Phorbol derivatives

The phorbol derivative (131) has been isolated from Croton rhamnifolius A group of tumour-promoting esters, based on 12-desoxyphorbol, have been... 

Bergquist, K. E., Obianwu, H., and Wickberg, B. (1989). Isolation and structure determination of a novel phorbol derivative in an intramolecular diester macrolide. J. Chem. Soc. Chem. Commun. 183-184. 

In contrast to the TPA-type tumor promoters, palytoxin, thapsigargin, and okadaic acid are classified as non-TPA type tumor promoters, which do not bind to phorbol ester receptors, or activate protein kinase C in vitro (Table II) (6,25-27). In this chapter, thapsigargin is not discussed, because it is derived from terrestrial plants. 

Abundance of Na /H exchanger transcripts in vascular smooth muscle and HL60 cells is increased by serum, phorbol esters, fibroblast growth factor and platelet-derived growth factor [78,79]. The increase in NHE-1 mRNA levels in PMA-treated HL60 cells is due to increased gene transcription. 

Although benz(a)anthracene (BA) is generally considered noncarcino-genic (27), it is a weak tumor initiator when administered with a phorbol ester promoter (28). More importantly, BA is a convenient model for the highly potent carcinogenic PAH 7,12-dimethylbenz(a)-anthracene and 3-methylcholanthrene (27), both of which are BA derivatives but which offer more serious synthetic problems. 

The phorbol esters are useful for studying the function of PKC since they mimic the stimulatory effects of DAG on the enzyme. These tumor-promoting plant products and their synthetic derivatives are able to penetrate intact cells. Many inferences regarding the intracellular actions of PKC are based on results of studies on whole-cell preparations with the phorbol esters. These substances, like DAG, may produce feedback inhibition of signal transduction at a number of metabolic levels. Results of experiments using phorbol esters in whole cells are thus often complex and must be interpreted cautiously. Notwithstanding this consideration, based upon... 

NK cells express receptors for numerous monokines constitutively, and produce IFN-y and other NK-derived cytokines rapidly in response to stimulation by monokines [18, 19]. Freshly isolated CD56 "s human NK cells are the primary source of NK cell-derived immuno-regulatory cytokines, including IFN-y, TNF-(3 (lymphotoxin), IL-10, IL-13 and GM-CSF, whereas the CDSb NK-cell subset produces consistently negligible amounts of these cytokines following stimulation with recombinant monokines in vitro [20]. The production of cytokines by NK cell subsets was investigated following activation with phorbol esters (e.g. phorbol 12-myristate 13-acetate (PMA)) and ionomycin. 

A fully aromatic pyrazole derivative, FPL 62064 (107), also inhibited 5-LO in the usual cellular and enzymatic systems, but was not seleetive with respect to CO [276]. This compound inhibited AAE (ED50 values against PGE2, LTC4, and oedema were 3.7,28.3, and 40.8 //g/ear, respeetively), guinea-pig UV-induced erythema and phorbol ester ear oedema. The aetivi-ty for FPL 62064 was also attributed to its antioxidant activity presumably in this case the 4-methoxyaniline group is the redox-active moiety. 

Armed with this new tool, Schena et al. (1996) created a microarray of 1,046 human cDNAs of unknown sequence. They were derived from human peripheral blood lymphocyfes fransformed wifh Epsfein-Barr virus. Suitably sized inserts [>600 base pairs (bp)] were cloned into a lambda vector, subsequently infected into an Escherichia coli strain, and finally amplified by polymerase chain reaction (PCR) using 5 -amino-modified primers. The resulting 5 -amino-modified cDNA amplicons were then arrayed onto sily-lated microscope slides. Next, the expression levels in human Jurkat cells undergoing heat shock or phorbol ester induction were examined. 

Long-chain ester derivatives of phorbol, a tetracyclic diterpene from the seed oil of Croton tiglium L., including its most abundant representative, 12-0-tetradecanoylphorbol-13-acetate (65), are potent activators of protein kinase G (PKG) and are used as standard tumor promoters for the study of experimental carcinogenesis in animal models." ... 

Shibasaki and co-workers used an intramolecular nitrile oxide cycloaddition to prepare the skeleton of phorbol (272) (Scheme 6.99), a tumor promoter that activates protein kinase C (PKC) (333). Nitroalkene 268 was elaborated in several steps from (+)-3-carene (267) and was subjected to cycloaddition by means of -chlorophenyl isocyanate-triethylamine to give cycloadduct 269 in 88% yield. Reductive hydrolysis employing Raney Ni and boric acid afforded hydroxyketone 270, that was subsequently used for the construction of the optically active derivative 271, which contains the phorbol skeleton (333). 

TUmor promotion has been demonstrated in a number of experimental models, but the mechanism of promotion has been studied most extensively in mouse skin, rat liver, and cell culture. In skin, the most potent promoters are fatty add esters of phorbol, a plant-derived ditei>... 

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