Abstract
First-generation nonsteroidal androgen receptor (AR) antagonists, such as flutamide (2a) and bicalutamide (3), are effective for most prostate cancer patients, but resistance often appears after several years due to the mutation of AR. Second-generation AR antagonists are effective against some of these castration-resistant prostate cancers, but their structural variety is still limited. In this study, we designed and synthesized 4-methyl-7-(N-alkyl-arylcarboxamido)coumarins as AR antagonist candidates and evaluated their growth-inhibitory activity toward androgen-dependent SC-3 cells. Coumarinamides with a secondary amide bond did not show inhibitory activity, but their N-methylated derivatives exhibited AR-antagonistic activity. Especially, 19b and 31b were more potent than the lead compound 7b, which was comparable to hydroxyflutamide (2b). Conformational analysis showed that the inactive coumarinamides with a secondary amide bond have an extended structure with a trans-amide bond, while the active N-methylated coumarinamides have a folded structure with a cis-amide bond, in which the two aromatic rings are placed face-to-face. Docking study suggested that this folded structure is important for binding to AR. Selected coumarinamide derivatives showed AR-antagonistic activity toward LNCaP cells with T877A AR, and they had weak progesterone receptor (PR)-antagonistic activity. The folded coumarinamide structure appears to be a unique pharmacophore, different from those of conventional AR antagonists.
Highlights
IntroductionAndrogen receptor (AR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily [1,2], and its endogenous ligands, so-called androgens, are testosterone (1a)
Androgen receptor (AR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily [1,2], and its endogenous ligands, so-called androgens, are testosterone (1a)(see Supplementary Materials) and dihydrotestosterone (DHT, 1b) (Figure 1)
7-(N-methyl-benzoylamino) moiety showed with rather low coumarin compound library, and we found that compound 7b bearing a
Summary
Androgen receptor (AR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily [1,2], and its endogenous ligands, so-called androgens, are testosterone (1a). These antagonists enzalutamide (4) [16,17], apalutamide [18,19], and darolutamide [20] These AR have the same pharmacophore as the lead compounds, flutamide (2a) and bicalutamide (3), and they antagonists have the same pharmacophore as the lead compounds, flutamide (2a) and bicalutamide contain an anilide structure with electron-withdrawing functional groups on the phenyl ring Coumarinthe ring providesring an progesterone (PR)(Figure antagonists In these the compounds, coumarin alternative hydrophobic core structure to the sterane ring of steroidal derivatives or to the bicyclic anilide provides an alternative hydrophobic core structure to the sterane ring of steroidal derivatives or to scaffold of known nonsteroidal. 5 and 6 with (PR)-antagonistic (PR)-antagonistic activity and (b) androgen receptor (AR)-antagonistic coumarin activity and (b) androgen receptor (AR)-antagonistic coumarin 7
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