A Novel Antimycin-like Compound, JBIR-06, from Streptomyces sp. ML55

Abstract

A novel compound of antimycin family, JBIR-06 (1), was isolated from Streptomyces sp. ML55. The structure of 1 was established as a twelve-membered macrocyclic skeleton with a 3-(formylamino)-2-hydroxybenzamide based on the spectroscopic data. Compound 1 inhibited the expression of GRP78 induced by 2-deoxyglucose at the IC 50 value of 250 nM.Keywords antimycin, JBIR-06, molecular chaperone, GRP78, Streptomyces sp. GRP78, which is well-known as a molecular chaperone in the endoplasmic reticulum (ER), also plays an important role as a survival factor in solid tumors, due to its acquisition of a resistant mechanism against both chemotherapy and hypoglycemic stress [1]. Thus, specific down-regulators of GRP78 transcription can reasonably be expected to become promising drugs in cancer chemotherapy [2]. In the course of our screening program for down-regulators of GRP78/Bip molecular chaperone expression, we isolated versipelostatin [3], prunustatin A [4, 5], JBIR-04, -05 [6] and SW-163A [6]. Further screening resulted in the isolation of a novel inhibitor of GRP78 expression, designated as JBIR-06 (1, Fig. 1), a new member of antimycin [7] family from mycelium of Streptomyces sp. ML55 [8]. In this paper, we report the isolation, structure elucidation, and brief biological activities of 1.The Streptomyces sp. ML55 was cultured at 27°C for 5 days in 500-ml Erlenmeyer flasks containing a medium consisting of 2.0% glycerin (Nacalai Tesque), 1.0% molasses (Dai-Nippon Meiji Sugar), 0.5% casein (KANTO CHEMICAL), 0.1% polypepton (NIHON PHARMACEUTICAL), 0.4% CaCO 3 (KOZAKAI PHARMACEUTICAL) (pH 7.2 before sterilization). The mycelium from the culture broth (2.0 liters) was extracted with Me 2 CO (400 ml). After concentrated in vacuo, the residue was extracted with EtOAc for two times. The organic layer was dried over Na 2 SO 4 , and concentrated in vacuo. The dried residue was applied to normal-phase MPLC (Purif-Pack SI-60, Moritex) and developed with a

The regulation and biosynthesis of antimycins

“…JBIR-06 and neoantimycin inhibit GRB78 chaperone involved in the unfolded protein response [45–46]. Although the DNA sequence for the gene clusters for these ring-expanded antimycins has not yet been made publically available, they all encode the machinery necessary to assemble the 9-membered antimycin core suggesting a common evolutionary past [44].…”

Paradigm Shifts in Fungal Secondary Metabolite Research: Unusual Fatty Acids Incorporated into Fungal Peptides

“…ML55; and it inhibited the expression of GRP78 induced by 2-deoxyglucose at the IC 50 value of 250 nM (Ueda et al, 2008). JBIR-52, same compound, but with a different fatty acid, was produced by Streptomyces sp.…”

JBIR-52, a new antimycin-like compound, from Streptomyces sp. ML55

“…Thus, a 2,6-dimethyl-3-oxo-4-oxyheptanoic acid moiety was elucidated as a partial structure of 1 (Figure 1b Figure 1b) and the UV spectrum of 1 also suggested the existence of the 3-(formylamino)-2-hydroxybenzoyl moiety, which is the same chromophore as those of the antimycin-related compounds. [12][13][14][15] The sequence from an amide proton 6-NH (d H 7.10) to a methyl proton 26-H (d H 1.38) through an a-methine proton 6-H (d H 5.29) and an oxymethine proton 7-H (d H 5.60) was observed in the DQF-COSY spectrum of 1. In addition to these correlations, the long-range couplings from the methine proton 6-H to a carbonyl carbon C-5 (d C 168.8) and the amide carbonyl carbon C-18 were observed.…”

“…2 In the course of our screening program for downregulators of GRP78 expression, we have isolated versipelostatin A-F, 3-11 prunustatin A, 12,13 JBIR-04, -05 14 and JBIR-06. 15 Further screening resulted in the isolation of a new inhibitor designated as JBIR-52 (1, Figure 1) from culture of a JBIR-06 producer, Streptomyces sp. ML55.…”

“…ML55. 15,16 In this paper, we report the isolation, structure elucidation and brief biological activity of a new member of antimycin, 1.…”