Substituted Tetrahydroisoquinolines as Microtubule-destabilizing Agents in Triple Νegative Human Breast Cancer Cells

Abstract

Triple-negative breast cancer (TNBC) occurs in greater frequency amongst African-Americans, and is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal receptor 2 (HER2). TNBC is often invasive and typically treated with cytostatic agents such as taxanes in combination with anthracyclines or platinum-based drugs. In this study, we synthesized a number of tetrahydroisoquinoline moieties by N-amination of substituted isoquinolines by O-mesytelene sulfonylhydroxylamine followed by ylide formation and reduction, which yielded the desired, substituted tetrahydroisoquinolines (THIQs) in moderate to good yield. Using a differential scatter plot to identify potential selective ER-modulating drugs in ER-positive control cells (MCF-7) driven by estradiol vs. TNBC (MDA-MB-231) cells, the in vitro data showed an absence of effects on the ER (compared to 4-hydroxy-tamoxifen and raloxifene). In contrast, two lead compounds halted proliferation (cytostatic) in MDA-MB-231 TNBC cells at a potency level below 2.5 µM concomitant with mitotic arrest, attenuated replicative DNA synthesis, halted microtubule nucleation/stunted tubulin polymerization, abnormal expansive cytoskeletal tubulin and actin morphologies with multinucleation of cells. The most effective cytostatic compounds GM-4-53 and GM-3-121 blocked replicative processes at the G2 growth phase. These findings suggest that specific THIQs work independently of the ER, by holding static the microtubule network thereby preventing mitosis. Future work will be required to establish the safety and efficacy of these drugs and their potential adjunct therapeutic gain in the presence of taxanes in TNBC.

Transcriptome Profile Analysis of Triple-Negative Breast Cancer Cells in Response to a Novel Cytostatic Tetrahydroisoquinoline Compared to Paclitaxel

“…As a result, there is a continuous demand for safe and efficient alternatives to TNBC cytostatic drugs, which may work through a different mechanism, enabling improved antitumor response and patient outcome. After our lab revealed GM-4-53 to be a potent cytostatic agent, the first obvious target evaluated was its effect on the tubulin polymerization/depolymerization processes; where the data failed to show any effect and showed only mild effects on the process of tubulin nucleation, suggesting there must be additional mechanisms in play [ 37 ].…”

“…The synthesis and characterization of tetrahydroisoquinoline GM-4-53 have been described previously [ 37 ]. O-mesitylene sulfonyl hydroxylamine (MSH) was used to prepare the N -amino salt as an aminating agent, as previously reported [ 36 ].…”

“…Due to the great need for novel drug development in the area of TNBC, we synthesized a novel cytostatic compound; GM-4-53 (Figure 1), with similarities to paclitaxel in terms of therapeutic effect, without the well-known tubulin polymerization and thwarted retraction and treadmilling actions of the latter, which are the primary mechanism behind abrogated mitosis [37][38][39][40]. In this work, we further examine how paclitaxel and GM-4-53 affect the transcriptome of TNBC, to elucidate a plausible mechanism of action underpinning cytostatic effects [41].…”

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

“…They proved to be effective in halting proliferation without any observed toxicity. These findings appear to suggest that some specific THIQs might work independently of the ER, e.g., by holding the microtubule network static, thereby preventing mitosis [ 30 ].…”