A New Mild Method for Synthesis of Marine Alkaloid Fascaplysin and Its Therapeutically Promising Derivatives
Oleg A. Tryapkin,
Alexey V. Kantemirov,
Sergey A. Dyshlovoy,
Vladimir S. Prassolov,
Pavel V. Spirin,
Gunhild von Amsberg,
Maria A. Sidorova,
Maxim E. Zhidkov
Affiliations
Oleg A. Tryapkin
Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia
Alexey V. Kantemirov
Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia
Sergey A. Dyshlovoy
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
Vladimir S. Prassolov
Department of Cancer Cell Biology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, 119991 Moscow, Russia
Pavel V. Spirin
Department of Cancer Cell Biology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova 32, 119991 Moscow, Russia
Gunhild von Amsberg
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
Maria A. Sidorova
Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia
Maxim E. Zhidkov
Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia
Fascaplysin is a marine alkaloid which is considered to be a lead drug candidate due to its diverse and potent biological activity. As an anticancer agent, fascaplysin holds a great potential due to the multiple targets affected by this alkaloid in cancer cells, including inhibition of cyclin-dependent kinase 4 (CDK4) and induction of intrinsic apoptosis. At the same time, the studies on structural optimization are hampered by its rather high toxicity, mainly caused by DNA intercalation. In addition, the number of methods for the syntheses of its derivatives is limited. In the current study, we report a new two-step method of synthesis of fascaplysin derivatives based on low temperature UV quaternization for the synthesis of thermolabile 9-benzyloxyfascaplysin and 6-tert-butylfascaplysin. 9-Benzyloxyfascaplysin was used as the starting compound to obtain 9-hydroxyfascaplysin. However, the latter was found to be chemically highly unstable. 6-tert-Butylfascaplysin revealed a significant decrease in DNA intercalation when compared to fascaplysin, while cytotoxicity was only slightly reduced. Therefore, the impact of DNA intercalation for the cytotoxic effects of fascaplysin and its derivatives needs to be questioned.
