Synthesis and anticancer activity of the derivatives of marine compound rhizochalin in castration resistant prostate cancer
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Synthesis and anticancer activity of the derivatives of marine compound rhizochalin in castration resistant prostate cancer. / Dyshlovoy, Sergey A; Otte, Katharina; Tabakmakher, Kseniya M; Hauschild, Jessica; Makarieva, Tatyana N; Shubina, Larisa K; Fedorov, Sergey N; Bokemeyer, Carsten; Stonik, Valentin A; von Amsberg, Gunhild.
in: ONCOTARGET, Jahrgang 9, Nr. 24, 30.03.2018, S. 16962-16973.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Synthesis and anticancer activity of the derivatives of marine compound rhizochalin in castration resistant prostate cancer
AU - Dyshlovoy, Sergey A
AU - Otte, Katharina
AU - Tabakmakher, Kseniya M
AU - Hauschild, Jessica
AU - Makarieva, Tatyana N
AU - Shubina, Larisa K
AU - Fedorov, Sergey N
AU - Bokemeyer, Carsten
AU - Stonik, Valentin A
AU - von Amsberg, Gunhild
PY - 2018/3/30
Y1 - 2018/3/30
N2 - Development of resistance to standard therapies complicates treatment of advanced prostate cancer. Alternative splicing variants of the androgen receptor (AR), e.g. AR-V7 can mediate resistance to AR-targeting substances abiraterone and enzalutamide. Semi-synthetic marine natural compound rhizochalinin decreases the expression of AR-V7 in human castration-resistant prostate cancer cells and thus resensitizes cells to enzalutamide. In the current study, we modified the structure of rhizochalin in order to determine structure-activity relationships (SAR) and optimize anticancer properties. Thus, we synthesized new 18-hydroxy- and 18-aminorhizochalins and its aglycones. All compounds exhibited anticancer properties in human castration-resistant prostate cancer cells, induced apoptosis and G2/M cell cycle arrest, and were capable of autophagy inhibition. SAR analysis showed an increase of pro-apoptotic activity in the row 18-amino < 18-hydroxy < 18-keto derivatives. In general, aglycones were more cytotoxic compared to glycosides. The sugar elimination was critical for the ability to suppress AR-signaling. Rhizochalinin (2) and 18-hydroxyrhizochalinin (4) were identified as the most promising derivatives and are promoted for further development.
AB - Development of resistance to standard therapies complicates treatment of advanced prostate cancer. Alternative splicing variants of the androgen receptor (AR), e.g. AR-V7 can mediate resistance to AR-targeting substances abiraterone and enzalutamide. Semi-synthetic marine natural compound rhizochalinin decreases the expression of AR-V7 in human castration-resistant prostate cancer cells and thus resensitizes cells to enzalutamide. In the current study, we modified the structure of rhizochalin in order to determine structure-activity relationships (SAR) and optimize anticancer properties. Thus, we synthesized new 18-hydroxy- and 18-aminorhizochalins and its aglycones. All compounds exhibited anticancer properties in human castration-resistant prostate cancer cells, induced apoptosis and G2/M cell cycle arrest, and were capable of autophagy inhibition. SAR analysis showed an increase of pro-apoptotic activity in the row 18-amino < 18-hydroxy < 18-keto derivatives. In general, aglycones were more cytotoxic compared to glycosides. The sugar elimination was critical for the ability to suppress AR-signaling. Rhizochalinin (2) and 18-hydroxyrhizochalinin (4) were identified as the most promising derivatives and are promoted for further development.
KW - Journal Article
U2 - 10.18632/oncotarget.24764
DO - 10.18632/oncotarget.24764
M3 - SCORING: Journal article
C2 - 29682197
VL - 9
SP - 16962
EP - 16973
JO - ONCOTARGET
JF - ONCOTARGET
SN - 1949-2553
IS - 24
ER -
