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首页> 外文期刊>Archiv der Pharmazie >Synthesis, anticancer activity, and molecular modeling of etodolac‐thioether derivatives as potent methionine aminopeptidase (type II) inhibitors
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Synthesis, anticancer activity, and molecular modeling of etodolac‐thioether derivatives as potent methionine aminopeptidase (type II) inhibitors

机译：Etodolac-硫醚衍生物作为有效蛋氨酸氨基肽酶（II型）抑制剂的合成，抗癌活性和分子建模

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Abstract A series of ( R , S )‐1‐{[5‐(substituted)sulfanyl‐4‐substituted‐4 H ‐1,2,4‐triazole‐3‐yl]methyl}‐1,8‐diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐ b ]indoles ( 5a–v ) were designed and synthesized using a five‐step synthetic protocol that involves substituted benzyl chlorides and ( R , S )‐5‐[(1,8‐diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐ b ]indole‐1‐yl)methyl]‐4‐substituted‐2,4‐dihydro‐3 H ‐1,2,4‐triazole‐3‐thiones in the final step. The synthesized derivatives were evaluated for cytotoxicity and anticancer activity in vitro using the MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) colorimetric method against VERO, HEPG2 (human hepatocellular liver carcinoma), SKOV3 (ovarian carcinoma), MCF7 (human breast adenocarcinoma), PC3 and DU145 (prostate carcinoma) cells at 10 ?5 ?M (10?μM) for 24?h. Compounds 5d and 5h showed the best biological potency against the SKOV3 cancer cell line (IC 50 ?=?7.22 and 5.10?μM, respectively) and did not display cytotoxicity toward VERO cells compared to etodolac. Compounds 5k , 5s , and 5v showed the most potent biological activity against the PC3 cancer cell line (IC 50 ?=?8.18, 3.10, and 4.00?μM, respectively) and did not display cytotoxicity. Moreover, these compounds were evaluated for caspase‐3, ‐9, and ‐8 protein expression and activation in the apoptosis pathway for 6, 12, and 24?h, which play a key role in the treatment of cancer. In this study, we also investigated the apoptotic mechanism and molecular modeling of compounds 5k and 5v on the methionine aminopeptidase (type II) enzyme active site in order to get insights into the binding mode and energy.
机译：摘要一系列（R，S）-1 - {[5-（取代）磺酰基-4-取代-4h -1,2,4-三唑-3-基]甲基} -1,8-二乙基-1 ，使用五步合成方案设计和合成3,4-四氢吡喃[3,4- b]吲哚（5A-V），所述五步合成方案涉及取代的苄酰氯和（R，S）-5 - [（1， 8-二乙基-1,3,4,9-四氢吡喃[3,4- b]吲哚-1-基）甲基] -4-取代-2,4-二氢-3H -1,2,4-三唑 - 最后一步的3脚。使用MTT（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑粒溴化物）比色法针对Vero，HepG2（人肝细胞癌），评估合成衍生物的细胞毒性和抗癌活性。 SKOV3（卵巢癌），MCF7（人乳腺腺癌），PC3和DU145（前列腺癌）细胞10？5？m（10≤μm）24Ω·h。化合物5d和5h显示了抗skov3癌细胞系（Ic 50？=α.7.22和5.10≤μm）的最佳生物效力，与etodolac相比，没有向Vero细胞显示细胞毒性。化合物5K，5S和5V显示出对PC3癌细胞系（IC50≤X=α=Δ= 18.18,3.10和4.00μm）的最有效的生物活性，并且没有显示细胞毒性。此外，这些化合物被评估用于Caspase-3，-9和-8蛋白表达和在凋亡途径中的活化，6,12和24μl，在治疗癌症中起关键作用。在本研究中，我们还研究了在蛋氨酸氨基肽酶（II型）酶活性位点上的化合物5K和5V的凋亡机制和分子建模，以便在结合模式和能量中获得见解。

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