Design and Synthesis of Trisubstituted Pyrimidine Derivatives as Coactivator Binding Inhibitors (CBIs) of Estrogen Receptor Signaling
Date
2016-01-09
Authors
ميران محمد جمال طلال مسودى
Miran M.Jamal Talal Masswadeh
Journal Title
Journal ISSN
Volume Title
Publisher
AL-Quds University
جامعة القدس
جامعة القدس
Abstract
Breast cancer (BC) is one of the most commonly diagnosed cancers in women. Estrogen signaling
and the estrogen receptors (ERα, ERβ) are implicated in breast cancer progression. Majority of
breast cancers start out as estrogen dependent as a result of overexpression of ER-regulated genes:
Estrogen deprivation therapy using anti-estrogens (AEs) and aromatase inhibitors (AIs) to block ER
activity and arrest the estrogen-dependent growth of BC still represents the primary treatment for
breast cancer patients. This approach, however, frequently fails and patients develop resistant breast
cancer, which is almost untreatable. In this project we focused on synthesizing a potent coactivator
binding inhibitors (CBIs) molecules that block ER activity through a different mechanism that may
arrest the estrogen-dependent growth of BC and offer a solution to the existing resistance. Coactivator
binding inhibitors (CBIs) act by blocking the conformational change needed for DNA
binding and gene expression. In this project set of compounds have been designed, synthesized
through sequential substitution of the chlorine atoms of 2,4,6-trichloropyrimidine with amines or
other nucleophiles. The synthesized compounds were purified using chromatography techniques,
and characterized by (1H-NMR, 13C-NMR, FT-IR and MS (ESI)) spectroscopy. Some of these
compounds were screened for their inhibitory activity against the acute myeloid leukemia cells
(Molm-13) cells. Two forms of Molm-13 had been used to evaluate the role of p53. In one case
cells were transfected with empty vector and in the other the cells were tranfected with sh-p53 RNA(sh-p53). The viability of cells was determined using WST-1 assay.
Initial results of the tested compounds demonstrated that MY12 (35) and MY3 (26) exhibited potent
activities against the two forms of Molm-13 cell lines and have a dose dependent effect while the
compound MY2 (25) showed no significant inhibitory action on the same cell lines.
Description
Keywords
العلوم الصيدلانية , Pharmaceutical Sciences
Citation
Masswadeh، Miran Mohammad. (2016). Design and Synthesis of Trisubstituted
Pyrimidine Derivatives as Coactivator Binding Inhibitors (CBIs) of Estrogen
Receptor Signaling[A published thesis, Al-Quds University, Palestine].Al-Quds
University digital repository https://arab-scholars.com/fb7b3b