Sintokamides A to E, Chlorinated Peptides from the Sponge Dysidea sp. that Inhibit Transactivation of the N-Terminus of the Androgen Receptor in Prostate Cancer Cells

Abstract

The new chlorinated peptides sintokamides A to E (1-5) have been isolated from specimens of the marine sponge Dysidea sp. collected in Indonesia. Their structures were elucidated by a combination of spectroscopic and single-crystal X-ray diffraction analyses. Sintokamide A (1) is an inhibitor of N-terminus transactivation of the androgen receptor in prostate cancer cells.

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“…EPI-001 also inhibited constitutively active AR devoid of an LBD [35], which implies that it may have use in combating the splice variants of the AR that may mediate abiraterone resistance. EPI-001 does not reduce levels of AR protein nor does it prevent nuclear translocation of the AR in response to androgen [35]. Other androgen-directed agents that are in development include AR antagonists (ODM-201, Clinicaltrials.gov NCT01317641) and AR production inhibitors (ZD 3514, Clinicaltrials.gov NCT01162395).…”

“…Deletion experiments have shown that the N-terminal domain is essential for transcriptional activity of the AR in response to ligand as well as in the absence of ligand [34]. EPI-001 inhibits AR activity induced by a variety of non-canonical activators such as forskolin, IL-6, and by factors secreted by osteoblasts (bone-derived factors [35]). EPI-001 also inhibited constitutively active AR devoid of an LBD [35], which implies that it may have use in combating the splice variants of the AR that may mediate abiraterone resistance.…”

“…EPI-001 inhibits AR activity induced by a variety of non-canonical activators such as forskolin, IL-6, and by factors secreted by osteoblasts (bone-derived factors [35]). EPI-001 also inhibited constitutively active AR devoid of an LBD [35], which implies that it may have use in combating the splice variants of the AR that may mediate abiraterone resistance. EPI-001 does not reduce levels of AR protein nor does it prevent nuclear translocation of the AR in response to androgen [35].…”

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“…Senyawa celebesides A dan C tersebut mempunyai aktivitas sebagai anti tumor dan anti ?HIV. Senyawa Sintokamide A yang merupakan inhibitor transaktivasi N?terminal dari reseptor androgen pada kanker prostate telah diisolasi oleh Sadar et al (2008) dari spons Dysidea sp. asal Indonesia.…”

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“…Also, there are two new classes of small molecules isolated from sponge (Dysidea sp.) extract that exhibit anti-AR activity (Andersen et al, 2010;Quayle et al, 2007;Sadar, 2011;Sadar et al, 2008). One type of these sponge compounds are small chlorinated peptide called sintokamides, and the other is EPI-001 (i.e., bisphenol A diglycidic ether.HCl.H 2 O).…”