Teleocidine

This method has been successfully applied to the substituted indole 2.6B, an analogue of the teleocidin type of protein kinase activators[ll]. 

Teleocidin isolated from Streptomyces mediocidicus is a mixture of two isomers of teleocidin A and four isomers of teleocidin B (Figure 1 and Table I) (11,12). (-)-Indolactam-V is a biosynthetic intermediate of teleocidins A and B (7J). Des-O-methylolivoretin C is a regioisomer of teleocidin B-1 (Table I) (14). 

A series of remarkable stoichiometric CH functionalization reactions have been employed, including transmetalla-tion with a vinylboronic acid moiety, to synthesize the core of teleocidin B-4 (Equation (200)).1... 

The teleocidin B4 core 15 is synthesized from the Shiff base of 2-/< //-butyl-5-methoxyaniline, as shown in Scheme 16.161 The key sequence of this synthesis consists of two G-H bond functionalizations, alkenylation and oxidative carbonylation of two methyl groups, via palladacycle formations. 

Teleocidines are known as tumor-promoting compounds characterized by an indolactam V core structure. Such indolactams adopt two stable conformations at room temperature. With the intention to investigate the biologically active conformer, Irie and Wender synthesized conformationally restricted analogs of indolactam V 50 (R=Me) [17]. Starting from desmethylindolactam... 

X-ray structural data are available for TPA (35) and dihydro-teleocidin B (36-37), but only the absolute stereochemistry of TPA is known. As mentioned above the structure of aplysiatoxin has been solved by X-ray crystallography and its absolute stereochemistry has been determined from other data (10). These three tumor promoters, which represent three distinct classes of natural products, appear to have common structural features that enable it to bind to the same membrane receptors. 

The teleocidins from terrestrial actinomycetales and the lyngbyatoxins from marine cyanobacteria (Chart 8.3.P) are peptide alkaloids well known for their tumor promoting ability. 

As morusin (3) was assumed to interact with the phorbol ester receptor, we examined whether it inhibited the activation of protein kinase C by teleocidin in vitro [73]. Fig. (9) shows that morusin (3) inhibited the phosphorylation of histone type III-S by protein kinase C dose-dependent and that 80 pmol/L morusin caused 50% inhibition. 

Fig. (9). Inhibition by morusin (3) of activation of protein kinase C by teleocidin in vitro.

The assay mixture (0.25 mL) contained 20 pmol/L CaClj, 7.5 pg of phosphatidylserine, 2.3 pmol/L teleocidin, and various concentrations of morusin (3) with 0.05 units of partially purified enzyme. Enzyme activity was measured as the incorporation of 32P from [y-32P]ATP into histone type lll-S during incubation for 3 min. at 30 C. 

Furthermore, we examined the inhibition of the induction of ODC induction by teleocidin in mouse skin. Application of 11.4 nmol morusin (3) caused 43% inhibition of the induction of ODC by 11.4 nmol teleocidin [73]. From the results of these three tests, morusin (3) might inhibit the tumor-promoting activity of teleocidin on mouse skin. 

Figs. (10) and (11). Inhibition by monism (3) of tumor promotion by teleocidin in a two-stage carcinogenesis experiment on mouse skin. Inhibition was achieved by a single application of 100 pg of DMBA, and teleocidin (2.5 pg) and morusin (1 mg) were applied twice a week throughout the experiments. 

While the other biochemical tests and the inhibition of tumor promotion of teleocidin in a two-stage carcinogenesis experiment have not been carried out, due to limitation in their amounts available, some of isoprenylated flavonoids from the moraceous plants showed the similar inhibitory potencies to those of morusin (3) and the related compounds, Figs. (6) and (12), as shown in Table 3. 

As described in Chapter III, morusin (3) has been found to be anti-tumor promoter in a two-stage carcinogenesis experiment with teleocidin. Considering the similarity of the structures between morusin (3) and artonin E (7), artonin E (7) was expected to be an anti-tumor promoter. Furthermore we found a novel photo-oxidative cyclization of artonin E (7) as follow photo-reaction of artonin E (7) in CHCI3 containing 4% ethanol solution with high-pressure mercury lamp produced artobiloxanthone (8) and cycloartobiloxanthone (9), and the treatment of artonin E (7) with radical reagent (2,2-diphenyl-1-picrylhydrazyl DPPH) resulted in the same products, Fig. (15), [84]. 

Methylation at C-4 of sterol nucleus was one of the other factors affecting activity enhancement. Thus, in general, 4-methylsterols (14,15) and 4,4-dimethylsterols (8,13) exhibited higher activity than 4-desmethylsterols. A similar structure-activity relationship was observed also in the HHPA-induced inflammation on mouse ear [35]. Whereas cholesterol (7) did not show inhibitory activity, several 4,4-dimethylcholestane derivatives, 0-12, exhibited activity. 4,4-Dimethylcholestane-3a,5a-diol (12) was the most potent inhibitor its activity was comparable to that of ursolic acid (210) [35]. Compound 12 reduced also the inflammation induced by teleocidin B (3), one of the indole alkaloid-type of tumor promoters [53]. 

Glycyrrhetic acid (147) and retinoic acid are known in vivo antitumor-promoters which inhibit EBV-EA induction by tumor promoters [77]. Oleanolic acid (142) and ursolic acid (210) significantly inhibit the activation induced by TPA and teleocidin B (3) as do 147 and retinoic acid... 

---