NBRI17671, a new antitumor compound, produced by Acremonium sp. CR17671

Abstract

The interaction between the receptor for advanced glycation end-product (RAGE) and amphoterin has an important role in tumor growth and metastasis. Because the abrogation of the interaction results in the inhibition of the tumor growth and metastasis, we designed a screening system for an inhibitor of the interaction between RAGE and amphoterin. In the course of our screening of the inhibitor, we isolated a novel natural compound NBRI17671 (1) from the fermentation broth of Acremonium sp. CR17671. We also modified 1 into a more active NBRI17671al (2). Although 1 at 50 lg ml -1 weakly inhibited binding of various cells to amphoterin, 2 at 50 lg ml -1 inhibited it by >50% of control. Compound 2 effectively inhibited the tumor growth of glioma and lung tumor xenografts in mice at 25 mg kg -1 . Furthermore, 2 was found to downregulate mitogen-activated protein kinase (MAPK) activity in the tumor cells. Keywords: amphoterin; antitumor drug; natural compound; RAGE; tumor growth INTRODUCTIONThe receptor for advanced glycation end-products (RAGE) 1 is a multiligand cell surface receptor and has a critical role in various diseases such as diabetes, 2 Alzheimer's disease 3 and tumor. 4 It is reported that soluble RAGE suppresses accelerated diabetic atherosclerosis by interfering the association between advanced glycation end-products and RAGE in the cells of blood vessels. 5 Because the abrogation of the association between RAGE and a respective ligand is an attractive therapeutic target, we have especially focused on tumor therapy. Amphoterin, also known as HMGB1, is one of the ligands of RAGE,6 and is expressed at high levels in various kinds of cancers. 7 RAGE expression is not restricted to tumor cells, as cells in blood vessels also express RAGE. Thus, the interaction between RAGE and amphoterin involves not only tumor growth and motility directly, but also tumor angiogenesis. 8 Indeed, several papers reported that blockade of RAGE-amphoterin interaction suppresses tumor growth and metastasis using soluble RAGE, truncated amphoterin or antisense. 4,9,10 We therefore hypothesized that a small molecule inhibitor of the interaction between RAGE and amphoterin will become a new antitumor drug. We then designed the screening system and searched for the inhibitor. As a result, we have found a novel natural compound from a fungal strain Acremonium sp. CR17671. In this study we describe the isolation, structure determination and biological activity of NBRI17671 (1) and the synthesis and biological activity of a more active derivative of 1, (2).

The function and mechanism of HMGB1 in lung cancer and its potential therapeutic implications (Review)

“…RAGE also interacts with amphoterin, which contributes to tumor growth and metastasis (29). Compound NBRI17671 (2) is a RAGE inhibitor that downregulates MAPK activity and effectively inhibits the growth of lung tumor xenografts in mice (30). This phenomenon maybe attributed to the blockade of RAGE-amphoterin.…”

Prospect of natural products in glioma: A novel avenue in glioma management

“…CR17671. It inhibits the interaction between Receptor for Advanced Glycation End products (RAGE) and amphoterin to induce antitumor effect (Kawada et al, ). Rue extract is also known to cause cell death by promoting AKT and ERK1/2 pathways in A1 cells.…”

Intramolecular Diels–Alder (IMDA) Studies toward the Synthesis of Australifungin. Stereocontrol in the Acetate Aldol Reaction of β,β′-Branched Aldehydes

“…Ceramide may also function as an intracellular messenger in a lipid signal transduction pathway implicated in several processes linked to cell differentiation, apoptosis, and cell proliferation . A recent study has identified the natural metabolite NBRI17671 ( 3 ) and the reduced derivative 4 as novel inhibitors of the interaction of RAGE (receptor for advanced glycation end-product) and amphoterin . Blocking the interaction of RAGE and amphoterin results in an inhibition of tumor growth, motility, and angiogenesis …”

“…4 A recent study has identified the natural metabolite NBRI17671 (3) and the reduced derivative 4 as novel inhibitors of the interaction of RAGE (receptor for advanced glycation end-product) and amphoterin. 5 Blocking the interaction of RAGE and amphoterin results in an inhibition of tumor growth, motility, and angiogenesis. 6 Cytosporic acid (5) has similar structural features and has been shown to inhibit HIV-1 integrase, an enzyme essential for viral replication.…”