Transition metal-catalysed A-ring C–H activations and C(sp²)–C(sp²) couplings in the 13α-oestrone series and in vitro evaluation of antiproliferative properties

Abstract

Facile syntheses of 3-O-carbamoyl, -sulfamoyl, or -pivaloyl derivatives of 13a-oestrone and its 17-deoxy counterpart have been carried out. Microwave-induced, Ni-catalysed Suzuki-Miyaura couplings of the newly synthesised phenol esters with phenylboronic acid afforded 3-deoxy-3-phenyl-13a-oestrone derivatives. The carbamate and pivalate esters proved to be suitable for regioselective arylations. 2-(4-Substituted) phenyl derivatives were synthesised via Pd-catalysed, microwave-assisted C-H activation reactions. An efficient, one-pot, tandem methodology was elaborated for the introduction of the carbamoyl or pivaloyl group followed by regioselective C-2-arylation and subsequent removal of the directing group. The antiproliferative properties of the novel 13a-oestrone derivatives were evaluated in vitro on five human adherent cancer cell lines of gynaecological origin. 3-Sulfamate derivatives displayed substantial cell growth inhibitory potential against certain cell lines. The newly identified antiproliferative compounds having hormonally inactive core might be promising candidates for the design of more active anticancer agents.

Investigation of the Antineoplastic Effects of 2-(4-Chlorophenyl)-13α-Estrone Sulfamate against the HPV16-Positive Human Invasive Cervical Carcinoma Cell Line SiHa

“…The tested steroidal sulfamates (13AES1-3, Figure 1 ) were synthesized as described previously in detail [ 28 ]. For all in vitro experiments, 10 µM stock solutions of the test compounds were prepared with dimethyl sulfoxide (DMSO).…”

“…The antiproliferative properties of the test compounds were determined on a panel of human gynecological cancer cell lines and were reported previously [ 28 ]. These previous results were now completed with assays on cells from breast (T47-D) and cervical (C33A) cancer using the same protocol.…”

“…Certain estrone sulfamates possess anticancer activity on triple-negative breast cancer cells as well [ 27 ]. We have recently demonstrated that the introduction of a sulfamoyl moiety at the 3-OH or C-2–phenylation of 13α-estrone (13AES1–3, Figure 1 ) results in marked cell growth-inhibitory action against breast, ovarian and cervical cancer cell lines [ 28 ]. The 2-(4-chlorophenyl)-3- O -sulfamoyl derivative (13AES3) was found to be superior in terms of its antiproliferative activity against the HPV16-positive SiHa cell line.…”

Synthesis and Antiproliferative Activity of Steroidal Diaryl Ethers

“…The group of 13α-estrone derivatives proved to be promising concerning their enzyme inhibitory and/or antiproliferative properties. However, their biological activity greatly depends on their structure [ 33 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. We have observed that the substitution pattern of ring A influences bioactivity markedly.…”

“…Consequently, triazole derivative 11b might be considered as an MSA agent with remarkable tumor selectivity concerning the cell lines investigated. More recently we have shown that 3-deoxy-3-phenyl-13α-estra-1,3,5(10)-triene ( 12 ) displays weak antiproliferative action [ 47 ]. This observation suggests that direct phenylation at C-3 by the simultaneous removal of the hydroxy group is detrimental regarding the antiproliferative action.…”