新一类磷脂酰肌醇特异性磷脂酶Cγ1（PI-PLCγ1）抑制剂外文翻译资料

 2022-07-26 15:48:20

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Ten phenolic compounds were isolated from the CHCl3 extract of Ginkgo biloba sarcotestas (Ginkgoaceae) as a new class of phosphatidylinositol-specific phospholipase Cgamma;1 (PI-PLCgamma;1) inhibitors. The substances without the long chain were ineffective. On the other hand, the activities of these compounds were dramatically decreased by acetylation of aromatic hydroxyl groups of cardanol, phenolic acid, and bilobol and by methylation of the aromatic carboxyl group of phenolic acid. The unsaturated long chain as well as the aromatic hydroxyl and carboxyl groups might play a key role for the PI-PLCgamma;1 inhibitory activity. These compounds also inhibited the growth of a number of human cancer cell lines, but were less cytotoxic against a human normal colon cell line.

摘要：作为新一类磷脂酰肌醇特异性磷脂酶Cgamma;1（PI-PLCgamma;1）抑制剂，从银杏叶银杏叶提取物中分离出10种酚类化合物。没有长链的物质是无效的。 另一方面，这些化合物的活性通过乙烯化羟基的腰果酚，酚酸和生物酚酚和苯甲酸芳香族羧酸甲基化显着降低。 不饱和长链以及芳族羟基和羧基可能对PI-PLCgamma;1的抑制活性起关键作用。 这些化合物还抑制许多人癌细胞系的生长，但对人正常结肠细胞系的细胞毒性较小。

Phosphatidylinositol-specific phospholipase C (PIPLC) plays a central role in the intracellular signal transduction by hydrolyzing phosphatidylinositol 4,5- biphosphate to give two second messengers, inositol 1,4,5-triphosphate and diacylglycerol, which lead to a series of events that culminate in DNA synthesis and cell proliferation.1,2 PI-PLC is known to have isozymes such as acirc;1, acirc;2, gamma;1, gamma;2, delta;1, and delta;2.

磷脂酰肌醇特异性磷脂酶C（PIPLC）通过水解磷脂酰肌醇4,5-二磷酸来产生两个第二信使，1,4,5-三磷酸肌醇和二酰基甘油，在细胞内信号转导中起着核心作用，导致一系列事件 最终导致DNA合成和细胞增殖.12 PI-PLC已知具有同功酶如alpha;1，gamma;2，gamma;2，delta;1和delta;2。

Recent reports suggested that an inhibitor of PI-PLC, especially the gamma; isoform, would be a useful tool for development of anticancer agents.5 Microinjection of PIPLCgamma; into quiescent NIH3T3 cells induced DNA synthesis and transformation.6 On the other hand,specific mutation-restoration of PI-PLCgamma; binding to a tyrosinemutated platelet-derived growth factor (PDGF) receptor is sufficient to confer a mitogenic response to PDGF.7 Specifically, the overexpression of PI-PLCgamma;1 in human cancers such as those of lung,8 bladder,8 breast,9 glia,10 and colorectum11,12 as compared to normal tissues, have suggested a role for the PI-PLCgamma;1 isoform in the generation of mitogenic signals associated with tumor progression.

最近的报道表明，PI-PLC的抑制剂，特别是gamma;同种型，将是开发抗癌药物的有用工具.PIPLCgamma;显微注射入静止的NIH3T3细胞诱导DNA合成和转化。另一方面， PI-PLCgamma;与酪氨酸激酶血小板衍生生长因子（PDGF）受体结合的恢复足以赋予PDGF的有丝分裂反应。具体来说，PI-PLCgamma;1在人类癌症中的过表达，如肺，8膀胱，8 乳腺，9胶质细胞，10和结肠直肠癌细胞11,12与正常组织相比，提示PI-PLCgamma;1同种型在与肿瘤进展相关的促有丝分裂信号的产生中起作用。

We have studied natural products as PI-PLCgamma;1 inhibitors for development of anticancer agents.13,14 In the course of screening of the Korean medicinal plants, the CHCl3 extract of Ginkgo biloba sarcotestas showed potent inhibitory activity against PI-PLCgamma;1. G. biloba principles on this enzyme activity have not previously been reported. Thus, this paper describes the isolation of inhibitory principles, their effects, and the modes of inhibitory action on PI-PLCgamma;1. In addition, growth inhibitory effects on normal and human cancer cell lines were studied.

研究天然产物为PI-PLCgamma;1抑制剂，用于开发抗癌剂.13,14在韩国药用植物筛选过程中，银杏叶提取物对PI-PLCgamma;1具有强烈的抑制活性。 关于该酶活性的G.biloba原理尚未有报道。 因此，本文介绍了对PI-PLCgamma;1的抑制原理及其作用及抑制作用模式的分离。 此外，研究了对正常人和癌细胞株的生长抑制作用。

结果与讨论：

The CHCl3 extract of G. biloba L. (Ginkgoaceae) sarcotestas was found to exhibit potent inhibitory activity against PI-PLCgamma;1. We isolated 10 PI-PLCgamma;1 inhibitors by bioassay-guided separation of the CHCl3 extract. This extract inhibited activity of PI-PLCgamma;1 by 82.38% at 125 micro;g/mL, and fractions 1-6 obtained by Si gel column chromatography produced inhibitions of 3.51, 95.02, 87.95, 92.58, 76.32, and 74.02% at the same concentration, respectively. Compounds 1-10 were purified from the fractions 2 and 4. The chemical structures of these compounds were identified as cardanols (1-4), phenolic acids (5-7), and bilobols (8-10) (Figure 1) from their physical and spectral data in comparison with those of published values.

发现银杏（Ginkgoaceae）的CHCl3提取物对PI-PLCgamma;1表现出强烈的抑制活性。 我们通过CHCl3提取物的生物分析指导分离分离了10个PI-PLCgamma;1抑制剂。 该提取物以125mu;g/ mL抑制PI-PLCgamma;1的活性为82.38％，通过硅胶柱色谱法得到的级分1-6分别产生相同浓度的3.51,95.02,87.95,92.58,76.32和74.02％的抑制浓度。 化合物1-10从级分2和4中纯化。这些化合物的化学结构从它们的化合物鉴定为洋甘醇（1-4），酚酸（5-7）和生物酚（8-10）（图1） 物理和光谱数据与公布的数据相比。

These phenolic compounds from G. biloba (C15:1, C17: 1, and C13:0) have been reported as antitumor principles,15 and those from Anacardium occidentale (C15:0, C15:1, C15:2, and C15:3) have been known as molluscicides,16 antibacterial agents,17 cytotoxic agents in BT- 20 (breast carcinoma) and Hela (epithelioid cervix carcinoma) cells,18 prostaglandin synthetase inhibitors,19,20 lipoxygenase inhibitors,21 antiacne agents,22 and tyrosinase inhibitors.23

已经报道了这些来自绿脓杆菌（C15：1，C17：1和C13：0）的酚类化合物作为抗肿瘤原理，和来自西卡那菌（C15：0，C15：1，C15：2和C15： 3）已知为杀软体动物剂，种抗菌剂，BT-20（乳腺癌）和（上皮样癌子宫颈癌）细胞中的17种细胞毒性剂，18种前列腺素合成酶抑制剂，20种脂肪氧化酶抑制剂，21种抗痤疮剂，22种酪氨酸酶inhibitors.

Compounds 1-10 were evaluated for their ability to inhibit PI-PLCgamma;1 in vitro, and showed concentrationdependent inhibitory effects (Table 1). These phenolic compounds are a new class of PI-PLCgamma;1 inhibitors. Among them, phenolic acid C17:1 {6-[10′ (Z)-heptadecenyl]salicylic acid, (6)} showed the most powerful activity, with an IC50 of 0.83 micro;g/mL (2.22 micro;M), whereas bilobol C13:0 [5-tridecyl resorcinol, (10)] was the least active inhibitor, with an IC50 of 26.63 micro;g/mL (72.32 micro;M). Activities of these compounds were either greater or similar in comparison with the previously reported inhibitory substances against PI-PLCgamma;1 from bovine, pig, and rat brain; amentoflavone (IC50; 29 micro;M, bovine brain), prenylated flavonoids (7.5-35 micro;M, bovine brain), Q12723 (8.8 micro;M, bovine brain), vinaxanthone (5.4 micro;M, rat brain), hispidospermidin (16 micro;M, rat brain), and caloporoside (18-31 micro;M, pig brain).13,24-28 Specifically, phenolic acids bearing unsaturated long-chain substituents (5, 6) were very potent inhibitors of PI-PLCgamma;1. Structurally related 6-alkenyl salicylic acids were previously isolated a

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