2. Academic Validation
  3. Synthesis and new DNA targeting activity of 6- and 7-tert-butylfascaplysins

Synthesis and new DNA targeting activity of 6- and 7-tert-butylfascaplysins

  • Sci Rep. 2024 May 23;14(1):11788. doi: 10.1038/s41598-024-62358-8.
Sergey A Dyshlovoy 1,  Wael Y Mansour 2 3,  Natalia A Ramm 4,  Jessica Hauschild 5,  Maxim E Zhidkov 4,  Malte Kriegs 2 6,  Alexandra Zielinski 2,  Konstantin Hoffer 2 6,  Tobias Busenbender 5,  Ksenia A Glumakova 7,  Pavel V Spirin 7 8,  Vladimir S Prassolov 7 8,  Derya Tilki 9 10 11,  Markus Graefen 11,  Carsten Bokemeyer 5,  Gunhild von Amsberg 5 11
Affiliations

Affiliations

  • 1 Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. s.dyshlovoy@uke.de.
  • 2 Department of Radiotherapy and Radiation Oncology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
  • 3 Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
  • 4 Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, Far Eastern Federal University, FEFU Campus, Ajax Bay 10, 690922, Vladivostok, Russky Island, Russian Federation.
  • 5 Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
  • 6 UCCH Kinomics Core Facility, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
  • 7 Department of Cancer Cell Biology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, 119991, Moscow, Russian Federation.
  • 8 Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, 119991, Moscow, Russian Federation.
  • 9 Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
  • 10 Department of Urology, Koc University Hospital, 34010, Istanbul, Turkey.
  • 11 Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
PMID: 38783016 DOI: 10.1038/s41598-024-62358-8
Abstract

Fascaplysin is a red cytotoxic pigment with Anticancer properties isolated from the marine Sponge Fascaplysinopsis sp. Recently, structure-activity relationship analysis reported by our group suggested that selective cytotoxicity of fascaplysin derivatives towards tumor cells negatively correlates with their ability to intercalate into DNA. To validate this hypothesis, we synthesized 6- and 7-tert-butylfascaplysins which reveal mitigated DNA-intercalating properties. These derivatives were found to be strongly cytotoxic to drug-resistant human prostate Cancer cells, albeit did not demonstrate improved selectivity towards Cancer cells when compared to fascaplysin. At the same time, kinome analysis suggested an activation of Chk1/ATR axis in Cancer cells shortly after the drug exposure. Further experiments revealed induction of replication stress that is eventually converted to the toxic DNA double-strand breaks, resulting in caspase-independent apoptosis-like cell death. Our observations highlight new DNA-targeting effect of some fascaplysin derivatives and indicate more complex structure-activity relationships within the fascaplysin family, suggesting that cytotoxicity and selectivity of these Alkaloids are influenced by multiple factors. Furthermore, combination with clinically-approved inhibitors of ATR/Chk1 as well as testing in tumors particularly sensitive to the DNA damage should be considered in further studies.

Keywords

DNA targeting; Fascaplysin; Marine compound; Natural products; Prostate cancer; Synergism; Synthesis.

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