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Synthesis and Biological Evaluations of Ring Substituted Tetrahydroisoquinolines (THIQs) as Anti-Breast Cancer Agents

机译：环取代的四氢异喹啉（THIQs）作为抗乳腺癌药物的合成及生物学评价

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Breast cancer is a leading cause of mortality among women, resulting in more than half a million deaths worldwide every year. Although chemotherapeutic drugs remain the main stay of cancer treatment, it is observed that toxicity to normal cells poses a limitation to their therapeutic values. Moreover, the patient recovery rate from advanced breast cancer by chemotherapy is still unacceptably low. Tetrahydroisoqinoline derivatives (THIQs) were reported to act as selective subtype estrogen receptor antagonists/agonists and may serve as potential therapeutic agents for breast cancer. In continuation of previous work we systematically synthesized and characterized the tetrahydroisoquinoline (THIQs) analogs. In-vitro antiproliferative activity of new substituted tetrahydroisoquinoline analogs were evaluated against human ER (+) MCF-7 (breast), ER (−) MDA-MB-231 (breast) and Ishikawa (endometrial) cancer cell lines using the CellTiter-Glo luminescent cell viability assay. The most active compounds obtained in this study were 2b, 2i, and 3 g as demonstrated by their activity (IC50=0.2 μg/mL, 0.08 μg/mL; 0.61 μg/mL, 0.09 μg/mL; 0.25 μg/mL, 0.11 μg/mL) against MCF-7 and Ishikawa cell lines respectively, in comparison to Tamoxifen activity (IC50=3.99 μg/mL, 7.87 μg/ml). The newly synthesized molecules were docked in the active sites of the ER-α (PDB: 3ERT), ER-β (PDB: 1QKN) and alpha-beta tubulin taxol complex (1JFF) crystal structures to determine the probable binding modes (bioactive conformations) of the active compounds.
机译：乳腺癌是导致妇女死亡的主要原因，每年导致全世界一半以上的死亡。尽管化学治疗药物仍然是癌症治疗的主要手段，但已观察到对正常细胞的毒性对其治疗价值构成了限制。此外，通过化学疗法从晚期乳腺癌中恢复的患者的比率仍然低得令人无法接受。据报道，四氢异喹啉衍生物（THIQs）可作为选择性亚型雌激素受体拮抗剂/激动剂，并可作为潜在的乳腺癌治疗剂。在先前工作的延续中，我们系统地合成并表征了四氢异喹啉（THIQs）类似物。使用CellTiter-Glo评估了新的取代四氢异喹啉类似物对人ER（+）MCF-7（乳腺），ER（-）MDA-MB-231（乳腺）和Ishikawa（子宫内膜）癌细胞系的体外抗增殖活性发光细胞活力测定。本研究中获得的活性最高的化合物分别为2b，2i和3 g（IC50 = 0.2μg/ mL，0.08μg/ mL; 0.61μg/ mL，0.09μg/ mL; 0.25μg/ mL，0.11）与他莫昔芬活性（IC50 = 3.99μg/ mL，7.87μg/ ml）相比，分别针对MCF-7和Ishikawa细胞系的μg/ mL）。新合成的分子停靠在ER-α（PDB：3ERT），ER-β（PDB：1QKN）和α-β微管蛋白紫杉醇复合物（1JFF）晶体结构的活性位点中，以确定可能的结合模式（生物活性构象） ）的活性化合物。

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