Enzymatic synthesis of dehydro cyclo(His-Phe)s, analogs of the potent cell cycle inhibitor, dehydrophenylahistin, and their inhibitory activities toward cell division

Abstract

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-APhe) indicates that an isoprenyl group attached to an imidazole ring of the compound was essential for the inhibitory activity.