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

Abstract

GRP78/Bip is a molecular chaperone in the endoplasmic reticulum (ER) induced by ER stress that promotes protein folding and has an important role as a survival factor in solid tumors by providing resistance to both chemotherapy and hypoglycemic stress. 1 Thus, specific downregulators of GRP78 expression can reasonably be expected to become promising drugs in cancer chemotherapy. 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. 15,16 In this paper, we report the isolation, structure elucidation and brief biological activity of a new member of antimycin, 1.Streptomyces sp. ML55 was cultured on a rotary shaker (220 r.p.m.) at 27 1C for 5 days in 500-ml Erlenmeyer flasks containing 100 ml of a production medium consisting of 2% glycerol (Nacalai Tesque, Kyoto, Japan), 1% molasses (Dai-Nippon Meiji Sugar, Tokyo, Japan), 0.5% casein (Kanto Chemical, Tokyo, Japan), 0.1% polypepton (Nihon Pharmaceutical, Tokyo, Japan), 0.4% CaCO 3 (Kozaki Pharmaceutical, Tokyo, Japan) (pH 7.2 before sterilization). The mycelium from the culture broth (2 l) was extracted with Me 2 CO (400 ml). After concentration in vacuo, the residue was extracted twice with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The dried residue (1.99 g) was applied to normal-phase MPLC (Purif-Pack SI-60, size:60, Moritex, Tokyo, Japan) and developed with a n-hexane-EtOAc linear gradient system (0-100% EtOAc), and peak detection was carried out by UV absorption at 254 nm. The 60-75% EtOAc eluate (470 mg) was further chromatographed on normal-phase MPLC (Purif-Pack SI-60, size:20, Moritex) with n-hexane-EtOAc (80:20). A portion (44.5 mg) of the fraction (388 mg) including both 1 and JBIR-06 was finally purified by preparative reversed-phase HPLC using an L-column2 ODS (20 i.d.Â150 mm, Chemical Evaluation

Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

“…Examples are arctigenin [167], deoxyverrucosidin [168], efrapeptin J [169], analogs of JBIR [170], piericidin A [171], prunustatin A [172], pyrvinium [173], rottlerin [174], valinomycin [175], and versipelostatin [176]. Collectively, these compounds are considered GRP78 downregulators, because they were shown to block the adaptive induction of GRP78 transcription in response to hypoglycemia.…”

Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

“…13,55,58,59 The KS domain then catalyzes the decarboxylative condensation between the aminoacyl-S-T2 domain of AntC and the 2-carboxy-acyl-S-ACP domain of AntD, and following stereoselective reduction of the b-keto functionality by AntM, a 3-oxoacyl-ACP reductase, AntD-TE catalyzes the regiospecic macrolactone cyclization and release of the nine-membered dilactone product. 13,55,61 The structurebased engineering of AntE also further expanded its substrate scope and resulted in the production of antimycins with R 1 groups containing sec-butyl (41), phenyl (39), thienyl (75), and toluene (76) (Fig. 13,60 Evidence for this pathway has been provided by gene disruption experiments, heterologous expression of the gene cluster, and biochemical analysis.…”

“…Recently, antimycintype depsipeptides with 12-and 15-membered macrocyclic rings were characterized as down-regulators of 39,45,47 As a molecular chaperone in the endoplasmic reticulum (ER), GRP-78 promotes protein folding and provides resistance to both chemotherapy and hypoglycemic stress; consequently, the inhibition of its expression may be useful for the development of anti-cancer therapies. Recently, antimycintype depsipeptides with 12-and 15-membered macrocyclic rings were characterized as down-regulators of 39,45,47 As a molecular chaperone in the endoplasmic reticulum (ER), GRP-78 promotes protein folding and provides resistance to both chemotherapy and hypoglycemic stress; consequently, the inhibition of its expression may be useful for the development of anti-cancer therapies.…”

Repositioning of Verrucosidin, a Purported Inhibitor of Chaperone Protein GRP78, as an Inhibitor of Mitochondrial Electron Transport Chain Complex I

“…Other members of this group are arctigenin [15], biguanides (metformin, phenformin, buformin) [16], deoxyverrucosidin [17], efrapeptin J [18], analogs of JBIR [19], piericidin A [20], prunustatin A [21], pyrvinium [22], rottlerin [23], valinomycin [24], and versipelostatin [25]. Because GRP78 plays an important role in tumorigenesis, such inhibitors might harbor cancer therapeutic potential.…”