Structure–Activity Relationships of C-17 Cyano-Substituted Estratrienes as Anticancer Agents

Abstract

The synthesis, SAR, and preclinical evaluation of 17-cyanated 2-substituted estra-1,3,5(10)-trienes as anticancer agents are discussed. 2-Methoxy-17beta-cyanomethylestra-1,3,5(10)-trien-3-ol ( 14), but not the related 2-ethyl derivative 7, and the related 3- O-sulfamates 8 and 15 display potent antiproliferative effects (MCF-7 GI 50 300, 60 and 70 nM, respectively) against human cancer cells in vitro. Investigation of the SAR reveals that a sterically unhindered hydrogen bond acceptor attached to C-17 is most likely key to the enhanced activity. Compound 8 displayed significant in vitro antiangiogenic activity, and its ability to act as a microtubule disruptor was confirmed. Inhibitory activity of the sulfamate derivatives against steroid sulfatase and carbonic anhydrase II (hCAII) was also observed, and the interaction between 15 and hCAII was investigated by protein crystallography. The potential of these multimechanism anticancer agents was confirmed in vivo, with promising activity observed for both 14 and 15 in an athymic nude mouse MDA-MB-231 human breast cancer xenograft model.

Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations

“…Crystal structure of hCA II in complex with compound 3 was determined at 1.80 Å resolution, revealing a clear electron density for the inhibitor molecule in the enzyme active site (Figure 2 [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] , compound 1 interacts directly with the zinc ion of the active site, with its sulphamate nitrogen atom N1 (for atom numbering see Figure 1) displacing the water molecule/hydroxide ion, which in the not-inhibited enzyme occupies the fourth coordination position. Additional hydrogen bonds between the sulphamate moiety and residues within the enzyme active site contribute to stabilise the binding.…”

“…To understand if the different position assumed by N2 and O3 atoms in the enzyme active site was associated to a peculiarity of the two complexes under investigation, or to a more general behaviour of sulphamate and sulphamide derivatives, a comparative analysis of all hCA II/sulphamate and hCA II/sulphamide structures available in the PDB was undertaken 25,26,[49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][67][68][69][70][71] . Surprisingly, the analysis of all these structures revealed that, independently of the nature of the moiety attached to the ZBG, the distance between the Thr200OG1 atom and the sulphamide nitrogen N2 in hCA II/sulphamide complexes was generally shorter than the corresponding distance between the sulphamate oxygen O3 and the same enzyme atom in hCA II/sulphamate complexes (see Tables 3 and 4).…”

Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography

“…These include steroid sulfatase inhibitors EMATE (39) and STX64 (40), two examples of a dual aromatase sulfatase inhibitor (41), 2-MeOE2bisMATE, a multitargeted antitumor agent (37), and a related agent STX641 (42). Given the excellent potency of (4) against hCAII, we explored cocrystallization of (4) with the enzyme and now report the interaction of this compound with hCAII using protein crystallography (Fig.…”

Design and Synthesis of Non-peptide RGD Mimics for Evaluation of Their Utility as Anti-platelet Agents

“…The indene core compound 3d was also synthesized from a Hajos-Parrish ketone (6), 35,36) following the same procedure as described for compound 3c (Chart 5).…”