Synthesis of novel sclareol derivatives and evaluation of their anticancer activity
2022
Аутори:
Stojković, PavleStepanović, Ana
Terzić Jovanović, Nataša
Novaković, Miroslav
Trendafilova, Antoaneta
Pešić, Milica
Opsenica, Igor M.
Остала ауторства
Silva, Artur M. S.Galvão, Adelino M.
Machado, Bruno F.
Faria, Joaquim L.
Тип документа:
Конференцијски прилог (Објављена верзија)
,
© 2022 by the Sociedade Portuguesa de Química
Метаподаци
Приказ свих података о документуАпстракт:
Sclareol is a labdane diterpenoid found in clary sage (Salvia sclarea L.) with various biological activities,
most notably anticancer and cytotoxic activity [1]. There are several examples of synthetic derivatives
of sclareol with antischistosomal [2], antifungal [3], and anticancer activity [4]. Since it is known that
modifications of biologically active molecules can lead to the improvement of physicochemical
properties and modes of interactions with target cells, we have envisioned the derivatization of sclareol
to obtain molecules with more potent cytotoxic activity.
Sclareol used as a starting material in this research was isolated from Clary sage harvested in Bulgaria.
New compounds were obtained by derivatization of sclareol at its Δ14,15 double bond using oxidative
Heck coupling catalyzed by palladium-acetate with copper(II)-acetate as oxidant, followed by the
introduction of different diamine-moieties. Finally, the terminal amino-group was coupled with a
nitrogen-rich heterocycle to obtain desired compounds. During the course of the synthesis, both tertiary
and tertiary allylic hydroxyl groups remained unchanged, which was of particular interest, since it was
shown that the tertiary allylic group is crucial for the biological activity of sclareol.
Synthesized compounds were tested on human cancer cell lines, primarily glioblastoma cells. It was
shown that certain derivatives have caused a significant reduction of glioblastoma cell viability at low
concentrations. Moreover, some derivatives inhibited cell membrane transporter P-glycoprotein (P-gp)
responsible for multidrug resistance and increased accumulation of doxorubicin to the same extent as
tariquidar (a well-known P-gp inhibitor). Most importantly, novel molecules exhibited more potent
biological activity than sclareol itself.
Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200168 (Универзитет у Београду, Хемијски факултет) (RS-MESTD-inst-2020-200168)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200026 (Универзитет у Београду, Институт за хемију, технологију и металургију - ИХТМ) (RS-MESTD-inst-2020-200026)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200007 (Универзитет у Београду, Институт за биолошка истраживања 'Синиша Станковић') (RS-MESTD-inst-2020-200007)
У:
- Silva AMS, Galvão AM, Machado BF, Faria JL, editors. Abstract Book: 8th EuChemS Chemistry Congress; 2022 Aug 28 - Sep 1; Lisbon, Portugal. Sociedade Portuguesa de Química; 2022. p. 604.