A New Mild Method for Synthesis of Marine Alkaloid Fascaplysin and Its Therapeutically Promising Derivatives
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A New Mild Method for Synthesis of Marine Alkaloid Fascaplysin and Its Therapeutically Promising Derivatives. / Tryapkin, Oleg A; Kantemirov, Alexey V; Dyshlovoy, Sergey A; Prassolov, Vladimir S; Spirin, Pavel V; von Amsberg, Gunhild; Sidorova, Maria A; Zhidkov, Maxim E.
in: MAR DRUGS, Jahrgang 21, Nr. 8, 424, 25.07.2023.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A New Mild Method for Synthesis of Marine Alkaloid Fascaplysin and Its Therapeutically Promising Derivatives
AU - Tryapkin, Oleg A
AU - Kantemirov, Alexey V
AU - Dyshlovoy, Sergey A
AU - Prassolov, Vladimir S
AU - Spirin, Pavel V
AU - von Amsberg, Gunhild
AU - Sidorova, Maria A
AU - Zhidkov, Maxim E
PY - 2023/7/25
Y1 - 2023/7/25
N2 - 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.
AB - 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.
KW - Alkaloids/pharmacology
KW - Antineoplastic Agents/pharmacology
KW - Carbolines
KW - DNA
U2 - 10.3390/md21080424
DO - 10.3390/md21080424
M3 - SCORING: Journal article
C2 - 37623705
VL - 21
JO - MAR DRUGS
JF - MAR DRUGS
SN - 1660-3397
IS - 8
M1 - 424
ER -
