Isolation, synthesis, and biological activities of signal transduction inhibitors

Oncogene product functions are mainly disturbance of cellular signal transduction and modification of specific gene expression. Several oncogenes are known to be related to human neoplastic diseases. If these onocogenes play important roles in the progression of cancer, it should be possible to develop new antitumor drugs inhibiting oncogene product activities. We have isolated various signal transduction inhibitors such as tyrosine kinase inhibitors, Ras function inhibitors, and phosphatidylinositol turnover inhibitors from microorganisms and plants. In the present review, we describe isolation, synthesis and biological activities of tyrosine phosphatase and Ras function inhibitors which were recently isolated. Intracellular tyrosine phosphorylation should be regulated by both tyrosine kinases and tyrosine phosphatases. Therefore, we screened microbial culture filtrates for tyrosine phosphatase inhibitors and isolated a novel nitrosamine dephostatin from Streptomyces. We also established a practical synthetic route for dephostatin. Since dephostatin is not stable enough, we synthesized several structurally related dephostatin analogs. Among them a regioisomer of dephostatin showed tyrosine phosphatase inhibitory activity equivalent to that of dephostatin, and also had increased stability. We isolated conophylline and the novel aglaiastatin from tropical plant extracts as Ras function inhibitors. Conophyline and aglaiastatin induced normal phenotypes in K-ras-expressing cells. Since farnesl protein transferase (FPTase) is necessary for the Ras activity, we also screened microbial culture filtrates for FPTase inhibitors. As a result, we isolated 4 novel compounds, valinoctin A and B, and saquayamaycin E and F. The absolute configuration of valinoctin A was determined by a synthetic method together with crystallographic analysis.