Department of Pharmaceutical Chemistry, K B Institute of Pharmaceutical Education and Research, Kadi Sarva Vishvavidhyalay, Gandhinagar, Gujarat, 382023, India.
Department of Pharmaceutical Chemistry, Dr. Prabhakar B Kore Basic Science Research Center, Off-campus, KLE College of Pharmacy (A constituent unit of KAHER-Belagavi), Rajajinagar, Bangalore 560010, Karnataka, India.
Curr Drug Discov Technol. 2022;19(1):e140122189603. doi: 10.2174/1570163817666201229154848.
Fluorine containing hexahydroquinoline-3-carbonitrile derivatives were found to have potent cytotoxicity. Furthermore, fluorine can modulate pharmacokinetic and pharmacodynamic profile of drugs. Hence, new derivatives containing fluorine were explored as potential cytotoxic agents.
Difluoro substituted compounds containing aromatic/heteroaromatic rings were designed, synthesized and screened for in vitro cytotoxicity on cancer cell lines. The active compounds were subjected to docking on Mcl-1 and ADME/T prediction.
The synthesized compounds were characterized using various spectral techniques like FT-IR, H NMR, C NMR and Mass spectra. Compounds were screened for cytotoxicity on NCI-60 cell lines at the National Cancer Institute. The active compounds were evaluated additionally by MTT and SRB assay.
Compounds (6l and 6o) showed maximum cytotoxicity with (% GI) of 69 and 63.7 at 10 μM drug concentration, respectively. Compound 6i showed potent cytotoxicity with GI of 7.2 μM against Ishikawa cell line. Compound 6o was nearly as active as a reference with IC of 9.39 μM and 13.54 μM against HT-29 and HCT-116, respectively, and compound 6l also showed equal potency to that of reference with IC of 9.66 μM against Caco-2. Compounds 6i, 6o and 6l showed high docking scores, suggesting their cytotoxicity. Furthermore, ADME/T prediction revealed that all the compounds had drug-likeness properties.
Enhanced lipophilic interaction of compounds due to the presence of fluorine in compounds 6i and 6l was revealed during the docking study. Compound 6i can be explored as a lead molecule against other endometrial cancer in futuristic drug development.
含氟六氢喹啉-3-甲腈衍生物被发现具有很强的细胞毒性。此外，氟可以调节药物的药代动力学和药效学特征。因此，探索了含有氟的新衍生物作为潜在的细胞毒性剂。
设计、合成并筛选了含有芳香/杂环的二氟取代化合物，以评估其对癌细胞系的体外细胞毒性。对活性化合物进行 Mcl-1 对接和 ADME/T 预测。
采用各种光谱技术，如傅里叶变换红外光谱（FT-IR）、核磁共振氢谱（1H NMR）、核磁共振碳谱（13C NMR）和质谱对合成的化合物进行了表征。在国立癌症研究所（National Cancer Institute）的 NCI-60 细胞系上对化合物进行了细胞毒性筛选。通过 MTT 和 SRB 测定法对活性化合物进行了进一步评估。
化合物（6l 和 6o）在 10 μM 药物浓度下显示出最大的细胞毒性，其最大细胞抑制率（%GI）分别为 69%和 63.7%。化合物 6i 对 Ishikawa 细胞系表现出很强的细胞毒性，GI 为 7.2 μM。化合物 6o 对 HT-29 和 HCT-116 的 IC 分别为 9.39 μM 和 13.54 μM，与参比药物相当，化合物 6l 对 Caco-2 的 IC 也与参比药物相当，为 9.66 μM。化合物 6i、6o 和 6l 的 docking 得分较高，提示其具有细胞毒性。此外，ADME/T 预测表明所有化合物均具有类药性。
在对接研究中，发现由于化合物 6i 和 6l 中存在氟，化合物的亲脂性相互作用增强。化合物 6i 可以作为未来开发针对其他子宫内膜癌的先导化合物进行探索。
