Hibarimicin G

Strain TP-AO121 which produces a complex of novel tyrosine kinase inhibitors designated hibarimicins A, B, C, D and G was considered to be a new subspecies of Microbispora rosea, and the name, Microbispora rosea subsp. hibaria, was proposed. Hibarimicins A, B, C and D specifically inhibited the src tyrosine kinase activity without affecting protein kinase A or protein kinase C. They also showed in vitro anti-Gram-positive bacterial and antitumor activities. The molecular formulae of hibarimicins A, B, C, D and G were assigned to be C85H112O37, C85H112O37, C83H110O36, C85H112O38, and C85H112O39 respectively.

We studied the effects of hibarimicins and hibarimicin-related compounds produced by Microbispora rosea subsp. hibaria [glycosides (hibarimicins A, B, C, D, E, G, H and I) and aglycon (hibarimicinone)] or compounds produced by its mutants [glycosides (HMP-P4 and -Y6), aglycons (HMP-P1 and -Y1) and shunt products (HMP-M1, M2, M3 and -M4)] on v-Src tyrosine kinase and growth and differentiation of human myeloid leukemia HL-60 cells. Among them, hibarimicin B was a strong and the most selective v-Src kinase inhibitor with differentiation inducing activity of HL-60 cells. Hibarimicin E similarly induced HL-60 cell differentiation but had no v-Src kinase inhibitory activity. Hibarimicinone was the most potent v-Src kinase inhibitor, although less selective, and did not induce differentiation of HL-60 cells. Hibarimicin B competitively inhibited ATP binding to the v-Src kinase, but hibarimicinone showed noncompetitive inhibition. These two compounds, however, showed similar mixed types of inhibition against a Src substrate binding to the v-Src kinase. Altogether, these results suggest that signaling molecules other than Src might be more important in the differentiation induction of HL-60 cells.

The structure of hibarimicins A, B, C, D and G which are inhibitors for tyrosine specific protein kinase are determined using spectroscopic techniques. Hibarimicins described in this report consist of a common aglycon and six deoxyhexoses. The aglycon contains a highly oxidized naphtylnaphthoquinone as a chromophore. Among them, hibarimicin B was identical with angelmicin B.