Abstract
This work demonstrates the effects of a newly synthesized conjugate of the plant triterpenoid betulin and the penetrating cation F16 used for mitochondrial targeting. The resulting F16-betulin conjugate revealed a mitochondria-targeted effect, decreasing the mitochondrial potential and inducing superoxide overproduction in rat thymocytes in vitro. It has been suggested that this may cause the cytotoxic effect of the conjugate, which significantly exceeds the effectiveness of its precursors, betulin and F16. Using isolated rat liver mitochondria, we found that the F16-betulin conjugate has a surface-active effect on mitochondrial membranes, causing organelle aggregation. This effect of the derivative resulted in a dose-dependent decrease in mitochondrial transmembrane potential, as well as suppression of respiration and oxidative phosphorylation, especially in the case of nicotinamide adenine dinucleotide (NAD)-fueled organelles. In addition, the F16-betulin conjugate caused an increase in H2O2 generation by mitochondria fueled with glutamate and malate. These effects of the derivative can presumably be due to the powerful suppression of the redox activity of complex I of the mitochondrial electron transport chain. The paper discusses how the mitochondria-targeted effects of the F16-betulin conjugate may be related to its cytotoxic effects.
Highlights
Triterpenoids, widespread in the plant kingdom, are well-known modifiers of biological and artificial membranes [1]
The main chemical agents successfully used to create hybrid molecules that can be targeted to mitochondria include delocalized lipophilic cationic compounds (DLCs) such as rhodamine 123, F16, MKT-077, and lipophilic cationic dequalinium and triphenylphosphonium salts [11,12,13,14,15,16,17,18]
It is known that native betulin, as well as F16, have an antitumor effect [22,33], while their effectiveness is significantly increased by combining into a hybrid conjugate that
Summary
Triterpenoids, widespread in the plant kingdom, are well-known modifiers of biological and artificial membranes [1]. The main chemical agents successfully used to create hybrid molecules that can be targeted to mitochondria include delocalized lipophilic cationic compounds (DLCs) such as rhodamine 123, F16, MKT-077, and lipophilic cationic dequalinium and triphenylphosphonium salts [11,12,13,14,15,16,17,18]. Available natural pentacyclic triterpenoids, represented by betulin, The main chemical agents successfully used to create hybrid molecules that can be targeted to mitochondria include delocalized lipophilic cationic compounds (DLCs)2soufc1h4 as rhodamine 123, F16, MKT-077, and lipophilic cationic dequalinium and triphenylphosphonium salts [11,12,13,14,15,16,17,18]. Oisninegopf ethneetprartoimngisciantgiopnesnsehtorawtiinngg cmaittioonchsosnhdowriainl gtamrgietoticnhgonisdtrhiaelltiaprogpehtiinligcidsethloeclaipliozepdhiFli1c6dcealoticoanlizeexdhiFb1it6incagtiaonntiecxahnicbeirtiancgatinvtiitcyanincetrheacfrtieveitfyorimn t[h2e2]f,rweehficohrm, ho[2w2]e,vwerh, iicshm, hanoiwfoelvdelry, eisnhmaannciefdoludplyonenhhyabnrcieddizuatpioonn hwyitbhritdriitzeartpioennews.itIhntdreiteedr,pweneerse.cIenndtelyedf,owunedretcheanttclyonfojuugnadtetshaotf cFo1n6juangadtepshoafrmF1a6caonlodgpichaallrymacaticvoelobgeitcuallilnyiaccatcivide bheatvuelianitcaragceidtehdaevfefeacttaorngemteidtoecfhfeocntdorniam, iintodcuhcoinngdrRiaO, SinodvuecripnrgoRdOucSotivoenrparnoddpuecrtimonebailnidzaptieornmoefboilrigzaantieolnleomf eomrgbarnaenllees m[6e].mInbraadndesiti[o6n]., Iwneahdadviteiosny,nwtheeshizaevde sthyentchoensjiuzgedattehoefcnoantjiuvgeabteetouflinnatainvde bFe1t6u(lFinigaunrde F11)6an(Fdigduerme o1n) astnrdatdedemthoantsstruabtmedictrhoamt soulabrmcoincrcoemntoralatirocnosnocfenthtrisataiognens tohf athdisaapgoewntehrfaudl aanptoitwumerofurleafnfetcittu, msigonriefifcfeacntt,lsyigenxcifeiceadnintlgy tehxecaecetidviintyg othf ethaectpivariteyntofF1th6ecpatairoenn(t>F81060ctaimtioens)([>2830]0. times) [23]
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