaloid family. Scheme 8: Synthesis of L, The power of the intramolecular Diels—Alder strategy for the synthesis of the isoindolinone moiety was also recognized during the synthesis of aspergillin PZ 91 [73].

This secondary metabolite has a remarkable architecture and was first isolated from the fungus Aspergillus awamori in [74]. The highly functionalized pentacyclic skeleton comprises a unique oxatricyclo[6. The synthesis could be accomplished in 26 steps and includes two key steps: the 8-oxabicyclo[3.

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Activation of the anomeric position with tin IV chloride presumably led to the formation of the oxonium ion This intermediate was envisioned to undergo a Prins—Pinacol rearrangement via intermediate 84 to give the cis -aldehyde However, only the diastereomeric trans -aldehyde 83 was isolated in moderate yields from the reaction mixture. The authors concluded that a competing 2-oxonia-[3,3]-sigmatropic aldol pathway via 82a and 82b might be operative for this system. The stereochemical outcome could be attributed to the sterically less demanding transition state 82b.

The epimerization of 83 to 85 proceeded via an intermediate lactone and extended the route by seven steps. Oxidation of the secondary alcohol to the corresponding ketone and selective selenation with phenylselenyl chloride gave Following the reported sequence for the synthesis of cytochalasin D 70 , namely oxidation of the selenide to the selenoxide, elimination and intramolecular Diels—Alder reaction, isoindolinone 90 could be obtained in moderate yield. Removal of the protecting groups then yielded aspergillin PZ Though having established a rather long and low yielding synthesis, ample quantities could be obtained for a preliminary evaluation of the biological activity of In a first screen against A melanoma and DU prostate cancer cell lines, 79 showed to be inactive [73].

Isoindolinones derived from isoquinoline alkaloids: The aporhoeadane alkaloids, a term designated by Shamma [75] , are abundantly found in South American members of the botanical family of Berberis Berberidaceae. Figure 6: Representative Berberis alkaloids. Chilenine 93 was the first isoindolobenzazepine alkaloid isolated from Berberis empetrifolia in After oxidation and O -methylation, which is carried out by S -adenosylmethionine SAM , S -reticuline is obtained. Oxidation of the N -methyl group to the iminium ion and cyclization gives the tetracyclic carbon skeleton, which upon further methylation and oxidation furnishes berberine 92 [80].

Prechilenine , itself isolated as its O -methyl ether is formed via oxidation [78]. A base-catalyzed semipinacol-type rearrangement yields 93 [76].


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Chilenine 93 can be further transformed to the [4. Other members such as nuevamine 96 and magallanesine 97 contain the corresponding [4.

Medicinal Natural Products A Biosynthetic Approach

Scheme Proposed biosynthetic pathway to chilenine Most of this work is summarized in an excellent review by Leonard [81]. We confine this section to the syntheses of magallanesine 97 by Danishefsky and Kurihara, which were also mentioned by Evans and Bentley [82,83]. Magallanesine 97 , which was isolated in from Berberis darwinii , a plant native to southern Chile and Argentina, is the first known isoindolobenzazocine alkaloid.

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The isoindole unit of was prepared from the condensation of and Oxygen—sulfur exchange provided the thiophthalimide , which could be converted to magallanesine 97 via an intramolecular aldol condensation in one step [84]. Scheme Synthesis of magallanesine 97 by Danishefsky [84]. The synthesis commenced with the preparation of ester from piperonal according to a known procedure [86]. A four-step sequence yielded azetidine After oxidation with hydrogen peroxide, the resulting N -oxide cleanly underwent a [1,2]-Meisenheimer rearrangement upon heating in tetrahydrofuran.

The so-formed azocine was converted to amine by hydrogenolysis of the N—O bond. Amide formation with acid chloride gave , which upon sequential oxidation yielded enaminone Finally, the isoindolinone moiety was generated via an intramolecular Heck reaction using tetrakis triphenylphosphine palladium 0 and thallium acetate, to give magallanesine 97 in excellent yield [85].

Aporphine alkaloids: The aristolactam alkaloids are classified as members of the aporphine alkaloid family and contain a characteristic phenanthrene lactam core. Several comprehensive overviews of various aristolactams were published by Shamma, Parmar and Bentley [87,]. Table 1: Selected members of the aporphine alkaloid family.

The co-occurrence of aristolactams, aristolochic acids and 4,5-dioxoaporphines led to the assumption of a close biogenetic relationship between these three classes [87,96]. A de-aromatizing spirocyclization of leads to R -orientalinone , which, after reduction of the ketone to the secondary alcohol , undergoes a [1,2]-alkyl migration with concomitant loss of water.

Re-aromatization and dioxolane formation gives stephanine It is hypothesized that direct oxidation of forms 4,5-dioxoaporphine , which upon benzilic acid rearrangement, N -methyl cleavage and decarboxylation provides aristolactam I [96]. Additional oxidation of the amide function furnishes aristolochic acid I Scheme Proposed biosynthesis of , and The aristolactams and aristolochic acids have a broad spectrum of biologically interesting properties. Although both can be isolated from the same plants, their biological activity is highly variable. Herbal drugs containing aristolochic acids display cytotoxic activities and inhibitory effects on platelet aggregation and were traditionally used in folk medicine [].

The DNA damage is initiated by metabolic reduction and cyclization of to N -hydroxyaristolactam After loss of water, the aristolactam nitrenium ion , which is believed to be the main carcinogen, reacts with DNA bases such as adenosine, to give the corresponding 7- deoxyadenosin- N 6 -yl aristolactam I dA—AAI, Scheme DNA lesion caused by aristolochic acid I []. Interestingly, aristolactams are not mutagenic themselves but show immunosuppressant [] , antiplatelet [] , antimycobacterial [] , neuroprotective [] activities and are excellent inhibitors of cyclin-dependent kinases CDKs with IC 50 values in the nanomolar range [,].

CDKs are regulatory proteins, which play an important role in the cell cycle and are considered to be a potential target for anticancer treatment.


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