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/ZeitungSCORING: ZeitschriftenaufsätzeForschungBegutachtung

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@article{fcd4e064189a4469b4aed52ff089d521,
title = "Synthesis and anticancer activity of the derivatives of marine compound rhizochalin in castration resistant prostate cancer",
abstract = "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.",
keywords = "Journal Article",
author = "Dyshlovoy, {Sergey A} and Katharina Otte and Tabakmakher, {Kseniya M} and Jessica Hauschild and Makarieva, {Tatyana N} and Shubina, {Larisa K} and Fedorov, {Sergey N} and Carsten Bokemeyer and Stonik, {Valentin A} and {von Amsberg}, Gunhild",
year = "2018",
month = mar,
day = "30",
doi = "10.18632/oncotarget.24764",
language = "English",
volume = "9",
pages = "16962--16973",
journal = "ONCOTARGET",
issn = "1949-2553",
publisher = "IMPACT JOURNALS LLC",
number = "24",

}

RIS

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 articles

C2 - 29682197

VL - 9

SP - 16962

EP - 16973

JO - ONCOTARGET

JF - ONCOTARGET

SN - 1949-2553

IS - 24

ER -