Structure‐Activity Analysis of Bisphenol‐Z Derivatives for Anticancer Activity

Much of the research surrounding bisphenol derivatives focuses on their use as polymers and plasticizers for industry. Research has demonstrated that bisphenol‐A (BPA) adversely affects humans via endocrine disruption through hormonal modulation. Despite the recent explosion in BPA research, little effort has been devoted to researching the biological activities of other bisphenol derivatives, including bisphenol‐Z (BPZ). Initial screening of BPZ revealed moderate in vitro anticancer activity against four diverse human cancer cell lines (A375 malignant melanoma, A‐172 glioblastoma, HT‐29 colorectal adenocarcinoma, and MCF7 breast adenocarcinoma) with IC 50 values of approximately 65 μM following 24 hour treatments. In an attempt to enhance the activity of BPZ, seven analogs with varying degrees of polarity, lipophilicity, and sterics on the cyclohexane ring were synthesized. Screening of these analogs revealed that polar substitutions resulted in a loss of activity, while a simple methyl substitution had similar activity to BPZ. Anticancer activity was enhanced relative to BPZ following substitution with an ethyl, isopropyl, or N‐palmitoyl group at the 4‐ position. The most active compounds from this structure‐activity study were the N‐palmitoyl (LS4) and isopropyl (LS6) derivatives with 24 hour IC 50 values ranging from 25 to 53 μM and 33 to 42 μM respectively. Given the increased activity of LS4 and LS6, additional studies were performed including a trypan blue exclusion assay and a Caspase‐Glo® 3/7 assay. The results of these studies revealed exclusion of trypan blue at supra‐IC 50 concentrations six hours after treatments, suggestive of a non‐necrotic mechanism of death. To determine if caspase‐dependent apoptosis was involved, we performed a Caspase‐Glo® 3/7 assay. Functional screening of executioner caspase‐3 and ‐7 revealed significant increases in activity following a 12 hour treatment with LS4 in all cells lines. This effect was least evident in the MCF7 cells, potentially due to a mutation wherein these cells lack expression of caspase‐3. In contrast, LS6 failed to activate executioner caspases‐3 and ‐7 in these same cell lines. In conclusion, this structure‐activity study revealed that nonpolar substitution at the 4‐ position of BPZ enhanced anticancer activity. Additionally, membrane integrity remained intact following exposure to LS4 and LS6. While LS4 activated executioner caspases‐3/7, LS6 failed to activate this hallmark pathway of apoptotic death. Further investigations are ongoing to elucidate the mechanisms of cell death, identify putative cellular targets, and determine potential selectivity against normal human cell lines. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .