Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, 12622, Giza, Egypt.
Green Chemistry Department, National Research Centre, Dokki, 12622, Giza, Egypt.
Sci Rep. 2024 Nov 1;14(1):26327. doi: 10.1038/s41598-024-75411-3.
Nortopsentins are a vital class of deep-sea sponge metabolites which can be used as leads for antitumor agents. Although their action has been studied in several diseases' contexts, their cytotoxic activity against colorectal carcinoma has not yet been fully investigated. Therefore, a series of 2,6-bis(1H-indol-3-yl)-4-(substituted-phenyl)pyridin-5-carbonitriles 4a-j (nortopsentin analogs) was investigated for their cytotoxic activity against colorectal carcinoma. The analog 4i showed the highest antitumor activity via inducing cell cycle arrest at G1 phase. Cell cycle arrest was induced due to expression downregulation of CDK2, CDK4, and CDK6. In addition, 4i suppressed the enzymatic activity of CDK6. The theoretical study of some basic quantum factors and the geometric shape of compound 4i proved that the compound is stable and a soft molecule, in which the E and E energies were negative and had a small ∆E gap. 4i also demonstrated a high potential for oral bioavailability due to its adherence to Lipinski's rule of five. The molecular docking studies of 4i analog showed good binding mode with CDK6 active pocket through the formation of multiple interactions with its key amino acids.
诺托品是深海海绵代谢物的重要类别，可用作抗肿瘤药物的先导化合物。尽管已经在几种疾病的背景下研究了它们的作用，但它们对结直肠癌的细胞毒性活性尚未得到充分研究。因此，研究了一系列 2,6-双（1H-吲哚-3-基）-4-（取代苯基）吡啶-5-甲腈 4a-j（诺托品类似物）对结直肠癌的细胞毒性活性。类似物 4i 通过诱导 G1 期细胞周期停滞表现出最高的抗肿瘤活性。细胞周期停滞是由于 CDK2、CDK4 和 CDK6 的表达下调引起的。此外，4i 抑制了 CDK6 的酶活性。化合物 4i 的一些基本量子因素和几何形状的理论研究证明了该化合物是稳定的和软分子，其中 E 和 E 能量为负，并且具有较小的 ∆E 间隙。4i 还由于符合 Lipinski 的五规则而显示出高口服生物利用度的潜力。4i 类似物的分子对接研究表明，通过与关键氨基酸形成多种相互作用，该类似物与 CDK6 活性口袋具有良好的结合模式。
