Hibarimicin D

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.

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.

[structure: see text] A synthesis of arylnaphthoquinone 22 corresponding to the CD-D' unit of angelmicin B via the Suzuki coupling of the D' arylboronic acid 15 with the CD bromonaphthoquinone 21 is described. The mild conditions for the Suzuki cross-coupling leading to 22 may prove to be useful for the eventual late-stage coupling of the two highly functionalized halves of angelmicin B.