A reinvestigation of sponge natural products from additional Indo-Pacific collections of Xestospongiacf. carbonaria and X. cf. exigua has provided further insights on the structures, biological activities, and biosynthetic origin of bisannulated acridines. These alkaloids include one known pyridoacridine, neoamphimedine (2), and three new analogues, 5-methoxyneoamphimedine (4), neoamphimedine Y (5), and neoamphimedine Z (6). A completely new acridine, alpkinidine (7), was also isolated. A disk diffusion soft agar assay, using a panel of five cancer cell lines (solid tumors and leukemias) and two normal cells, was used to evaluate the differential cytotoxicity (solid tumor selectivity) of the sponge semipure extracts and selected compounds including amphimedine (1), 2, 4, and 7. While all four compounds were solid tumor selective, 1 and 2 were the most potent and 4 was the most selective. The rationale used to characterize the new structures is outlined along with the related biosynthetic pathways envisioned to generate 2 and 7.
We have utilized a broad approach to address whether tyrosine kinases and the growth pathways they regulate might be functionally aberrant in squamous cell carcinomas (SCC) of the upper aerodigestive tract. This strategy involved assaying for evidence of tyrosine kinase action in lysates of cell lines representing SCC. Our findings revealed a spectrum of elevated tyrosine phosphorylation in SCC lines ranging from less than 2-fold to more than 10-fold above that of control human epidermal keratinocytes. Thus the ability to regulate growth and other pathways controlled by tyrosine phosphorylation was impaired in all the 19 lines examined. Assessment of the receptor for epidermal growth factor (EGF) revealed that its activity was elevated above normal in 14 of the 19 cell lines examined, suggesting that at least a portion of the increased tyrosine phosphorylation observed could be attributed to excessive EGF receptor activity. Our findings provide functional evidence that growth pathways are aberrantly regulated in cell lines representing SCC of the upper aerodigestive tract.
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