title: Substituted Tetrahydroisoquinolines as Microtubule-destabilizing Agents in Triple Negative Human Breast Cancer Cells.
abstract: Triple-negative breast cancer (TNBC) occurs at greater frequency amongst African-Americans, being 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-hydroxytamoxifen 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 G2growth phase. These findings suggest that specific THIQs work independently of the ER, by holding static the microtubule network thereby preventing mitosis. Future work is required to establish the safety and efficacy of these drugs and their potential adjunct therapeutic gain in the presence of taxanes in TNBC.
authors: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A.
authors: Madhavi
authors: M
authors: Gangapuram
authors: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A.
authors: Riccardo
authors: R
authors: Jean
authors: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A.
authors: Elizabeth
authors: E
authors: Mazzio
authors: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A.
authors: Ramesh
authors: R
authors: Badisa
authors: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A.
authors: Suresh
authors: S
authors: Eyunni
authors: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A.
authors: Carl B
authors: CB
authors: Goodman
authors: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A.
authors: Kinfe K
authors: KK
authors: Redda
authors: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A. karam.soliman@famu.edu.
authors: Karam F
authors: KF
authors: Soliman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D058105:Polymerization / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D044005:Tetrahydroisoquinolines; D014404:Tubulin
keywords: Triple-negative breast cancer; taxanes; tetrahydroisoquinolines