AbstractsBiology & Animal Science

Furan- and pyran-based heterocycles as subtype-selective ligands of the estrogen receptor. Synthesis and biological characterisation

by Jochen Zimmermann

Institution: Universit├Ąt Regensburg
Department: Chemie und Pharmazie
Degree: PhD
Year: 2005
Record ID: 1105352
Full text PDF: http://epub.uni-regensburg.de/10393


The discovery of an estrogen binding protein in target tissues about 50 years ago provided a rational basis for the endocrine therapy of breast cancer. After the approval of tamoxifen as drug for treatment of hormone-dependent mammary carcinomas antiestrogen therapy has become an established treatment modality for this malignancy. More recently an isoform of the estrogen receptor was discovered and characterised. It was termed ERbeta to discriminate it from the original ERalpha. Both receptor forms share many similarities but show a different distribution in the body and, consequently, differ in their functions which are not yet completely assigned to the two subtypes ERalpaha and ERbeta. The objective of this study was the search for new agents, that can be applied to the treatment of hormone-dependent mammary carcinomas. These compounds should display a preference for one of the two estrogen receptor isoforms ERalpha and ERbeta, which have been shown to possess distinct tissue distribution profiles and functions in the body. The ERalpha was found to be the predominant estrogen receptor protein in malignant mammary tumours. Steroidal fulvestrant is the only pure antiestrogen in the clinics for the treatment of this malignancy, but it lacks subtype selectivity. Thus, pure antiestrogens with selectivity for ERalpha would be the drugs of choice for the treatment of breast cancer patients, who have become resistant to prior endocrine therapy. Potent ERbata-selective antagonists would represent an useful tool to elucidate the functions of this receptor isoform, which are not yet completely understood. In order to discover new structures that have not yet been investigated as ligands for the ER, virtual screening with the software programme LUDI was performed to select promising structures from a large database. Five compounds containing either a bridged bicyclic core structures or a 1,1-diaryl motif were chosen for primary testing. An ethanoanthracene-based compound was synthesised through the Diels-Alder reaction and synthetically modified with phenolic hydroxy groups. A number of non-steroidal compounds have been identified as ER ligands with a variable degree of subtype selectivity for ERalpha. The preference for one or the other receptor isoform depends mainly on the structure of the core. In this study furan- or pyran-based heterocycles linked with two hydroxylated phenyl rings were chosen as carrier molecules. These core structures, including 2,5- and 2,4-diphenylfurans, 2-phenylbenzo[b]furans and 3-phenyl-1-benzopyrans, were chemically modified with long aliphatic side chains incorporating appropriate functional groups in order to convert them into pure antiestrogens. The biological characterisation of the new ligands of the estrogen receptor comprises the determination of binding affinities for a native estrogen receptor isolated from calf uteri and for the two recombinant ER subtypes alpha and beta. Compounds with sufficient affinity were tested for antiproliferative activity in estrogen-sensitive human…