Abstract 173: Synthesis of substituted tetrahydroisoquinoline derivatives as anticancer agents

Breast cancer is the second leading cause of cancer-related deaths in women today and is the most common cancer among women, excluding non-melanoma skin cancers. Over 246,000 women will be diagnosed with breast cancer and 40,450 are expected to die of it in 2016. Estrogen receptors ERα, ERβ and their associated steroid hormones play vital role in breast cancer development and progression. Estrogen binds and activates the estrogen receptors in certain breast cancer cells. Endocrine therapy which aims to block ER action (antagonism) on breast tumor cells and thereby stopping the proliferation of cancer cells is a very useful strategy in treating breast cancer. Tamoxifen is the first selective estrogen receptor modulator (SERM) and is the leading drug used in treating breast cancer. Although Tamoxifen has shown great benefit in treating breast cancer, its agonistic effect on the uterus is said to be associated with an increased risk of developing endometrial cancer. We are interested in designing a single chemical entity which acts at specific multiple biomolecular targets. This strategy may exert favorable advantages in improving efficacy at desired multiple targets and lower incidence of side effects. Thus, alternative chemical entities, preferably non-steroidal molecules which act as estrogen receptor modulators and microtubule disruptors are sought. The tetrahydroisoquinoline (THIQ) core structure is an important pharmacophore in natural products and small molecules which act as drug molecules. The steroidomimetic tetrahydroisoquinoline moieties were reported to be selective SERMs and microtubule disruptors. Based on these considerations and in continuation with our previous research, herein we report in vitro cytotoxic and in silico docking studies of substituted THIQs. Novel substituted THIQ derivatives were designed and synthesized. N-amination of substituted isoquinolines by the aminating agent, O-mesytelene sulfnylhydroxylamine led to the formation of ylides. The ylides were reduced using sodium borohydride to yield the desired substituted tetrahydroisoquinolines in moderate to good yields. These compounds were evaluated for their cytotoxic effects using MCF-7, MDA-MB-231 and Ishikawa cells using the CellTiter-Glo luminescent cell viability assay. Among all the compounds screened, 4-ethyl-N-(8-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)benzamide showed IC50 values of 0.61, 1.36 and 0.09 µg/ml on MCF-7, MDA-MB-231 and Ishikawa cells respectively. This research was supported by the National Center for Research Resources and the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number 8 G12MD007582-28. Citation Format: Kinfe Ken Redda, Madhavi Gangapuram, Suresh Eyunni. Synthesis of substituted tetrahydroisoquinoline derivatives as anticancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 173. doi:10.1158/1538-7445.AM2017-173