Alkyne–azide cycloaddition analogues of dehydrozingerone as potential anti-prostate cancer inhibitors via the PI3K/Akt/NF-kB pathway,RSC Medicinal Chemistry

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Alkyne–azide cycloaddition analogues of dehydrozingerone as potential anti-prostate cancer inhibitors via the PI3K/Akt/NF-kB pathway
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-11-02 00:00:00 , DOI: 10.1039/c7md00267j
Chetan Kumar ₁ , Reyaz Ur Rasool _{2,

3} , Zainab Iqra ₃ , Yedukondalu Nalli ₁ , Prabhu Dutt ₁ , Naresh K Satti ₁ , Neha Sharma ₁ , Sumit G Gandhi ₄ , Anindya Goswami ₃ , Asif Ali ₁

Affiliation

Herein, we report the isolation and synthetic modification of dehydrozingerone (DHZ, 1), a secondary metabolite present in the rhizome of Zingiber officinale. We synthesized O-propargylated dehydrozingerone, which was subsequently coupled by alkyne–azide cycloaddition (3–20) using click chemistry. The compounds (1–20) were evaluated for their in vitro cytotoxic activity in a panel of three cancer cell lines. Among all the DHZ derivatives, 3, 6, 7, 8, 9 and 15 displayed potent cytotoxic potential with an IC₅₀ value ranging from 1.8–3.0 μM in MCF-7, PC-3 and HCT-116 cell lines. Furthermore, compound 7 has proven to be the most potent cytotoxic compound in all the three distinct cancer cell lines and also demonstrated significant anti-invasive potential in prostate cancer. The mechanistic study of compound 7 showed that it not only suppressed the AKT/mTOR signalling which regulates nuclear transcription factor-NF-kB but also augmented the expression of anti-invasive markers E-cadherin and TIMP. Compound 7 significantly decreased the expression of pro-invasive markers vimentin, MMP-2 and MMP-9, respectively. This study underscores an efficient synthetic approach employed to evaluate the structure–activity relationship of dehydrozingerone (1) in search of potential new anticancer agents.

中文翻译：

脱氢姜油酮的炔叠氮环加成类似物通过 PI3K/Akt/NF-kB 途径作为潜在的抗前列腺癌抑制剂

在此，我们报告了脱氢姜酮（DHZ， 1 ）的分离和合成修饰，脱氢姜酮是姜根茎中存在的次生代谢产物。我们合成了O-炔丙基化脱氢姜油酮，随后使用点击化学通过炔烃-叠氮化物环加成 ( 3-20 ) 进行偶联。在一组三种癌细胞系中评估了化合物 ( 1-20 ) 的体外细胞毒活性。在所有 DHZ 衍生物中， 3 、 6 、 7 、 8 、 9和15在 MCF-7、PC-3 和 HCT-116 细胞系中表现出有效的细胞毒性潜力，IC ₅₀值范围为 1.8–3.0 μM。此外，化合物7已被证明是所有三种不同癌细胞系中最有效的细胞毒性化合物，并且在前列腺癌中也表现出显着的抗侵袭潜力。化合物7的机制研究表明，它不仅抑制调节核转录因子-NF-kB的AKT/mTOR信号传导，而且增强抗侵袭标记物E-钙粘蛋白和TIMP的表达。化合物7分别显着降低促侵袭标记物波形蛋白、MMP-2和MMP-9的表达。这项研究强调了一种有效的合成方法，用于评估脱氢姜酮 ( 1 ) 的结构-活性关系，以寻找潜在的新型抗癌药物。

更新日期：2017-11-02

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