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Phosphoinositide Metabolism
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
A number of exogenous inhibitors of protein kinase C have been described but many of them may be unspecific and their action mechanism is frequently unknown. Staurosporine, an alkaloid purified from Streptomyces actuosus, is a potent inhibitor of protein kinase C, but it may also inhibit protein kinase A and tyrosine kinases at similar concentrations. The 7-hydroxy derivative of staurosporine, UCN-10, is a more selective and potent inhibitor of protein kinase C activity. Calphostin C, isolated from the fungus Cladosporium cladosporioides, is potent and more selective for protein kinase C due to its interaction with the regulatory domain of the enzyme.211 The protein K252a, isolated from a microbe (Nocardipsis sp.), inhibits protein kinase C activity in vivo by competing with ATP.212 The application of protein kinase C inhibitors may contribute to the elucidation of the precise functions of the enzyme in normal and tumor cells. The discovery that sangivamycin, a purine nucleotide analog with antitumor activity, is an inhibitor of protein kinase C could open new possibilities for the design of antitumor compounds.213 However, protein kinase C inhibitors may have toxic effects on a number of metabolic processes. The study of mutant cell clones that lack functional protein kinase C molecules may give clues to make clearer the role of the enzyme in physiological processes occurring in different types of cells.214
Rna as a Target for Antimetabolites
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
A variety of purine and pyrimidine analogs have been examined with respect to their ability to affect rRNA production. These have included agents such as FUra, as well as a variety of other compounds such as azacytidine, sangivamycin, deazaguanine, 6-TG, preo-camycin, tubercidin, cordycepin, and xylosyladenine.10,11,22,23 A recent review of many of these agents and their effect on rRNA was reported by Cohen and Glazer, to which the reader is referred for additional discussion.11 Two characteristic results on rRNA are observed, one of which can be exemplified with the FUra precursor FUrd. S-180 cells were treated concurrently with [3H]cytidine and either 1 or 10 μM FUrd for 6 hr. The nuclear and cytoplasmic RNAs were isolated and then electrophoresed. This allows for the individual rRNA species to be resolved from each other and the level of production can be monitored by quantitating the level of [3H] incorporation. The results of such an experiment are shown in Figure 5. Quantitating the appearance of [3H]cytidine label in mature cytoplasmic RNA provided an easy way to assess the blocked production of rRNA. In cells treated with 10 μM FUrd, a complete loss of the mature 28 and 18S rRNA species was observed in the cytoplasm. In the somewhat less toxic concentration of 1 μM FUrd, the level of production of these RNAs was markedly reduced from control, but not to the extent observed with the more toxic 10 μM concentration. The nuclear RNA profile demonstrated just the opposite. With the 10 μM FUrd which completely suppressed the production of cytoplasmic 28 and 18S rRNA, a large increase in the levels of the higher molecular weight nuclear species was observed compared to control or the less toxic 1 μM FUrd. This result is characteristic of many reported previously for FUra, where a complete block of the mature rRNA was observed, but an increase in the nuclear species resulted as well.
Synthesis of novel pyrroles and fused pyrroles as antifungal and antibacterial agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Rania Helmy Abd El-Hameed, Amira Ibrahim Sayed, Shima Mahmoud Ali, Mohamed A. Mosa, Zainab M. Khoder, Samar Said Fatahala
Pyrroles and its fused derivatives, are an important class of naturally22,23 and synthetically24–26 occurring compounds with a wide-range of biological activities; antibacterial27–29, antifungal30–33, antiviral34–39, anticancer40,41 and anti-inflammatory42,43. Pyrrolnitin and fludioxonil, are two naturally secreted pyrroles, reported to bear a broad spectrum antifungal activities44–46. 7-deazapurine, naturally secreted pyrrolopyrimidines antibiotics, toyocamycin, tubercidin and sangivamycin, commonly have antibacterial, antifungal, anticancer, antiviral and anti-inflammatory activities22,47. Due to structural resemblance to purine, 7-deazapurines interfered with various cellular processes; toyocamycin united with tRNA, pyrrolopyrimidine inhibits tRNA aminoacylation. Sangivamycin has lately been revealed to inhibit protein kinases22, as revealed in Figure 2.