Identification and characterization of MAM03055A: A novel bivalent sigma-2 receptor/TMEM97 ligand with cytotoxic activity.
Identification and characterization of MAM03055A: A novel bivalent sigma-2 receptor/TMEM97 ligand with cytotoxic activity.
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MAM03055A的鉴定和表征：具有细胞毒性活性的新型二价Sigma-2受体/TMEM97配体。
DOI：
10.1016/j.ejphar.2021.174263
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发表时间：
2021-09-05
影响因子：
5
通讯作者：
Bowen WD
中科院分区：
文献类型：
--
作者：
Liu CZ;Mottinelli M;Nicholson HE;McVeigh BM;Wong NK;McCurdy CR;Bowen WD
与正常细胞相比，Sigma-2受体/跨膜蛋白97(TMEM97)在癌细胞中表达上调。传统的Sigma-2受体激动剂诱导细胞凋亡和自噬，使其在癌症治疗中受到关注。最近，我们报道了Sigma-2受体的一种新的代谢刺激功能，表现出3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四氮唑溴化物(MTT)还原和刺激糖酵解标志的增加。典型的Sigma-2受体拮抗剂6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one(SN79)的6-取代类似物既能产生代谢刺激作用，又能产生细胞毒性作用。在这里，我们比较了两个相关的化合物：6-amino-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one(CM571)，SN79的6-氨基衍生物，与Sigma-1和Sigma-2受体都有高亲和力结合，以及1，3-bis(3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-2-oxo-2，3-dihydrobenzo[d]oxazol-6-yl)thiourea(MAM03055A)，CM571的同源二价二聚体。MAM03055A是细胞毒性6-异硫氰酸酯SN79衍生物3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-6-isothiocyanatobenzo[d]oxazol-2(3H)-one(CM572)降解的产物。MAM03055A对Sigma-2受体具有较高的亲和力和较强的选择性(Sigma-1KI=3371 nM；Sigma-2受体KI=55.9 NM)。在功能上，MAM03055A能有效地诱导SK-N-SH神经母细胞瘤、MDA-MB-231乳腺癌细胞以及SW48和SW480结直肠癌细胞系的细胞死亡，导致SK-N-SH细胞中促凋亡的BH3相互作用域死亡激动剂(BID)的裂解。反之，CM571可诱导代谢刺激。CM571与这两种受体可逆结合，而MAM03055A与sigma-2受体假不可逆结合，并在急性暴露和从介质中移除化合物后产生残留的细胞毒活性。有趣的是，MAM03055A诱导Sigma-2受体/TMEM97蛋白的时间依赖性丢失，而单体CM571对受体水平没有影响。这些结果表明，该系列中的单价和双价sigma-2受体配体与受体相互作用的方式不同，从而导致不同的作用。
Sigma-2 receptor/transmembrane protein 97 (TMEM97) is upregulated in cancer cells compared to normal cells. Traditional sigma-2 receptor agonists induce apoptosis and autophagy, making them of interest in cancer therapy. Recently, we reported a novel metabolically stimulative function of the sigma-2 receptor, showing increased 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction and stimulation of glycolytic hallmarks. 6-Substituted analogs of the canonical sigma-2 receptor antagonist, 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), produce both metabolically stimulative and cytotoxic effects. Here, we compare the activities of two related compounds: 6-amino-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (CM571), the 6-amino derivative of SN79, which binds with high affinity to both sigma-1 and sigma-2 receptors, and 1,3-bis(3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)thiourea (MAM03055A), a homo-bivalent dimer of CM571. MAM03055A resulted from the degradation of 3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-6-isothiocyanatobenzo[d]oxazol-2(3H)-one (CM572), the cytotoxic 6-isothiocyanato SN79 derivative. MAM03055A exhibited high affinity and strong preference for sigma-2 receptors (sigma-1 Ki = 3,371 nM; sigma-2 receptor Ki = 55.9 nM). Functionally, MAM03055A treatment potently induced cell death in SK-N-SH neuroblastoma, MDA-MB-231 breast, and both SW48 and SW480 colorectal cancer cell lines, causing proapoptotic BH3 interacting-domain death agonist (BID) cleavage in SK-N-SH cells. Conversely, CM571 induced metabolic stimulation. CM571 bound reversibly to both receptors, while MAM03055A bound pseudo-irreversibly to sigma-2 receptors and caused residual cytotoxic activity after acute exposure and removal of the compound from the media. Interestingly, MAM03055A induced a time-dependent loss of sigma-2 receptor/TMEM97 protein from cells, whereas monomer CM571 had no effect on receptor levels. These results suggest that monovalent and bivalent sigma-2 receptor ligands in this series interact differently with the receptor, thus resulting in divergent effects.
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影响因子：
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