[structure: see text] Versipelostatin is the first compound which specifically inhibits the expression of GRP78 and the resultant robust cell death under stress conditions, in contrast to the weak cytotoxicity under normal conditions. Versipelostatin consists of a macrocyclic aglycone with an alpha-acyltetronic acid and three sugar moieties. The relative and absolute configuration of the aglycone moiety was established to be 4S, 5S, 6R, 9S, 10S, 13S, 16R, 18R, 19R, 20R, 24R, 27R, and 29S utilizing NMR techniques.

In the course of our screening program for regulators of a molecular chaperone GRP78 expression, we isolated a novel inhibitor of GRP78 expression, designated as prunustatin A, from Streptomyces violaceoniger 4521-SVS3. The structure of prunustatin A was determined by a series of NMR analyses to be an oxidized type of the neoantimycin family. Prunustatin A inhibited the expression of GRP78 induced by 2-deoxyglucose in human fibrosarcoma HT1080 cells accompanied by global cell death without showing cytotoxicity under normal nutrient condition.Keywords molecular chaperone, GRP78, glucose deprivation, prunustatin GRP78 acts as a molecular chaperone in the endoplasmic reticulum (ER) to promote protein folding. The enhancement of ER stress response has been proven to play a role in mechanisms of resistance to chemotherapy and hypoglycemic stress in solid tumor [1], while the reduction of ER stress response is involved in the pathology of central nervous diseases such as Alzheimer's and Parkinson's diseases [2]. The ER stress response causes an increase in gene expression of a number of ER chaperones such as GRP78/Bip and GRP94 [3]. Thus, substances that directly, either down-or up-regulate grp78 transcription are expected to be promising drugs for the treatment of cancer and Alzheimer's disease, respectively. In the course of our screening program for regulators of GRP78/Bip molecular chaperone expression, we isolated versipelostatin [4] by employing a reporter gene assay system under the control of the GRP78 promoter. Further screening resulted in the isolation of a novel inhibitor of GRP78 expression, designated as prunustatin A (1, Figure 1), a new member of neoantimycin [5] family from an actinomycete identified as Streptomyces violaceoniger 4521-SVS3. In this paper, we report the fermentation of the producing organism and the isolation, physicochemical properties, structure elucidation and brief biological activities of prunustatin A.The prunustatin producing strain was isolated from a soil sample collected on Kumejima island in Okinawa

In the course of our screening program for regulators of the expression of GRP78 molecular chaperone, JBIR-04 (1) and -05 (2) were isolated from Streptomyces violaceoniger 4541-SVS3 as congeners of prunustatin A (3). The structures of 1 and 2 were determined by the analyses of the spectroscopic data. These compounds mainly consist of an amino acid and amino acid derived a -hydroxy acid residues. 1 and 2 inhibited the expression of GRP78 induced by 2-deoxyglucose in human fibrosarcoma HT1080 cells, but their activities were highly reduced compared with those of 3 and SW-163A.