Synthesis and evaluation of anticancer activities of 2- or 4-substituted 3-(N-benzyltriazolylmethyl)-13α-oestrone derivatives

Abstract

2- or 4-Substituted 3- N -benzyltriazolylmethyl-13α-oestrone derivatives were synthesised via bromination of ring A and subsequent microwave-assisted, Pd-catalysed C(sp 2 )–P couplings. The antiproliferative activities of the newly synthesised brominated and phosphonated compounds against a panel of human cancer cell lines (A2780, MCF-7, MDA-MB 231) were investigated by means of MTT assays. The most potent compound, the 3- N -benzyltriazolylmethyl-4-bromo-13α-oestrone derivative exerted substantial selective cell growth-inhibitory activity against A2780 cell line with a submicromolar IC 50 value. Computational calculations reveal strong interactions of the 4-bromo derivative with both colchicine and taxoid binding sites of tubulin. Disturbance of tubulin function has been confirmed by photometric polymerisation assay.

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

“…Having found functional groups responsible for the biological effect, we turned our attention to attach all crucial structural elements to the hormonally inactive 13α-oestrone core. As a result, certain derivatives were identified as dually acting agents, possessing both enzyme inhibitory and antiproliferative properties 20 , 55 . We demonstrated that a few of our potent anticancer compounds exert a direct effect on the tubulin-microtubule system by increasing the rate of tubulin polymerisation 50 , 52 , 55 .…”

“…As a result, certain derivatives were identified as dually acting agents, possessing both enzyme inhibitory and antiproliferative properties 20 , 55 . We demonstrated that a few of our potent anticancer compounds exert a direct effect on the tubulin-microtubule system by increasing the rate of tubulin polymerisation 50 , 52 , 55 . These compounds might give an important basis for the design of oestrone-based potent anticancer agents, lacking oestrogenic activity.…”

Microwave-assisted Phospha-Michael addition reactions in the 13α-oestrone series and in vitro antiproliferative properties

“…We have recently described the development of a number of potential anticancer compounds based on the hormonally inactive 13α-oestrane core 32–34 , 37 , 45 , 46 . Modifications at C-3 influenced the cytostatic properties markedly.…”

“…Modifications at C-3 influenced the cytostatic properties markedly. Introduction of a triazole moiety seemed to be highly advantageous 33 , 46 . The 3-[{1-benzyl-1 H -1,2,3-triazol-4-yl}methoxy]-13α-oestrone derivative ( 21 ) displayed substantial antiproliferative action against human cancer cell lines of gynaecological origin, with IC 50 values in the range of 0.3‒0.9 μM ( Figure 1 ) 33 .…”

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.…”