Dataset Information

Synthesis and Cytotoxicity Evaluation of DOTA-Conjugates of Ursolic Acid.

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.

SUBMITTER: Kahnt M

PROVIDER: S-EPMC6630699 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthesis and Cytotoxicity Evaluation of DOTA-Conjugates of Ursolic Acid.

Kahnt Michael M Hoenke Sophie S Fischer Lucie L Al-Harrasi Ahmed A Csuk René R

Molecules (Basel, Switzerland) 20190617 12

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 <i>tert</i>-butyl, benzyl, and allyl esters. Furthermore, three synthetic approaches were compared for the ethylenediamine-spacered conjugate <b>29</b> regardin ...[more]

PMID: 31212958

Similar Datasets

Project description:BackgroundBisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Conjugates of bisphosphonates with macrocyclic chelators open new possibilities in bone targeted radionuclide imaging and therapy. Subsequent to positron emission tomography (PET) examinations utilizing 68Ga-labelled analogues, endoradiotheraphy with 177Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases.MethodsBased on the established pharmaceuticals pamidronate and zoledronate two new DOTA-α-OH-bisphosphonates, DOTAPAM and DOTAZOL(MM1.MZ) were successfully synthesized. The ligands were labelled with the positron emitting nuclide 68Ga and the β- emitting nuclide 177Lu and compared in in vitro studies and in ex vivo biodistribution studies together with small animal PET and single photon emission computed tomography (SPECT) studies against [18F]NaF and a known DOTA-α-H-bisphosphonate conjugate (BPAPD) in healthy Wistar rats.ResultsThe new DOTA-bisphosphonates can be labelled in high yield of 80 to 95 % in 15 min with post-processed 68Ga and >98 % with 177Lu. The tracers showed very low uptake in soft tissue, a fast renal clearance and a high accumulation on bone. The best compound was [68Ga]DOTAZOL (SUV Femur = 5.4 ± 0.6) followed by [18F]NaF (SUV Femur = 4.8 ± 0.2), [68Ga]DOTAPAM (SUV Femur = 4.5 ± 0.2) and [68Ga]BPAPD (SUV Femur = 3.2 ± 0.3). [177Lu]DOTAZOL showed a similar distribution as the diagnostic 68Ga complex.ConclusionThe 68Ga labelled compounds showed a promising pharmacokinetics, with similar uptake profile and distribution kinetics. Bone accumulation was highest for [68Ga]DOTAZOL, which makes this compound probably an interesting bone targeting agent for a therapeutic approach with 177Lu. The therapeutic compound [177Lu]DOTAZOL showed a high target-to-background ratio. SPECT experiments showed concordance to the PET scans in healthy rats. [68Ga/177Lu]DOTAZOL appears to be a potential theranostic combination in the management of disseminated bone metastases.

Dataset Information

Synthesis and Cytotoxicity Evaluation of DOTA-Conjugates of Ursolic Acid.

Publications

Synthesis and Cytotoxicity Evaluation of DOTA-Conjugates of Ursolic Acid.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets