(6-Bromo-1,4-dimethyl-9<i>H</i>-carbazol-3-yl-methylene)-hydrazine (Carbhydraz) Acts as a GPER Agonist in Breast Cancer Cells

Abstract

Estrogens control a wide number of aspects of human physiology and play a key role in multiple diseases, including cancer. Estrogens act by binding to and activating the cognate receptor (ER), however numerous studies have revealed that the G protein-coupled receptor named GPR30/GPER mediates also estrogen signals. As ER and GPER share the ability to bind to same compounds, the use of GPER-selective ligands has allowed a better understanding of the biological responses mediated by GPER. In the present study, we designed and synthesized two novel carbazole derivatives and then investigated their ability to interact with and activate the GPER-mediated transduction pathway in breast cancer cells. Both compounds did not activate the classical ER in MCF7 cells, whereas one of the two compounds synthesized triggered through GPER the rapid ERK activation in ER-negative SkBr3 cells, demonstrating a good affinity for GPER in docking studies. The characterization of this novel selective GPER agonist could represent a potential useful tool to provide further insights into the physiopathological role exerted by GPER.

A calixpyrrole derivative acts as a GPER antagonist: mechanisms and models

“…Of note, GPER expression has been associated with negative clinical features and poor survival rates in patients with hormone-sensitive tumors ( Filardo et al, 2006 ; Smith et al, 2009 , 2007 ; Sjöström et al, 2014 ), suggesting that GPER might be involved in the stimulatory action exerted by estrogens in these malignancies. Considering that GPER and ER bind promiscuously to many compounds, including endogenous and environmental estrogens as well as antiestrogens ( Lappano et al, 2012a ; Prossnitz and Barton, 2011 ), an ongoing major challenge in dissecting the transduction network mediated by GPER is the discovery of novel agents able to act selectively through this receptor, although certain ligands have been identified in our and other previous studies ( Bologa et al, 2006 ; Dennis et al, 2009 , 2011 ; Lappano et al, 2012b ; Maggiolini et al, 2015 ; Sinicropi et al, 2015 ).…”

Macromolecular Modelling and Docking Simulations for the Discovery of Selective GPER Ligands

“…These two moieties, which were named GPER-L1 and GPER-L2, demonstrated the ability to act as GPER agonists without any affinity for ER. Furthermore, a derivative of the carbazole moiety, named carbhydraz, has been recently synthesized and characterized toward its stimulatory activity through GPER (35). To date, only a molecule exhibited inhibitory properties toward both GPER and ER.…”

“…Using the aforementioned approaches, several different natural and synthetic ligands of GPER (Fig. 1) have been identified along with their binding modes as resulting from docking simulations (13,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

Inhibition of Human Topoisomerase II by N,N,N‐Trimethylethanammonium Iodide Alkylcarbazole Derivatives

“…Of particular interest is the interaction with DNA or its metabolizing enzymes that induce programmed cell death, namely apoptosis . Several carbazole analogues structurally derived from ellipticine, an alkaloid from Ochrosia elliptica labill, introduced for the treatment of metastatic breast cancer, but later dismissed because of poor aqueous solubility and severe side effects, were synthesized …”

“…Trimethoxyphenylurea 1,4‐dimethylcarbazoles, N ‐thioalkylcarbazoles, 1,4‐dimethyl‐ N ‐alkylcarbazoles, N ‐(1,4‐dimethyl‐9 H ‐carbazol‐3‐yl)‐ N′ ‐alkylguanidines, benzofuro[2,3‐ f ]quinazolin‐1(2 H )‐ones, and hydrazine‐carbazole derivatives were also prepared, and some of them showed interesting anti‐proliferative activity against breast cancer cells without affecting the viability of non‐tumor cell lines. Several studies have reported that carbazole derivatives, such as ellipticine and celiptium (Figure ), are inhibitors of human topoisomerases I and II …”