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Structure‐Activity Relationship Studies of Oxypropanolamines: The Importance of Hydrophobicity About the Amine for Maintaining Anti‐Proliferative Effects in Lung Cancer Cells
Author(s) -
Hoffman J. Mason,
Wainscott Nathan W,
Taylor B. Frazier,
Burlison Joseph A.,
Trent John O.,
States J. Christopher
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.823.16
Subject(s) - cell growth , cell cycle , mitosis , chemistry , cancer cell , a549 cell , microbiology and biotechnology , cancer research , cell , cancer , biology , biochemistry , genetics
Background Mitosis‐inhibiting chemotherapeutics are frequently used to treat cancer. Successful therapy is often hindered by drug‐resistant tumors, neurotoxicity, and limited supply. There is high demand for new drugs with diverse cellular targets. The anaphase promoting complex/cyclosome (APC/C) is a multi‐subunit E3 ubiquitin ligase that promotes cell cycle progression, especially mitosis, by marking key proteins for degradation. Thus, the APC/C offers great potential as an alternative target for anti‐mitotic drug development. The APC/C catalytic core consists of an ANAPC2/ANAPC11 dimer. Homology models of the ANAPC2/ANAPC11 subunits were analyzed in silico to identify lead compounds predicted to bind the ANPAC11‐binding domain of ANAPC2, and prevent ANAPC11 association and inhibit APC/C function. Among these leads were oxypropanolamine‐containing compounds. Preliminary studies indicate several of these compounds possess anti‐proliferative effects in various cancer cell lines. Based on this finding, a series of amine derivatives were synthesized to probe the effect of steric bulk and hydrophobicity in this region. Objective We aim to determine how modification of the amine substituent groups influences the ability to inhibit proliferation in several lung cancer cell lines in vitro.Methods To quantify the anti‐proliferative effect of compounds, AlamarBlue and colony forming assays were performed in A549 and H460 lung cancer cells and HBEC‐3KT immortalized non‐transformed bronchial epithelial cells. Results Outcomes of AlamarBlue and colony forming assays indicate that derivatives containing a secondary amine, but not tertiary, cause a decrease in cell proliferation. This anti‐proliferative effect is strengthened by increased steric bulk and hydrophobicity of the substituent amine. Summary These results provide structural insights to guide development of ANAPC2‐targeting compounds and are consistent with the hypothesis that the APC/C is a promising target for development of novel chemotherapeutics. Support or Funding Information KY Lung Cancer Research Program (JCS,); KY Science and Engineering Foundation (JCS); ASPET Summer Undergraduate Research Fellowship (NCW); Kosair Charities Pediatric Oncology Research Program (JOT); NIH P30GM106396 (JOT)