Nejvíce citovaný článek - PubMed ID 30731148
Structural modification of trilobolide for upgrading its immunobiological properties and reducing its cytotoxic action
Trilobolide and its analogues belong to the guaianolide type of sesquiterpene lactones, which are characteristic and widely distributed within the families Asteraceae and Apiaceae. Certain guaianolides are receiving continuously increasing attention for their promising sarco-endoplasmic reticulum Ca2+-ATPase (SERCA)-inhibitory activity. However, because of their alkylation capabilities, they are generally toxic. Therefore, the search for compounds with significant immunobiological properties but with decreased cytotoxicities suitable for use in immune-based pharmacotherapy is ongoing. Therefore, we extended our previous investigation of the immunobiological effects of trilobolide to a series of structurally related guaianolides and germacranolides. To evaluate the relationship, we tested a series of selected derivatives containing α-methyl lactone or exomethylene lactone ring. For a wider comparison, we also included some of their glycosidic derivatives. We assessed the in vitro immunobiological effects of the tested compounds on nitric oxide (NO) production, cytokine secretion, and prostaglandin E2 (PGE2) release by mouse peritoneal cells, activated primarily by lipopolysaccharide (LPS), and evaluated their viability. The inhibitory effects of the apparently most active substance, 8-deoxylactucin, seem to be the most promising.
- Klíčová slova
- 8-deoxylactucin, 8-epiisoamberboin, germacranolides, guaianolides, immune-modulatory effects,
- MeSH
- butyráty MeSH
- cytokiny metabolismus MeSH
- dinoproston metabolismus biosyntéza MeSH
- furany MeSH
- laktony * farmakologie chemie MeSH
- lipopolysacharidy farmakologie MeSH
- myši MeSH
- oxid dusnatý * metabolismus MeSH
- peritoneální makrofágy účinky léků metabolismus MeSH
- seskviterpeny germakranové * farmakologie chemie MeSH
- seskviterpeny guajanové * farmakologie chemie MeSH
- seskviterpeny farmakologie chemie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- butyráty MeSH
- cytokiny MeSH
- dinoproston MeSH
- furany MeSH
- germacranolide MeSH Prohlížeč
- laktony * MeSH
- lipopolysacharidy MeSH
- oxid dusnatý * MeSH
- seskviterpeny germakranové * MeSH
- seskviterpeny guajanové * MeSH
- seskviterpeny MeSH
- trilobolide MeSH Prohlížeč
Saponins, a diverse group of natural compounds, offer an interesting pool of derivatives with biomedical application. In this study, three structurally related spirostanol saponins were isolated and identified from the leek flowers of Allium porrum L. (garden leek). Two of them were identical with the already known leek plant constituents: aginoside (1) and 6-deoxyaginoside (2). The third one was identified as new component of A. porrum; however, it was found identical with yayoisaponin A (3) obtained earlier from a mutant of elephant garlic Allium ampeloprasun L. It is a derivative of the aginoside (1) with additional glucose in its glycosidic chain, identified by MS and NMR analysis as (2α, 3β, 6β, 25R)-2,6-dihydroxyspirostan-3-yl β-D-glucopyranosyl-(1 → 3)-β-D-glucopranosyl-(1 → 2)-[β-D-xylopyranosyl-(1 → 3)]-β-D-glucopyranosyl]-(1 → 4)-β-D-galactopyranoside, previously reported also under the name alliporin. The leek native saponins were tested together with other known and structurally related saponins (tomatonin and digitonin) and with their related aglycones (agigenin and diosgenin) for in vitro cytotoxicity and for effects on NO production in mouse peritoneal cells. The highest inhibitory effects were exhibited by 6-deoxyaginoside. The obtained toxicity data, however, closely correlated with the suppression of NO production. Therefore, an unambiguous linking of obtained bioactivities of saponins with their expected immunobiological properties remained uncertain.
- Klíčová slova
- Allium porrum, NO production, aginoside, alliporin, cytotoxicity, leek flowers, steroid saponins,
- MeSH
- Allium chemie MeSH
- buněčné linie MeSH
- květy chemie MeSH
- lipopolysacharidy antagonisté a inhibitory farmakologie MeSH
- molekulární konformace MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- oxid dusnatý antagonisté a inhibitory biosyntéza MeSH
- peritoneální makrofágy účinky léků metabolismus MeSH
- saponiny chemie izolace a purifikace farmakologie MeSH
- spirostany chemie izolace a purifikace farmakologie MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- lipopolysacharidy MeSH
- oxid dusnatý MeSH
- saponiny MeSH
- spirostany MeSH
In spite of the impressing cytotoxicity of thapsigargin (Tg), this compound cannot be used as a chemotherapeutic drug because of general toxicity, causing unacceptable side effects. Instead, a prodrug targeted towards tumors, mipsagargin, was brought into clinical trials. What substantially reduces the clinical potential is the limited access to Tg and its derivatives and cost-inefficient syntheses with unacceptably low yields. Laser trilobum, which contains a structurally related sesquiterpene lactone, trilobolide (Tb), is successfully cultivated. Here, we report scalable isolation of Tb from L. trilobum and a transformation of Tb to 8-O-(12-aminododecanoyl)-8-O-debutanoylthapsigargin in seven steps. The use of cultivated L. trilobum offers an unlimited source of the active principle in mipsagargin.
- Klíčová slova
- 8-O-(12-aminododecanoyl)-8-O-debutanoylthapsigargin, Laser trilobum cultivation, chemical synthesis, extraction, mipsagargin, optimization and scale-up, sarco/endoplasmic reticulum calcium ATPase (SERCA), sesquiterpene lactones, thapsigargin, trilobolide, trilobolide isolation from fruits,
- MeSH
- Apiaceae chemie metabolismus MeSH
- butyráty chemie izolace a purifikace MeSH
- furany chemie izolace a purifikace MeSH
- fytogenní protinádorové látky chemie izolace a purifikace MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádory farmakoterapie patologie MeSH
- ovoce chemie metabolismus MeSH
- oxid uhličitý chemie MeSH
- rostlinné extrakty chemie MeSH
- sarkoplazmatická Ca2+-ATPáza antagonisté a inhibitory metabolismus MeSH
- superkritická fluidní chromatografie metody MeSH
- techniky syntetické chemie * MeSH
- thapsigargin analogy a deriváty izolace a purifikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- butyráty MeSH
- furany MeSH
- fytogenní protinádorové látky MeSH
- oxid uhličitý MeSH
- rostlinné extrakty MeSH
- sarkoplazmatická Ca2+-ATPáza MeSH
- thapsigargin MeSH
- trilobolide MeSH Prohlížeč
Sesquiterpene lactones are secondary plant metabolites with sundry biological effects. In plants, they are synthesized, among others, for pesticidal and antimicrobial effects. Two such compounds, archangelolide and trilobolide of the guaianolide type, are structurally similar to the well-known and clinically tested lactone thapsigargin. While trilobolide has already been studied by us and others, there are only scarce reports on the biological activity of archangelolide. Here we present the preparation of its fluorescent derivative based on a dansyl moiety using azide-alkyne Huisgen cycloaddition having obtained the two sesquiterpene lactones from the seeds of Laserpitium archangelica Wulfen using supercritical CO2 extraction. We show that dansyl-archangelolide localizes in the endoplasmic reticulum of living cells similarly to trilobolide; localization in mitochondria was also detected. This led us to a more detailed study of the anticancer potential of archangelolide. Interestingly, we found that neither archangelolide nor its dansyl conjugate did exhibit cytotoxic effects in contrast to the structurally closely related counterparts trilobolide and thapsigargin. We explain this observation by a molecular dynamics simulation, in which, in contrast to trilobolide, archangelolide did not bind into the sarco/endoplasmic reticular calcium ATPase cavity utilized by thapsigargin. Last, but not least, archangelolide exhibited anti-inflammatory activity, which makes it promising compound for medicinal purposes.
