Synthesis and Pharmacological Evolution of Tetrahydroisoquinolines as Anti Breast Cancer Agents

Abstract

Breast cancer is leading cause of mortality among women, resulting in more than half a million deaths worldwide each year. Unfortunately, the recovery rate of advanced breast cancer by current available drug treatment is till unacceptably low. Chemotherapy is the main stay of cancer treatment and most of the drugs cause general toxicity to any non-proliferating cells, which can severely limit the therapeutic values of these drugs. Tetrahydroisoqinoline derivatives (THIQs) were identified as subtype selective estrogen receptor antagonists/agonists hence, potential therapeutic agents for breast cancer. Substituted THIQs were synthesized and well characterized. Antiproliferative activity against human ER (+) MCF-7 (Breast), ER(−) MDA-MB-231 (breast) and Ishikawa (endometrial) cancer cell lines were studied after 72 hours drug exposure employing CellTiter-Glo assay at concentrations ranging from 0.01–100,000 nM. The activities of these compounds were compared with Tamoxifen (TAM). In-vitro results indicated that most of the compounds showed better activity than TAM. The most active compounds obtained in this study were 6a, 6b, 6d and 6j (IC50=0.63, 0.23; 0.93, 0.21; 043, 0.01; 0.7, 0.02 μg/ml) against MCF-7 and Ishikawa cell lines, in comparison to Tamoxifen activity (IC50=5.14, 4.55 μg/ml). The newly synthesized molecules were docked in the active sites of the ER-α (PDB: 3ERT) and ER-β (PDB: 3ERT) crystal structures and probable binding modes of this class of molecules were determined.

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

“…The aminating agent 10 was prepared using a reported procedure [ 32 ]. The amino salts of ring substituted 2-aminoisoquinolinium mesitylenesulfonates of general structure 11 used in the present study were prepared by the reaction of substituted isoquinolines and the aminating agent 10 as previously reported [ 31 ]. Reaction of 11 with corresponding substituted acylating agents (acyl chlorides) afforded N-ylides 12a–2m as stable crystalline solids.…”

“…O -mesitylene sulfonyl hydroxylamine (MSH) (10) was used to prepare the N-amino salt as an aminating agent [ 32 ] as previously reported [ 31 ]. To an ice-cooled solution of substituted isoquinolines (20.67 mmol) in anhydrous methylene chloride and anhydrous methanol (1:1) (60 mL) was added MSH (10) (22.74 mmol) in dry methylene chloride (10 mL) over 5 min with stirring.…”

“…In our recent studies [ 31 ], we reported the most potent substituted THIQ 1, as the lead structure. Here we report the synthesis of new ring substituted THIQs and their in-vitro anti-proliferative activities were tested against MCF-7, MDA-MB-231 human breast cancer cell lines and Ishikawa human endometrial adenocarcinoma cell lines.…”

Effect of FGF/FGFR Signal in Fluid Shear Stress and Estrogen Regulating Bone Metabolism

“…There is expression of ERα and ERβ in bone tissues yet with difference in distribution. In cortical bone, ERα is the main subtype expressed, while in bone trabecula it is ERβ [35]. The activity and number of ER change with the level of estrogen, while with the increase of age or after menopause among females, the expression of ER drops [36].…”

Innovative Cancer Treatments

“…The overall process of integration of virus into cellular DNA, leading to the delivery of desired genetic Material is called as integration. This process sometimes may or may not alter host's genetic material [2,3].…”