New selenosteroids as antiproliferative agents

Abstract

Starting from natural steroids (diosgenin, hecogenin, smilagenin, estrone), we have prepared a wide panel of selenoderivatives, including benzoselenazolones, selenosemicarbazones, isoselenocyanates, selenoureas, selenocyanates and diselenides, with the aim of developing new families of potential chemotherapeutic agents. The modification of the organoselenium moieties, and their position on the steroid provided valuable information concerning the antiproliferative activities. Among all the families accessed herein, the best profile was achieved for selenoureas on the A ring of estrone, which exhibited GI values in the range 2.0-4.1 μM for all the tested tumor cell lines, with increased potency compared with commonly used chemotherapeutic agents, like 5-fluorouracil and cisplatin. Cell cycle analysis revealed that selenoureas induced accumulation of cells in the G phase of the cell cycle in the breast cancer cell lines HBL-100 and T-47D; therefore, a different mechanism than cisplatin, that induces cell cycle accumulation in the S phase as a result of DNA damage, must be involved. In the rest of the tumor cells, a slight increase of the S compartment was observed. Moreover, selenosteoids turned out to be excellent glutathione peroxidase (GPx) mimics for the catalytic removal of deleterious HO (t 8.0-22.5 min) and alkyl peroxides (t 23.0-38.9 min) when used in substoichiometric amounts (1% molar ratio), thus providing a valuable tool for reducing the intrinsic oxidative stress in tumor progression.

Selenides and Diselenides: A Review of Their Anticancer and Chemopreventive Activity

“…When evaluating the GPx-like activity of a group of selenosteroids ( 26 and 27 , among others), Fuentes-Aguilar et al [ 67 ] found that the GPx-like activity was under that of ebselen for all the compounds considered.…”

“…For estrone and diosgenin-based diselenides ( 26 and 27 ) , the in vitro antiproliferative activity against a panel of six human solid tumor cell lines, when tested up to a 100 µM concentration, was negligible [ 67 ]. Cancer cell lines included non-small cell lung (A549 and SW1573), breast (HBL-100 and T-47D), cervix (HeLa) and colon (WiDr) [ 67 ].…”

“… Synthetic diselenides and related selenides or selenols with antioxidant and/or prooxidant studies [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. …”

The first Pd-catalyzed Buchwald–Hartwig aminations at C-2 or C-4 in the estrone series

“…Literature reveals that besides the inversion of C-13, the introduction of an amino group onto C-2 or C-4 of estrone also leads to significant decreases in its binding affinity for nuclear estrogen receptors (ERα and ERβ) [ 28 ]. Certain derivatives of 2- or 4-aminoestrone or their 3-methyl ether possess diverse biological activities, including enzyme inhibitory or antiproliferative properties [ 1 – 3 29 – 30 ]. The 17β-HSD1 enzyme is responsible for the reduction of estrone into 17β-estradiol, which may enhance the proliferation of tumor cells [ 31 ].…”

The Influence of O/S Exchange on the Biocatalytical Activity of Benzisoselenazol-3(2H)-ones

“…To increase the activity and selectivity of ebselen, various modifications of its structure were efficiently conducted by several research groups. Promising results exposed the significant potential in this field of organoselenium chemistry [15][16][17][18][19]. However, there are only few examples of derivatives bearing a sulfur atom in the place of oxygen [20].…”