2. Academic Validation
  3. Synthesis and Cytotoxicity Evaluation of DOTA-Conjugates of Ursolic Acid

Synthesis and Cytotoxicity Evaluation of DOTA-Conjugates of Ursolic Acid

  • Molecules. 2019 Jun 17;24(12):2254. doi: 10.3390/molecules24122254.
Michael Kahnt 1,  Sophie Hoenke 2,  Lucie Fischer 3,  Ahmed Al-Harrasi 4,  René Csuk 5
Affiliations

Affiliations

  • 1 Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany. michael.kahnt@chemie.uni-halle.de.
  • 2 Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany. sophie.hoenke@chemie.uni-halle.de.
  • 3 Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany. lucie.fischer2018@gmx.de.
  • 4 Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, Birkat Al-Mauz, Nizwa 616, Oman. aharrasi@unizwa.edu.om.
  • 5 Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany. rene.csuk@chemie.uni-halle.de.
PMID: 31212958 DOI: 10.3390/molecules24122254
Abstract

In this study, we report the synthesis of several amine-spacered conjugates of ursolic acid (UA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Thus, a total of 11 UA-DOTA conjugates were prepared holding various oligo-methylene diamine spacers as well as different substituents at the acetate units of DOTA including tert-butyl, benzyl, and allyl esters. Furthermore, three synthetic approaches were compared for the ethylenediamine-spacered conjugate 29 regarding reaction steps, yields, and precursor availability. The prepared conjugates were investigated regarding cytotoxicity using SRB assays and a set of human tumor cell lines. The highest cytotoxicity was observed for piperazinyl spacered compound 22. Thereby, EC50 values of 1.5 µM (for A375 melanoma) and 1.7 µM (for A2780 ovarian carcinoma) were determined. Conjugates 22 and 24 were selected for further cytotoxicity investigations including fluorescence microscopy, annexin V assays and cell cycle analysis.

Keywords

DOTA; cytotoxicity; triterpenoids; ursolic acid.

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