Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
Bioorg Med Chem. 2010 Aug 15;18(16):6031-43. doi: 10.1016/j.bmc.2010.06.068. Epub 2010 Jul 1.
A series of mold metabolites of Ascomycetes, structurally belonging to the class of azaphilones, were found to inhibit the heat shock protein Hsp90. In particular, bulgarialactone B was tested for its binding to Hsp90 using surface plasmon resonance and limited proteolysis assays and for its effects on Hsp90 client proteins expression in a series of human tumor cell lines. This compound showed high affinity for Hsp90, interacting with the 90-280 region of the N-terminal domain and down-regulated the Hsp90 client proteins Raf-1, survivin, Cdk4, Akt, and EGFR. Bulgarialactone B and other natural azaphilones showed antiproliferative activity in a panel of human tumor cell lines; their conversion into semisynthetic derivatives by reaction with primary amines increased the antiproliferative activity. Preliminary results indicated in vivo activity of bulgarialactone B against an ascitic ovarian carcinoma xenograft, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.
发现一系列属于氮杂茂酮类的子囊菌代谢产物能够抑制热休克蛋白 Hsp90。特别是，利用表面等离子体共振和有限蛋白水解试验测试了保加利亚内酯 B 与 Hsp90 的结合，并在一系列人肿瘤细胞系中测试了其对 Hsp90 客户蛋白表达的影响。该化合物对 Hsp90 具有高亲和力，与 N 端结构域的 90-280 区域相互作用，并下调了 Raf-1、存活素、Cdk4、Akt 和 EGFR 等 Hsp90 客户蛋白。保加利亚内酯 B 和其他天然氮杂茂酮在一组人肿瘤细胞系中表现出抗增殖活性；通过与伯胺反应将其转化为半合成衍生物增加了抗增殖活性。初步结果表明，保加利亚内酯 B 对腹水卵巢癌异种移植物具有体内活性，从而支持这一系列新型 Hsp90 抑制剂的治疗潜力。
