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Synthesis, characterization, and relaxation studies of Gd‐DO3A conjugate of chlorambucil as a potential theranostic agent
Author(s) -
Kaur Jasleen,
Tsvetkova Yoanna,
Arroub Karim,
Sahnoun Sabri,
Kiessling Fabian,
Mathur Sanjay
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12827
Subject(s) - chemistry , conjugate , chlorambucil , dota , gadolinium , ligand (biochemistry) , cytotoxicity , mri contrast agent , hela , combinatorial chemistry , chelation , stereochemistry , biochemistry , cell , in vitro , organic chemistry , medicine , mathematical analysis , receptor , mathematics , surgery , chemotherapy , cyclophosphamide
DO 3A‐based macrocycles serve as attractive templates from which clinically useful theranostic agents can be obtained after coupling with molecular targeted therapeutic drugs. In this study, we describe the chemical synthesis, relaxation, and cytotoxicity studies of a new DO 3A conjugate of chlorambucil ( CHL ) as a magnetic resonance imaging ( MRI ) theranostic agent. A convenient route of synthesis is reported, which allowed conjugation of the macrocyclic ligand ( DO 3A) to the chemotherapeutic drug ( CHL ) via tyrosine for the preparation of an attractive chelate‐drug ensemble ( DO 3A‐ TR ‐ CHL ). The structures of all intermediates and final compound have been determined by 1 H, 13 C NMR , and MS . The efficacy of DO 3A‐ TR ‐ CHL as a non‐ionic magnetic contrast agent was tested by performing relaxometric studies on its gadolinium complex. The complex exhibited relaxivities (7.11 m m −1 /s) higher than that of currently used MR contrast agents and showed enhanced contrast in T 1 ‐weighted images. MTT assays revealed that both DO 3A‐ TR ‐ CHL and Gd( III )‐ DO 3A‐ TR ‐ CHL conjugates exhibited dose‐dependent toxicity and an enhanced antiproliferative activity against tumor (A549 and HeLa) cell lines compared to that of parent drug ( CHL ), thereby demonstrating their potential to be used as a magnetic resonance imaging theranostic for improved molecular imaging and therapy of human cancers.