Diphenyl phosphorazidate (DPPA), diethyl phosphorocyanidate (DEPC), and trimethylsilyldiazomethane (TMSCHN2) have been introduced as versatile reagents for organic synthesis. Total syntheses of several biologically active natural products containing various different carbon skeletons have been achieved by use of DPPA, DEPC, and reactions developed by our group. Cytotoxic and/or antineoplastic cyclic peptides 1-7 of marine origin have been prepared using DPPA and DEPC as peptide coupling reagents and their cytotoxic activities against L 1210 murine leukemia cells have been explored. Preferred conformation of ascidiacyclamide (4), a representative of cytotoxic cyclic peptides, has been determined by X-ray crystallography and it has been proven that ascidiacyclamide (4) has no ionophoric activity toward alkali metal ions. Synthesis of dolastatin 3 bearing the revised structure 2 has been described. Cytotoxic depsipeptides from a tunicate, didemnins A (11c), B (12c), and their relatives (11b and 12b), have been efficiently prepared by condensation of the key eastern (13) and western (14b and 14a) fragments. The absolute configuration of avellanin B (26b), a fungal cyclic peptide exhibiting a pressor effect, has been determined by its synthesis. Its analog, avellanin A (26a), has been also efficiently prepared. Synthesis of AI-77-B (27), which was isolated from Baccilus pumilus AI-77 and has an interesting antiulcer activity, has been stereoselectively achieved starting from the 6-methylsalicylic acid ester (30), the L-leucinal derivative (31), and D-pyroglutamic acid (36).
New anticancer agents and oncogene function inhibitors isolated from microorganisms in Institute of Microbial Chemistry are reviewed. Aclacinomycin found in 1975 is a less toxic and non-mutagenic anthracycline. It is now in clinical use mainly for acute nonlymphocytic leukaemia. Tetrahydropyranyl-adriamycin was synthesized in 1979 as a structural analogue of baumycin, and proved to be effective in inhibiting leukaemias and various solid tumours in patients. FAD-104 is a new semisynthetic anthracycline consisting of the 14-hemipimelate derivative of adriamycinone and 2, 6-dideoxy-2-fluoro-a-L-talopyranose. It shows apparently stronger antitumour activity than adriamycin against L 1210 mouse leukaemia. It is effective over a very broad range. Liblomycin is a derivative of bleomycin, which is clinically used mainly for squamous cell carcinoma but has pulmonary toxicity. Liblomycin shows much less pulmonary toxicity than bleomycin and potent antitumour activity in animals. Spergualin and 15-deoxyspergualin are new anticancer agents with unique structures. They showed potent antitumour activity against many experimental leukaemias and some solid tumours. Their mechanism of antitumour action may include induction of tumour cell immunity. More than 40 oncogenes have been identified. Many of them are considered to act through tyrosine kinase activity. Erbstatin was isolated as an inhibitor of tyrosine kinase associated with epidermal growth factor receptor. It also inhibits tyrosine kinase of src oncogene product. Herbimycin inhibits src oncogene functions. It changes the morphology of src-transformed cells into the normal morphology. Oxanosine inhibits ras oncogene functions. It changes the phenotypes of K-rasts-NRK cells completely into the normal phenotypes by decreasing the intracellular levels of guanine nucleotides. Various oncogenes induces activation of cellular phosphatidylinositol turnover. We have isolated psi-tectorigenin, an isoflavonoid, as an inhibitor of phosphatidylinositol turnover.
Reissert Henze reactions of phenanthroline N-oxides (1-2) with methanesulfonyl chloride gave the corresponding α-(5, 7) and, β-methylsulfonylphenanthroline (6, 8), respectively. In a similar manner, 8-methylsulfonylated 1-oxide (10) was obtained from 1, 7-phenanthroline 1, 7-dioxide (3), but the reaction of 4, 7-phenanthroline 4, 7-dioxide (4) resulted in the recovery of dioxide (4). The reactions of 1 4 with benzenesulfonyl chloride used instead of methanesulfonyl chloride did not give any reaction products, except tor the reaction of 2 giving 4, 7-phenanthroline-3-carbonitrile. Meisenheimer reactions of 1-3 with phosphorous oxychloride gave the corresponding α-(11, 14, 17), β-(12, 15, 18), and r-chlorophenanthrolines (13, 16, 19), respectively, while in a similar reaction, the a-chlorophenanthroline (20) as a sole product was obtained from 4 in a high yield. As for 11 18, 20, minimum inhibitory concentrations (MIC) were 12.5μg/ml for Pseudomonas aeruginosa.
The effects of three chelating agents, sodium N-benzyl-o-glucamine dithiocarbamate (NBG-DTC), 2, 3-dimercaptopropanol (BAL), and D-penicillamine (D-PEN), on the distribution and excretion of inorganic mercury were compared in rats exposed to HgCl2. Rats were injected i. p. with 203HgCl2 (300μg and 2μCi of 203Hg/kg) and after 24h they were treated with the chelating agents (a quarter of an LD50) every day for 7d. NBG-DTC and BAL promoted fecal and urinary excretions of mercury, while o-PEN promoted urinary excretion of mercury. NBG-DTC and BAL reduced the contents of mercury in the liver and kidney. BAL reduced the contents of mercury in the spleen, testes, heart, pancreas, and lung. D-PEN reduced only the content of mercury in the kidney. These chelating agents did not result in a redistribution of mercury to the brain, heart, and lung. The treatment with these chelating agents decreased the amounts of Zn, Fe, Cu, and Mn in the tissue as compared with control. The growth of rats was little retarded by treatment with these chelating agents. There was no damage to the liver and kidney by treatment with NBG-DTC. The results of this study reveal that the injection of NBG-DTC to rats pretreated with mercury can effectively remove mercury from the body as well as the injection of BAL.