Eyunni Suresh Vk, Gangapuram Madhavi, Mochona Bereket, Mateeva Nelly, Redda Kinfe K
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, USA.
College of Science and Technology, Florida A&M University, Tallahassee, FL-32307, USA.
J Cancer Sci Ther. 2017;9(7):528-540. doi: 10.4172/1948-5956.1000470. Epub 2017 Jul 13.
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. antiproliferative activity of new substituted tetrahydroisoquinoline analogs were evaluated against human ER (+) (breast), ER (-) (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 (IC=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 and Ishikawa cell lines respectively, in comparison to Tamoxifen activity (IC=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.
乳腺癌是女性死亡的主要原因，每年在全球导致超过50万人死亡。尽管化疗药物仍然是癌症治疗的主要手段，但人们观察到，其对正常细胞的毒性限制了它们的治疗价值。此外，晚期乳腺癌患者通过化疗的康复率仍然低得令人难以接受。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，可能成为乳腺癌的潜在治疗药物。在之前工作的基础上，我们系统地合成并表征了四氢异喹啉（THIQs）类似物。使用CellTiter-Glo发光细胞活力测定法，评估了新的取代四氢异喹啉类似物对人ER(+)（乳腺）、ER(-)（乳腺）和石川（子宫内膜）癌细胞系的抗增殖活性。与他莫昔芬活性（IC=3.99μg/mL，7.87μg/ml）相比，本研究中获得的最具活性的化合物是2b、2i和3g，它们分别对[具体细胞系]和石川细胞系表现出活性（IC=0.2μg/mL，0.08μg/mL；0.61μg/mL，0.09μg/mL；0.25μg/mL，0.11μg/mL）。将新合成的分子对接至ER-α（PDB：3ERT）、ER-β（PDB：1QKN）和α-β微管蛋白紫杉醇复合物（1JFF）晶体结构中的活性位点，以确定活性化合物的可能结合模式（生物活性构象）。
