Hepatocellular Carcinoma (HCC) is the third leading cause of deaths worldwide. It is associated with chronic liver diseases such as chronic hepatitis, and chronic alcohol consumption. Epidermal growth factor receptor (EGFR) tyrosine kinase (TK) has been identified as molecular target for designing potential drug candidates. EGFR TK is a validated drug target for the treatment of multiple cancers including HCC.<br/>Recent development in our group revealed novel estrone analogs possessing C-17 side chain has shown potent antiproliferative activity against HCC and HCC resistant to Erlotinib. Data showed that analogs previously synthesized MMA 132, and MMA102, IC<sub>50</sub> 2μM, and 3 μM respectively in comparison to Erlotinib 25 μM. These analogs have shown significant inhibition of EGFR/pEGFR, RAF/pRAF, MEK/pMEK, and ERK/PERK signal domain.  Moreover, the analogs have also showed inhibition of MRP1 and P-gp drug transporter proteins.  These effective analogs possess enone structure which could be Michael receptor and could increase side effect of potential drug candidates that may come out of these analogs.  Our hypothesis that using 1,4 Addition reaction to the enone and add HCN or HF will add cyano (CN) and fluorine (F) to the side chain respectively. The latter may contribute to binding of these analogs to molecular target. Design and synthesis of estrone analogs based on compounds synthesized in our group could lead the way for novel analogs to combat HCC and inhibition of MRPs associated with drug resistance.<br/>Redesign of MMA 102 and MMA132 respectively using OpenEye Software showed several analogs possessing CN and F derivates, NA85 AND NA27,  shown above, have the highest calculated binding affinity to vascular endothelial growth factors 1 & 2, phosphoinositide 3 kinase, protein kinase B, TRAILR2, heat shock protein 70 & 90, histone deacetylase, extracellular receptor kinase, mechanistic target of rapamyein, signal transducer and activator of transcription 3, p-glycoprotein. Synthesis of compound possessing the highest calculated binding affinity are currently in progress and anti-prolifeative activity against HCC will be presented.

Design, synthesis and biological evaluation of cucrbitacins inspired estrone analogs using Michael addition on hepatocellular carcinoma

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.