Enzymatic Synthesis of Dehydro Cyclo(His-Phe)s, Analogs of the Potent Cell Cycle Inhibitor, Dehydrophenylahistin, and Their Inhibitory Activities toward Cell Division

• Published in: Bioscience, biotechnology, and biochemistry biotechnology, and biochemistry, 2004-11, Vol.68 (11), p.2341-2345
• Main Authors: KANZAKI, Hiroshi, YANAGISAWA, Satohiro, NITODA, Teruhiko
• Format: Article
• Language: English
• Subjects: albonoursin; Animals; Biological and medical sciences; Cell Division - drug effects; Cell Survival - drug effects; dehydro cyclic dipeptide; diketopiperazine; enzymatic conversion; Fundamental and applied biological sciences. Psychology; Indicators and Reagents; inhibitor for cell division; Magnetic Resonance Spectroscopy; Molecular Weight; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Piperazines - chemical synthesis; Sea Urchins; Spectrometry, Mass, Electrospray Ionization; Streptomyces - drug effects; Streptomyces - metabolism; Streptomyces albulus; Structure-Activity Relationship
• ISSN: 0916-8451; 1347-6947
• DOI: 10.1271/bbb.68.2341

Cyclo(His-Phe) was effectively converted to its dehydro derivatives by the enzyme of Streptomyces albulus KO-23, an albonoursin-producing actinomycete. Two types of dehydro derivatives were isolated from the reaction mixture and identified as cyclo(ΔHis-ΔPhe) and cyclo(His-ΔPhe). This is the first report on cyclo(His-ΔPhe) and the enzymatic preparation of both compounds. Cyclo(ΔHis-ΔPhe), a tetradehydro cyclic dipeptide, exhibited a minimum inhibitory concentration of 0.78 μmol/ml inhibitory activity toward the first cleavage of sea urchin embryos, in contrast to cyclo(His-ΔPhe) that had no activity. The finding that the isoprenylated derivative of cyclo(ΔHis-ΔPhe), dehydrophyenylahistin, had 2,000 times higher activity than cyclo(ΔHis-ΔPhe) indicates that an isoprenyl group attached to an imidazole ring of the compound was essential for the inhibitory activity.