Synthesis and anticancer activity of the derivatives of marine compound rhizochalin in castration resistant prostate cancer

Sergey A. Dyshlovoy; Katharina Otte; Kseniya M. Tabakmakher; Jessica Hauschild; Tatyana N. Makarieva; Larisa K. Shubina; Sergey N. Fedorov; Carsten Bokemeyer; Valentin A. Stonik; Gunhild von Amsberg

doi:10.18632/oncotarget.24764

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Research Papers:

Synthesis and anticancer activity of the derivatives of marine compound rhizochalin in castration resistant prostate cancer

Sergey A. Dyshlovoy _, Katharina Otte, Kseniya M. Tabakmakher, Jessica Hauschild, Tatyana N. Makarieva, Larisa K. Shubina, Sergey N. Fedorov, Carsten Bokemeyer, Valentin A. Stonik and Gunhild von Amsberg

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Oncotarget. 2018; 9:16962-16973. https://doi.org/10.18632/oncotarget.24764

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Abstract

Sergey A. Dyshlovoy1,2,3, Katharina Otte1, Kseniya M. Tabakmakher2, Jessica Hauschild1, Tatyana N. Makarieva2, Larisa K. Shubina2, Sergey N. Fedorov2, Carsten Bokemeyer1, Valentin A. Stonik2 and Gunhild von Amsberg1

1Laboratory of Experimental Oncology, University Medical Center Hamburg-Eppendorf, Department of Oncology, Haematology and Bone Marrow Transplantation, Section Pneumology, Hubertus Wald-Tumorzentrum, Hamburg, Germany

2Laboratory of Marine Natural Products Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russian Federation

3School of Natural Sciences, Far Eastern Federal University, Vladivostok, Russian Federation

Correspondence to:

Sergey A. Dyshlovoy, email: [email protected]

Keywords: rhizochalin; castration resistant prostate cancer; androgen receptor; AR-V7; apoptosis

Received: December 17, 2017 Accepted: February 26, 2018 Published: March 30, 2018

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.

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Research Papers:

Synthesis and anticancer activity of the derivatives of marine compound rhizochalin in castration resistant prostate cancer

Abstract