81 Structures of pamamycin homologues, aerial mycelium-inducing substances from Streptomyces alboniger, and the differentiation mechanism of aerial mycelium
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Pamamycin-607 (1)(MW 607), which has been isolated from Streptomyces alboniger, induces aerial mycelium-differentiation from substrate mycelium in an aerial mycelium-less mutant of the same strain. Our previous study showed the presence of 6 pamamycin homologues ranging in MW from 593 to 663, and found that the homologues with smaller MW were higher than the larger ones in the aerial mycelium-inducing activity. We describe here the structure elucidation of four new homologues, pamamycin-635A(2), 635B(3), 649A(4) and 649B(5), preparation of desdimethylaminopamamycin-607, and the structure-activity relationship of pamamycins. The structures of pamamycins were elucidated from diol fragments obtained by their LiAlH_4 reduction, the structures of which were analyzed by GC-MS method being compared with those of the known diols, S and L, obtained from pamamycin-607 in a similar manner. Relative stereochernistries of pamamycins were determined by NOE difference spectroscopy, chemical shifts and J_<HH> values of their CF_3COOD salts. The absolute stereochemistry of pamamycin-607 was determined by derivatizing it to a furfuryl derivative(11), which coincided in the optical rotation with that of an authentic compound derived from nonactin antibiotic. The absolute stereochemistry of pamamycin-635A was elucidated by using the smaller LiAlH_4 reduction product, S_1. The secondary alcohol group at 8' of S_1 was converted to (S)- and (R)-MTPA esters, to which the advanced Mosher's method was applied, and the absolute stereochemistry at 8' of S_1, hence, that of pamamycin-635A was determined as S and 2, respectively. Pamamycin-635B showed aerial mycelium-inducing activity at 10μg/disc, which was ca. 1/3 that of pamamycin-607. In contrast, pamamycin-635A and the mixture of pamamycin-649A and 649B were not active. Characteristic structural feature to distinguish the active homologues from the inactive ones is that the active homologues have CH_3-group at C-9(R_2), whereas the inactive ones have C_2H_5. Desdimethylpamamycin-607 prepared by Hoffman degradation lost aerial mycelium-inducing activity. Thus, the dimethylamino-group in the side chain is necessary for the activity.
