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.
Highlights
Despite all medical advances in tumor therapy, cancer is still one of the most prevalent diseases worldwide, with 9.6 million cancer-related deaths counted in 2018 [1]
By variation of the coordinated metal ion or substituents, they are applicable for a number of imaging techniques, such as magnetic resonance imaging (MRI) [2,3,4], positron emission tomography (PET) [2,3,5,6] and single photon emission computed tomography (SPECT) [2,3,7]
Theand synthesis of ursolic acid (UA)-DOTA conjugates started with the structural modification of cyclen (2) as
Summary
Despite all medical advances in tumor therapy, cancer is still one of the most prevalent diseases worldwide, with 9.6 million cancer-related deaths counted in 2018 [1]. By variation of the coordinated metal ion or substituents, they are applicable for a number of imaging techniques, such as magnetic resonance imaging (MRI) [2,3,4], positron emission tomography (PET) [2,3,5,6] and single photon emission computed tomography (SPECT) [2,3,7] Because of this versatility, a crossover application of DOTA-derivatives as multimodal contrast agents for combined imaging modalities such as PET/MRI or PET/CT is possible and has already been described in the literature [2,3]
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