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

TY - JOUR

T1 - Synthesis and new DNA targeting activity of 6- and 7-tert-butylfascaplysins

AU - Dyshlovoy, Sergey A

AU - Mansour, Wael Y

AU - Ramm, Natalia A

AU - Hauschild, Jessica

AU - Zhidkov, Maxim E

AU - Kriegs, Malte

AU - Zielinski, Alexandra

AU - Hoffer, Konstantin

AU - Busenbender, Tobias

AU - Glumakova, Ksenia A

AU - Spirin, Pavel V

AU - Prassolov, Vladimir S

AU - Tilki, Derya

AU - Graefen, Markus

AU - Bokemeyer, Carsten

AU - von Amsberg, Gunhild

N1 - © 2024. The Author(s).

PY - 2024/5/23

Y1 - 2024/5/23

N2 - 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.

AB - 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.

KW - Humans

KW - Cell Line, Tumor

KW - Antineoplastic Agents/pharmacology

KW - Checkpoint Kinase 1/metabolism

KW - Indoles/pharmacology

KW - Apoptosis/drug effects

KW - Structure-Activity Relationship

KW - Male

KW - Ataxia Telangiectasia Mutated Proteins/metabolism

KW - DNA/metabolism

KW - Animals

KW - DNA Breaks, Double-Stranded/drug effects

KW - Quaternary Ammonium Compounds

KW - Carbolines

KW - Indolizines

U2 - 10.1038/s41598-024-62358-8

DO - 10.1038/s41598-024-62358-8

M3 - SCORING: Journal article

C2 - 38783016

VL - 14

SP - 11788

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

ER -