9 糸状菌が生産する新規細胞周期阻害剤スピロトリプロスタチンA、BおよびトリプロスタチンA、Bとその類縁ジケトピペラジン類新化合物の単離、構造解析および生物活性に関する研究(口頭発表の部)

抄録

As products of oncogenes and tumor suppressor genes are involved in the regulation of mam-malian cell cycle and also as cancers in fact are the uncontrolled cell proliferation with deregulation of cell cycle, new cell cycle inhibitors might be good candidates for cancer chemotherapy and also be a source for providing molecular probes useful in elucidating regulatory mechanism of the cell cycle. We have therefore begun on the screening for new cell cycle inhibitors from microbial origin. During the screening, we have isolated novel diketopiperazine alkaloids, spirotryprostatins A (1), B (2), tryprostatins A (3), B (4) and cyclotryprostatins B (6), D (8), together with three new natural diketopiperazines, cyclotryprostatins A (5), C (7) and demethoxyfumitremorgin C (9), as well as several known diketopiperazines such as fumitremorgin C (10) from the fermentation broth of a fungus, Aspergillus fumigatus BM939, through a separation procedure guided by inhibitory activity on the cell cycle progression of mouse tsFT210 cells. Structures of the new natural diketopiperazines obtained were determined mainly by the use of spectroscopic methods especially by detailed analyses of their ^1H and ^<13>C NMR spectra with the aid of 2D NMR spectroscopy including PFG-HMQC and PFG-HMBC techniques. The molecules of 1 and 2 had an unique structural skeleton with a spiro ring system composed from a γ-lactam fused to a benzene ring and a five-membered hetero ring fused to a diketopiperazine moiety, which are composed from a tryptophan unit, a proline residue and an isoprenyl group. The tryptophan units have been modified by dihydrogenation at C_2/C_3 and further oxidation at C_2 positions in both 1 and 2 and modified further by dehydrogenation at C_8/C_9 positions to form an enamine ring in 2. The isolation of 1 and 2 provided the first example of a novel class of natural diketopiperazines with an unique spiro ring skeleton. The molecules of 3 and 4 are composed from a 2-isoprenyl-L-tryptophan moiety and a L-proline residue, forming a diketopiperazine unit, which are distinguished from the molecules of fumitremorgin series by the opening of the central heterocyclic ring at the C-N bond between the 18 and 10 positions. Compounds 3 and 4 provided the first example of novel diketopiperazines as a new inhibitor of the mammalian cell cycle. Compounds 1-10 inhibited the cell cycle progression of tsFT210 cells in the dose range of micromolar order and certain structure-activity relationships were also observed. The present work provided diketopiperazines 1-10 as a new group of G2/M phase inhibitors of the mammalian cell cycle. In this symposium, we will mainly represent the production, isolation, structure determination and biological activities of the new natural diketopiperazines.