Studies on Heterocyde‐Based Pure Estrogen Antagonistsa

Abstract

2-Phenylindoles and isosteric structures such as benzo[b]furans and benzo[b]thiophenes were used as estrogen receptor binding moiety for the syntheses of new nonsteroidal antiestrogens. The antiestrogenic potency was considerably enhanced following the introduction of polar functional groups into the side chain in position 1 (indole) or 3 (benzofuran, benzothiophene). The amino compounds could be characterized as mixed agonist/antagonists. Among the derivatives with an amide group compounds without any agonistic activity both in vitro and in vivo were identified. The amide function can be replaced by alkylthio or alkylsulfonyl groups without changing the endocrine profile very much. In this study, the estrogenic activity was determined in a new transcription assay with luciferase as the reporter. The results obtained in this assay were in very good agreement with those from the conventional mouse uterine weight test. Antitumor activity was determined in hormone-sensitive MCF-7 breast cancer cells. There was no difference in activity between partial and pure estrogen antagonists. However, the derivatives with sulfur containing side chains were much more active than the corresponding heterocycles with amino or carbamoyl functions. They reached IC50-values of about 1 nM. 2-Phenylindoles and 2-phenylbenzothiophenes were rather similar in their potencies whereas the benzofuran derivatives were less active probably due to their lower binding affinities for the ER.

Modeling, design and synthesis of new heteroaryl ethylenes active against the MCF-7 breast cancer cell-line

“…All the designed structures possess a pyridinium or a quinolinium salt unit (except for the 1 that presents an imidazolium salt), separated through an ethylenic double bond from another unit, heterocyclic or not, variously substituted to explore a large chemical space with different biological behaviours and responses. As rationalized in previous studies [8][9][10][11][12][13][14][15][16] both the presence of four rings and the replacement of the pyridinium ring with a quinolinium one increased the in vitro activity. Starting from this assumption, in order to obtain compounds both active and inactive we designed new molecules by introducing new substituents and a fifth ring into the scaffold (Scheme 1).…”

“…7 A wide range of heterocyclic ring systems has been studied for the development of novel chemical entities as lead molecules in the drug discovery paradigm and many heterocycles have been tested as potential anticancer agents. 8,9 This prompted us to design and synthesize novel compounds with high efficacy and specificity for the treatment of breast tumors. Previous work of our group reported the synthesis of new heterocycles with potential antitumor activity against the MCF-7 cell line and the binding with an oligonucleotide.…”

Toward Selective ERβ Agonists for Central Nervous System Disorders: Synthesis and Characterization of Aryl Benzthiophenes

“…Related structures such as aryl indoles and aryl benzofuranes have been evaluated as estrogen receptor antagonists. 16 Here we report our findings in a series of aryl benzthiophenes.…”

“…We therefore decided to explore the potential of aryl benzthiophenes as lead structures for selective ERβ agonists. Related structures such as aryl indoles and aryl benzofuranes have been evaluated as estrogen receptor antagonists . Here we report our findings in a series of aryl benzthiophenes.…”

The Recent Impact of Solid-Phase Synthesis on Medicinally Relevant Benzoannelated Oxygen Heterocycles

“…A small selection of biologically and pharmacologically active benzofuran compounds is shown in Figure . For example, a variety of benzofuran derivatives, such as ebenfuran I ( 1 ), have been investigated as estrogen receptor (ER) ligands . Another example is prostaglandin D2 receptor agonist 2 , which belongs to a potent new class of antiallergic agents.…”