Design and synthesis of ERα/ERβ selective coumarin and chromene derivatives as potential anti-breast cancer and anti-osteoporotic agents

Abstract

Several new coumarin and chromene prototype derivatives have been synthesised and evaluated for their ERa and ERb selective activity. Coumarin prototype compounds 18 & 19 were found to be ERa selective and the most active, exhibiting potential antiproliferative activity against both ER +ve & ER Àve breast cancer cell lines. The surprise finding of the series, however, are the novel prototype III chromenes 45 & 46, with aroyl substitution at the 6 th position. Both the compounds have shown potent antiproliferative activity against both the breast cancer cell lines, promote alkaline phosphatase activity, enhance osteoblast mineralization in vitro, significantly decrease ERE-ERa dependent transactivation and induce ERb activity. This specific upregulation of ERb isoform activity of compound 45 may be responsible for the antiosteoporotic activity at picomolar concentration. In addition, both the compounds were also devoid of any estrogenic activity, which correlates to their antiestrogenic behaviour in the two breast cancer cell lines. Assessment of selectivity using specific SiRNAs for ERa and ERb revealed that most of the compounds showed ERa and ERb-mediated action, except compound 28, which showed selectivity to ERa only. Computational docking analysis of active compounds 18 and 45 was conducted to correlate the interaction with the two receptors and it was found that the docked conformations of the coumarin prototype, compound 18 at ERa and ERb active sites were more or less superimposable on each other. However, the unique orientation of the aminoalkoxy side chain of novel chromene (prototype III) compound 45 in the ERb binding cavity may be responsible for its potential biological response.

The value of pyrans as anticancer scaffolds in medicinal chemistry

“…81 Hussain et al further conducted a novel synthesis of coumarin derivatives as potent anti-breast cancer agents against ER +ve and ER Àve cell lines. 82 Compound 85 was found to be ER-a selective and most dynamic from all synthesised molecules, exhibiting prospective antiproliferative activity. The docking simulation showed that compound 85 could favorably t well in the receptor cavity of ER-a, following the binding pattern similar to the standard drug.…”

“…At the third position, the 4-methoxyphenyl group forms a hydrophobic interaction with the amino residues Met421, Gly472, His575, Leu298, Phe356, Met340, and Ile373, which are essential features for ER-b binding. 82 Coumarin is a modication of the benzopyran-2-one by directed introduction of a heterocyclic substituent. In most cases, a heteroaryl substituent is introduced at position 3 or 4 of the coumarin ring.…”

Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds

“…The antiproliferative activity of coumarin derivatives is well documented. It was in fact reported that coumarins could act as kinase inhibitors [ 150 ], sulfatase inhibitors [ 151 , 152 , 153 ], selective estrogen receptor modulators [ 154 , 155 , 156 ], particularly downregulators [ 157 , 158 , 159 ], 17βHSD3 inhibitors [ 160 ] cellular cycle blockers [ 161 , 162 , 163 , 164 , 165 ], and aromatase inhibitors [ 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 ]. The latter will be examined in more details herein.…”

Synthesis and Utility of New Polycyclic Compounds as Potential Antimicrobials Based on Chromene Moiety

“…Since ten years ago, the chromene derivatives have been extensively used as active compounds to treat cancer [26,27] inflammation [28], cardiovascular diseases (CVD) [29]. Moreover, they have been used as antimicrobial [30][31][32], antioxidant [33] antiviral [34], anthelminthic [35], anti-HIV [36], TNF-α-inhibitor [37], estrogenic [38,39] antitubercular [40][41] herbicidal [42], anticonvulsant, antiparkinsonian [43,44], antidepressant [45] and analgesic [46,47] activity. Moreover, some of chromene scaffold are well known as antimicrobial drugs and their analogues such as novobiocin, chlorobiocin and coumermycin Al [48][49][50].…”