ABSTRACT
A convenient route for the synthesis of some acyloxymethyl esters and carboxamides of levofloxacin (LV) with modulated lipophilicity is described. The synthesized compounds were evaluated in vitro for their growth inhibitory effect in five human cancer cell lines. The most efficient LV derivatives (ester 2e and amide 4d) displayed IC(50) values in the 0.2-2.2 µM range, while IC(50) values for parent LV ranged between 70 and 622 µM depending on the cell line. The esters displayed no in vivo toxicity up to 80 mg/kg when administered intraperitoneally. This study thus shows that LV analogs displayed antitumor efficacy, at least in vitro, a feature that appeared to be independent from the lipophilicity of the grafted substituent.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzene Derivatives/chemical synthesis , Carboxylic Acids/chemical synthesis , Amides , Antineoplastic Agents/pharmacology , Benzene Derivatives/pharmacology , Carboxylic Acids/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Esters , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Levofloxacin , OfloxacinABSTRACT
To improve the targeting to tumors expressing the cholecystokinin receptor subtype 2 (CCK2R) with limited kidney uptake, we synthesized a novel cholecystokinin C-terminal tetrapeptide (CCK4)-based derivative conjugated to an original bipyridine-chelator (BPCA), 111In-BPCA-(Ahx)2-CCK4. To our knowledge this is the first CCK4-based radioligand that presents a high affinity for the CCK2R, a high and specific tumor uptake, a low renal accumulation and a very good visualization of tumors in vivo compared with an internal control, 111Indium-trans-cyclohexyldiethylenetriaminepenta-acetic acid-cholecystokinin octapeptide (111In-CHX-A''-DTPA-CCK8). These properties make 111In-BPCA-(Ahx)2-CCK4, a promising candidate for imaging and peptide receptor radionuclide therapy of CCK2R positive tumors.
Subject(s)
Neoplasms/diagnostic imaging , Oligopeptides , Radionuclide Imaging/methods , Radiopharmaceuticals , Receptor, Cholecystokinin B/metabolism , Animals , COS Cells , Chlorocebus aethiops , Humans , Mice , Mice, Nude , Models, Molecular , NIH 3T3 Cells , Oligopeptides/chemistry , Oligopeptides/pharmacokinetics , Oligopeptides/pharmacology , Pentetic Acid/analogs & derivatives , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/pharmacology , Receptor, Cholecystokinin B/chemistryABSTRACT
The goal of this study is to design new (99m)Tc-radiolabelled shortened CCK derivatives that might be suitable for the molecular imaging of cholecystokinin-2 receptors (CCK2-R), these receptors being over-expressed in a number of neuroendocrine tumors such as medullary thyroid cancer and small-cell lung cancer. For this purpose, we designed several modified CCK4 analogs bearing an ON(2)S tetradentate chelating agent at the N-terminus, the CCK4 sequence representing the minimal peptide sequence that presents nanomolar affinity and activity towards the CCK2-R. Four peptide conjugates of general formula (Trt)SN(2)OPh-(X)(n)-CCK4 (X=beta-alanine or 6-aminohexanoic acid spacers; n=0, 2, 4) and their oxorhenium peptide conjugates have been synthesized and characterized. In vitro evaluation of these compounds showed a close relationship between the nature and the length of the spacer and the corresponding binding affinity values. The most promising oxorhenium complex 5-Re exhibited potent CCK2-receptor agonist properties in promoting the production of inositol phosphate in COS-7 cells (EC(50)=5.17nM). Preliminary (99m)Tc-radiolabelling studies with peptide conjugates 3 or 5 led exclusively to the corresponding (99m)TcO-complexes 3-Tc and 5-Tc, which exhibited high resistance towards an excess of cysteine and satisfactory stabilities in human serum. To conclude, the promising in vitro characteristics of compounds 5-Re, 5-Tc illustrate the feasibility to develop stable radiolabelled shortened CCK4 derivatives with a nanomolar CCK2-R affinity.
