Alkaloids staurosporine

The interest in indolocarbazoles began in the early 1950s with the first rational synthetic approaches. Since then, this interest has escalated dramatically as numerous derivatives of indolo[2,3-a]carbazole (1) have been isolated from various natural sources. These derivatives were demonstrated to possess highly potent and diverse biological effects, prompting novel efforts in the area. In particular, derivatives of indolo[2,3-n]pyrrolo[3,4-c]carbazole, such as the alkaloid staurosporine (8), have attracted much attention. 

The Michael addition of the carbanions derived from esters to nitroalkenes followed by reductive cycLizadon has been used extensively for the preparation of pyrrondin-3-ones fEq 1076 This strategy is used for synthesis of the carbaaole alkaloid staurosporine aglycon CK-352c ... 

Since the first isolation and the discovery of the potent inhibitory activity of the microbial alkaloid staurosporine (295) against protein kinase C (PKC), the indolo[2,3-fl] carbazole alkaloids have emerged as a rapidly growing family. This was attested to by the isolation of about 70 natural products. In addition to this large... 

A natural product s bioactivity is often due to a defined shape that complements the binding site of a protein. Meggers and co-workers have demonstrated that simple organometallic scaffolds can be substituted for structurally more complicated natural products in binding at a target protein s active site <2006AGE1580>. A ruthenium complex 41 was synthesized to mimic the shape of the alkaloid staurosporine 42, a potent inhibitor of protein kinase Pim-1. 

The earliest application of inverse-detected 2D NMR techniques to a terrestrial alkaloid of which we are aware was the assignment of the H and NMR spectra of the indolocarbazole alkaloid staurosporine (7) reported by Meksuriyeri and Cordell (1988). Later in 1988, Edwards et al. utilized HMQC in the elucidation of the structure of pumiliotoxin-A (10) and related indolizine alkaloids isolated from Panamanian poison frogs. These were the only applications of inverse-detected 2D NMR techniques in alkaloid to appear in 1988. We will thus begin with staurosporine (7) and proceed to related carbazole-based alkaloids before continuing to pumiliotoxin-A (10) and other terrestrial alkaloids. 

In 2013, the complex indolocarbazole alkaloid staurosporine (4) was employed as a model compound by Senior et al. [29] to evaluate the abibty of the 1ADEQUATE experiment to probe long-range carbon—carbon coupling pathways as a supplement to more traditional HMBC data in severely proton-deficient molecules. It was also interesting to note that while not all of the Jcc correlations were observed in the conventional 1,1-ADEQUATE spectrum, there were a number of the missing correlations that were observed in the dual-optimized inverted Jcc. l. -ADEQUATE spectrum that was also acquired for the sample. 

The cyclized products 393 can be prepared by the intramolecular coupling of diphenyl ether or diphenylamine(333,334]. The reaction has been applied to the synthesis of an alkaloid 394[335]. The intramolecular coupling of benzoyl-A-methylindole affords 5-methyl-5,10-dihydroindenol[l,2-b]indol-10-one (395) in 60% yield in AcOH[336]. Staurosporine aglycone (396) was prepared by the intramolecular coupling of an indole ring[337]. 

UCN-01 201 (staurosporine analog) (190) Alkaloidal antibiotic KRX-0601 (UCN-01, KW-2401) (190) Oncology Inhibition of CDKs Phase n (melanoma, TCL, SCLC) Keryx (Kyowa Hakko/NCl) 902-905... 

Independently, in 1998, the Cordell (290,379,380) and Pearce (381) groups published some preliminary biosynthetic results on staurosporine and rebeccamycin, typical representative members of the indolo[2,3-fl]pyrrolo[3,4-c]carbazole alkaloids. Cordell s biosynthetic studies on staurosporine were based on feeding experiments with L-tryptophan. These studies showed that two units of L-tryptophan, with the two carbon side-chains intact, were responsible for the biosynthesis of staurosporine aglycone. Further experimental studies are necessary to establish the nature of the intermediate in the biotransformation of L-tryptophan to staurosporine. Although these studies are not complete, they gave for the first time insight into the biosynthesis of staurosporine (379,380). 

The total synthesis of litseaverticillols D, F and G (172 and 173), which are natural products with anti-HIV activity, was achieved recently via a singlet oxygen initiated cascade proposed to be biomimetic (Scheme 64). Finally, allylic alcohols 174a and 174b (Scheme 64) were isolated in a 4/1 ratio via a stereoselective singlet oxygen ene reaction. Stereoisomer 174a is an intermediate in the synthetic route of staurosporine, which is a bioactive alkaloid with hypotensive, antimicrobial and cell cytotoxic properties. 

Isolated in 1977 from the bacterium Streptomyces staurosporeus, staurosporine (3) is a natural product that inhibits most protein kinases at low nanomolar concentrations [23]. Through small-molecule/protein complex cocrystallization, it was shown that staurosporine binds tightly to the adenosine binding pocket ofthe catalytic subunit of the cAMP-dependent protein kinase. Chelerythrine (4) was identified as an inhibitor of Bcl-XL-Bak BH3 peptide binding vdth an IC50 of 1.5 p,M, and also displaced Bax from Bcl-XL [24]. Chelidonine (S) is another example of an alkaloid natural product that inhibits the taxol-mediated polymerization of tubulin in the micromolar range ( 24.0 p,M). 

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... 

---