Assoc Prof Shaymaa Kassab

Damanhour University, Egypt

Title: Structure-based design and synthesis of conformationally constrained derivatives of methyl-piperidinopyrazole (MPP) with estrogen receptor (ER) antagonist activity

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Biography

Dr. Kassab is granted the degree of the philosophy of doctorate in pharmaceutical sciences (Pharmaceutical Chemistry) from Cairo University in 2009. Dr. Kassab’s teaching experience of drug design and medicinal chemistry courses is associated with engagement to several research projects set up inside Egypt and abroad, in the field of drug discovery and development. In 2014, she joined a research group at the University of Maryland in Baltimore in the USA as a research fellow via a personal grant and patented a compound of therapeutic value against B call lymphoma. In 2016, she went back to USA as a research fellow at top universities there, Virginia Commonwealth and Texas A&M to learn and get trained on advanced research instruments and join research projects targeting neurological disorders. Dr. Kassab received a research grant from Science and Technological Development Fund (STDF) in 2017 as a principal investigator aiming at elaborating pan inhibitors of breast cancer that is a life-threatening disease of high prevalence in Egyptian society. Dr. Kassab’s publications are in Q1-lead-international journals and specialized in Medicinal Chemistry and drug discovery. Recently, she published a book chapter entitled “Indomethacin from anti-inflammatory to Anticancer agent” in Intech Open publisher

Abstract

Nuclear Estrogen receptors (ER) are cytoplasmic proteins; translocated to the nucleus to induce transcriptional signals after getting bound to the estrogen hormone. ER activation implicated in cancer cell proliferation of female reproductive organs. Thus, the discovery of ER antagonists is a reliable strategy to combat estrogendependent breast cancer. Endometrial carcinoma is one of the complications encountered upon long-term therapy by selective estrogen receptor modulators (SERMs) like Tamoxifen (TMX) and methyl piperidinopyrazole (MPP). Thus, the ER-full antagonist is a solution to improve the safety of this class of therapeutics during the treatment of breast cancer. We selected MPP as a lead structure to design conformationally constrained analogs. Structural rigidification is a proven strategy to transform the SERMs into full antagonists. Accordingly, we synthesized 7-methoxy-3-(4-methoxyphenyl)-4,5-dihydro-2H-benzo[g]indazoles (4), (6a-c), (8–12) along with the biphenolic counterparts (13–19) that are the anticipated active metabolites. The 4-nitrophenyl derivative (4) is with the most balanced profile regarding the in vivo anti-uterotrophic potential (EC50 = 4.160 ?M); and the cytotoxicity assay of the corresponding active metabolite (13) against ER+ breast cancer cell lines (MCF7 IC50 = 7.200 ?M, T-47D IC50 = 11.710 ?M). The inconsiderable uterotrophic activities of the elaborated ERantagonists and weak antiproliferative activity of the compound (13) against ovarian cancer (SKOV-3 IC50 = 29.800 ?M) highlighted it as a good start point to elaborate potential ER-full antagonists devoid of endometrial carcinoma. Extending the pendant chain that protrudes from the 2-(4-(substituted)-phenyl) ring of the new benzo-indazoles is recommended for enhancing the potency based on the binding mode of compound (13) in the ligand-binding domain (LBD) of ER