Salinosporamides D-J from the marine actinomycete Salinispora tropica, bromosalinosporamide, and thioester derivatives are potent inhibitors of the 20S proteasome
Salinosporamides D-J from the marine actinomycete Salinispora tropica, bromosalinosporamide, and thioester derivatives are potent inhibitors of the 20S proteasome
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DOI：
10.1021/np0603471
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发表时间：
2007-02-01
影响因子：
5.1
通讯作者：
Potts, Barbara C. M.
中科院分区：
文献类型：
--
作者：
Reed, Katherine A.;Manam, Rama Rao;Potts, Barbara C. M.
Salinosporamide A (NPI-0052; 3) 是一种高效的 20S 蛋白酶体抑制剂，目前正处于治疗癌症的 I 期临床试验中。在从热带盐孢菌发酵提取物中纯化数克数量的 3 的过程中，分离并表征了几种新的盐孢菌酰胺，其中大多数代表了 C-2 处氯乙基取代基的修饰。具体而言，3 与已知化合物盐孢酰胺 B (4)、先前未描述的甲基同源物盐孢酰胺 D 7) 以及 3 和 7 的 C-2 差向异构体（分别为盐孢酰胺 F (9) 和 G (10)）一起分离。 Salinosporamide I (13)（其中环连接处的甲基被乙基取代）和 C-5 脱羟基类似物 salinosporamide J (14) 也已被鉴定。在发酵培养基中用溴化钠替代合成海盐产生了溴盐孢酰胺 (12)、4 及其 C-2 差向异构体 (11, 盐孢酰胺 H)。除了这八种新的盐孢酰胺外，还半合成产生了几种硫酯衍生物。测定了所有化合物对人多发性骨髓瘤细胞系 RPMI 8226 的细胞毒性和对纯化兔 20S 蛋白酶体的胰凝乳蛋白酶样 (CT-L) 活性的抑制的 IC50 值。结果表明，硫酯可以直接抑制蛋白酶体，尽管与β-内酯对应物相比，其效力有所降低。
Salinosporamide A (NPI-0052; 3), a highly potent inhibitor of the 20S proteasome, is currently in phase I clinical trials for the treatment of cancer. During the course of purifying multigram quantities of 3 from Salinispora tropica fermentation extracts, several new salinosporamides were isolated and characterized, most of which represent modifications to the chloroethyl substituent at C-2. Specifically, 3 was isolated along with the known compound salinosporamide B (4), the previously undescribed methyl congener salinosporamide D 7), and C-2 epimers of 3 and 7 (salinosporamides F (9) and G (10), respectively). Salinosporamide I (13), in which the methyl group at the ring junction is replaced with an ethyl group, and the C-5 deshydroxyl analogue salinosporamide J (14), were also identified. Replacement of synthetic sea salt with sodium bromide in the fermentation media produced bromosalinosporamide (12), 4, and its C-2 epimer (11, salinosporamide H). In addition to these eight new salinosporamides, several thioester derivatives were generated semisynthetically. IC50 values for cytotoxicity against human multiple myeloma cell line RPMI 8226 and inhibition of the chymotrypsin-like (CT-L) activity of purified rabbit 20S proteasomes were determined for all compounds. The results indicate that thioesters may directly inhibit the proteasome, albeit with reduced potency compared to their beta-lactone counterparts.