Mitocanic Di- and Triterpenoid Rhodamine B Conjugates

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2020 Nov 25

PMID 33233650

Citations 18

Authors

Sophie Hoenke

Immo Serbian

Hans-Peter Deigner

Rene Csuk

Affiliations

Soon will be listed here.

Abstract

The combination of the "correct" triterpenoid, the "correct" spacer and rhodamine B () seems to be decisive for the ability of the conjugate to accumulate in mitochondria. So far, several triterpenoid rhodamine B conjugates have been prepared and screened for their cytotoxic activity. To obtain cytotoxic compounds with EC values in a low nano-molar range combined with good tumor/non-tumor selectivity, the Rho B unit has to be attached via an amine spacer to the terpenoid skeleton. To avoid spirolactamization, secondary amines have to be used. First results indicate that a homopiperazinyl spacer is superior to a piperazinyl spacer. Hybrids derived from maslinic acid or tormentic acid are superior to those from oleanolic, ursolic, glycyrrhetinic or euscaphic acid. Thus, a tormentic acid-derived conjugate , holding a homopiperazinyl spacer can be regarded, at present, as the most promising candidate for further biological studies.

Citing Articles

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References

Fiers W, Beyaert R, Declercq W, Vandenabeele P . More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene. 2000; 18(54):7719-30. DOI: 10.1038/sj.onc.1203249. View

Ye Y, Zhang T, Yuan H, Li D, Lou H, Fan P . Mitochondria-Targeted Lupane Triterpenoid Derivatives and Their Selective Apoptosis-Inducing Anticancer Mechanisms. J Med Chem. 2017; 60(14):6353-6363. DOI: 10.1021/acs.jmedchem.7b00679. View

Barut B, Yalcin C, Sari S, Coban O, Keles T, Biyiklioglu Z . Novel water soluble BODIPY compounds: Synthesis, photochemical, DNA interaction, topoisomerases inhibition and photodynamic activity properties. Eur J Med Chem. 2019; 183:111685. DOI: 10.1016/j.ejmech.2019.111685. View

Siewert B, Pianowski E, Obernauer A, Csuk R . Towards cytotoxic and selective derivatives of maslinic acid. Bioorg Med Chem. 2013; 22(1):594-615. DOI: 10.1016/j.bmc.2013.10.047. View

Grymel M, Zawojak M, Adamek J . Triphenylphosphonium Analogues of Betulin and Betulinic Acid with Biological Activity: A Comprehensive Review. J Nat Prod. 2019; 82(6):1719-1730. DOI: 10.1021/acs.jnatprod.8b00830. View

Wolfram R, Heller L, Csuk R . Targeting mitochondria: Esters of rhodamine B with triterpenoids are mitocanic triggers of apoptosis. Eur J Med Chem. 2018; 152:21-30. DOI: 10.1016/j.ejmech.2018.04.031. View

Brandes B, Koch L, Hoenke S, Deigner H, Csuk R . The presence of a cationic center is not alone decisive for the cytotoxicity of triterpene carboxylic acid amides. Steroids. 2020; 163:108713. DOI: 10.1016/j.steroids.2020.108713. View

Nguyen C, Pandey S . Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells. Cancers (Basel). 2019; 11(7). PMC: 6678564. DOI: 10.3390/cancers11070916. View

Neuzil J, Wang X, Dong L, Low P, Ralph S . Molecular mechanism of 'mitocan'-induced apoptosis in cancer cells epitomizes the multiple roles of reactive oxygen species and Bcl-2 family proteins. FEBS Lett. 2006; 580(22):5125-9. DOI: 10.1016/j.febslet.2006.05.072. View

10.

Singh Y, Viswanadham K, Pawar V, Meher J, Jajoriya A, Omer A . Induction of Mitochondrial Cell Death and Reversal of Anticancer Drug Resistance via Nanocarriers Composed of a Triphenylphosphonium Derivative of Tocopheryl Polyethylene Glycol Succinate. Mol Pharm. 2019; 16(9):3744-3759. DOI: 10.1021/acs.molpharmaceut.9b00177. View

11.

Rohlena J, Dong L, Ralph S, Neuzil J . Anticancer drugs targeting the mitochondrial electron transport chain. Antioxid Redox Signal. 2011; 15(12):2951-74. DOI: 10.1089/ars.2011.3990. View

12.

Ralph S, Rodriguez-Enriquez S, Neuzil J, Moreno-Sanchez R . Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger. Mol Aspects Med. 2009; 31(1):29-59. DOI: 10.1016/j.mam.2009.12.006. View

13.

Rohlena J, Dong L, Neuzil J . Targeting the mitochondrial electron transport chain complexes for the induction of apoptosis and cancer treatment. Curr Pharm Biotechnol. 2011; 14(3):377-89. DOI: 10.2174/1389201011314030011. View

14.

Li M, Li X, Cao Z, Wu Y, Chen J, Gao J . Mitochondria-targeting BODIPY-loaded micelles as novel class of photosensitizer for photodynamic therapy. Eur J Med Chem. 2018; 157:599-609. DOI: 10.1016/j.ejmech.2018.08.024. View

15.

Pei J, Panina S, Kirienko N . An Automated Differential Nuclear Staining Assay for Accurate Determination of Mitocan Cytotoxicity. J Vis Exp. 2020; (159). PMC: 8310432. DOI: 10.3791/61295. View

16.

Beija M, Afonso C, Martinho J . Synthesis and applications of Rhodamine derivatives as fluorescent probes. Chem Soc Rev. 2009; 38(8):2410-33. DOI: 10.1039/b901612k. View

17.

Sommerwerk S, Heller L, Kuhfs J, Csuk R . Urea derivates of ursolic, oleanolic and maslinic acid induce apoptosis and are selective cytotoxic for several human tumor cell lines. Eur J Med Chem. 2016; 119:1-16. DOI: 10.1016/j.ejmech.2016.04.051. View

18.

Johnstone R, Ruefli A, Lowe S . Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002; 108(2):153-64. DOI: 10.1016/s0092-8674(02)00625-6. View

19.

Serafim T, Carvalho F, Bernardo T, Pereira G, Perkins E, Holy J . New derivatives of lupane triterpenoids disturb breast cancer mitochondria and induce cell death. Bioorg Med Chem. 2014; 22(21):6270-87. DOI: 10.1016/j.bmc.2014.08.013. View

20.

Ralph S, Rodriguez-Enriquez S, Neuzil J, Saavedra E, Moreno-Sanchez R . The causes of cancer revisited: "mitochondrial malignancy" and ROS-induced oncogenic transformation - why mitochondria are targets for cancer therapy. Mol Aspects Med. 2010; 31(2):145-70. DOI: 10.1016/j.mam.2010.02.008. View