Dept. of Chemistry, Standard Fireworks Rajaratnam College for Women, Sivakasi, Tamilnadu, India.
Department of Physics, Fatima Mata National College (Autonomous), Kollam, Kerala, India.
Comput Biol Chem. 2019 Feb;78:153-164. doi: 10.1016/j.compbiolchem.2018.11.022. Epub 2018 Nov 30.
A derivative of naphthaquinone, 2-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino)naphthalene-1,4-dione (DPDHN) was synthesized from lawsone by ultrasound accelerated technique. The compound was characterized by elemental analysis, IR, UV-vis, NMR and mass spectral studies. Single crystal X-ray diffraction studies revealed that the compound crystallized in monoclinic space group P2/c. Density functional calculations of DPDHN was performed using DFT (B3LYP) method with 6-311G (5D, 7F) basis set, geometrical optimization best fit to single crystal XRD values. The charge delocalization has been analyzed using natural orbital (NBO) analysis. Effects of halogenations at ortho, meta and para positions in the title compound is discussed for frontier molecular orbital analysis, molecular electrostatic potential plots and nonlinear optical properties. It exhibited significant antioxidant property. To predict the anticancer activity of the compound, molecular docking studies were done using Schrödinger software. Molecular docking studies for DPDHN was performed on the active site of protein kinase CK2 (PDB ID: 2OXX, 1M2R and 1M2P) and to explore the estrogen receptor binding ability, the target protein with PDB ID: 3ERT and 2YLY were selected. Docking scores of the designed compound was compared with FDA approved drugs, Tamoxifen, Daunorubicin and Doxorubicin. The compound DPDHN exhibited good Glide scores for all the proteins. Glide score of DPDHN (PDB ID: 2YLY) was -9.67 kcal/mol which was as good as the currently used breast cancer drug, Tamoxifen (-10.37 kcal/mol) and found better than the drug Doxorubicin (-7.3 kcal/mol). Lead compound that satisfies predefined minimum criteria further structure and activity optimization. In the present work, hence it was further subjected to in vitro studies towards human breast cancer (MCF-7) and colon cancer (HCT-15) cell lines. The IC value of compound DPDHN in MCF-7 cells was 15.21 μM and that of HCT-15 was 39.21 μM which was a lower value and better than that of lawsone. Therefore DPDHN exhibited much higher toxicity towards MCF-7 cell lines. Thus, the results indicate that DPDHN is a potential anti cancer lead molecule especially for breast cancer studies.
一种萘醌的衍生物，2-((1,5-二甲基-3-氧代-2-苯基-2,3-二氢-1H-吡唑-4-基)氨基)萘-1,4-二酮(DPDHN)是由洛索酮通过超声加速技术合成的。该化合物通过元素分析、IR、UV-vis、NMR 和质谱研究进行了表征。单晶 X 射线衍射研究表明，该化合物在单斜空间群 P2/c 中结晶。使用 DFT(B3LYP)方法和 6-311G(5D,7F)基组对 DPDHN 进行了密度泛函计算，几何优化与单晶 XRD 值最佳拟合。使用自然轨道(NBO)分析分析了电荷离域。讨论了标题化合物中对位、间位和对位取代基的卤化对前沿分子轨道分析、分子静电势图和非线性光学性质的影响。它表现出显著的抗氧化性能。为了预测化合物的抗癌活性，使用 Schrödinger 软件进行了分子对接研究。使用 Schrödinger 软件对 DPDHN 进行了蛋白激酶 CK2(PDID:2OXX,1M2R 和 1M2P)的活性位点和雌激素受体结合能力的分子对接研究，选择了目标蛋白 PDID:3ERT 和 2YLY。设计化合物的对接评分与 FDA 批准的药物他莫昔芬、柔红霉素和多柔比星进行了比较。该化合物 DPDHN 对所有蛋白质的 Glide 评分都很好。DPDHN(PDID:2YLY)的 Glide 评分为-9.67 kcal/mol，与目前使用的乳腺癌药物他莫昔芬(-10.37 kcal/mol)相当，并且优于药物多柔比星(-7.3 kcal/mol)。满足预定义最低标准的先导化合物进一步进行结构和活性优化。在本工作中，因此它进一步进行了人乳腺癌(MCF-7)和结肠癌(HCT-15)细胞系的体外研究。化合物 DPDHN 在 MCF-7 细胞中的 IC 值为 15.21 μM，在 HCT-15 中的 IC 值为 39.21 μM，这是一个较低的值，优于洛索酮。因此，DPDHN 对 MCF-7 细胞系表现出更高的毒性。因此，结果表明 DPDHN 是一种潜在的抗癌先导分子，特别是对乳腺癌研究。
