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,

2} , Reyaz Ur Rasool _{2,

3,

4,

5,

6} , Zainab Iqra _{2,

5,

6,

7} , Yedukondalu Nalli _{1,

2} , Prabhu Dutt _{1,

2} , Naresh K. Satti _{1,

2} , Neha Sharma _{1,

2} , Sumit G. Gandhi _{2,

6,

8,

9} , Anindya Goswami _{2,

5,

6,

7} , Asif Ali _{1,

2}

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：

通过PI3K / Akt / NF-kB途径将脱氢姜油酮的炔-叠氮化物环加成类似物作为潜在的抗前列腺癌抑制剂

在本文中，我们报道了姜中根茎中的次生代谢产物脱氢姜油酮（DHZ，1）的分离和合成修饰。我们合成了O-炔丙基化的脱氢姜油酮，随后通过点击化学将其与炔-叠氮化物环加成（3-20）偶联。在一组三种癌细胞系中评估了化合物（1–20）的体外细胞毒性活性。在所有的DHZ衍生物，3，6，7，8，9和15显示的有效的细胞毒性潜力，其IC ₅₀在MCF-7，PC-3和HCT-116细胞系中，该值的范围为1.8–3.0μM。此外，已证明化合物7是所有三种不同的癌细胞系中最有效的细胞毒性化合物，并且还显示出在前列腺癌中具有显着的抗侵袭潜力。化合物7的机理研究表明，它不仅抑制了调节核转录因子-NF-kB的AKT / mTOR信号传导，而且还增强了抗侵袭性标志物E-钙黏着蛋白和TIMP的表达。化合物7分别显着降低了侵袭性标志波形蛋白，MMP-2和MMP-9的表达。这项研究强调了一种有效的合成方法，用于评估脱氢姜油酮的结构与活性之间的关系（1）以寻找潜在的新型抗癌药。

更新日期：2017-11-16

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