In recent years, the field of medicinal inorganic chemistry has received considerable attention for the design of anticancer agents. Zinc(II) ion plays an important role in bioinorganic processes because of the potential formation of coordination compounds in which zinc(II) ion can readily accommodate four-, five-, or six molecules. The advantage of zinc-based anticancer drugs could be their selectivity toward specific cellular targets thanks to specific coordination ability and kinetic properties  (Bertini I., et al., Biological Inorganic Chemistry. Structure and Reactivity, University Science Books: Sausalito, CA, 2007; Roat-Malone R.M. (Ed.), Bioinorganic Chemistry: A Short Course, John Wiley & Sons, Inc., Hoboken, NJ, 2002). 

The mole-ratio method was used for determining metal-ligand stoichiometry between [ZnCl₂(en)] (where en=  1,2-diaminoethane or ethylenediamine) and imidazole at pH 7.2 in the presence of different chloride concentrations. The results indicated step-wise formation of 1:1 and 1:2 complexes in the presence of 0.010 M NaCl and 1:1 complexes in the presence of 0.001 M NaCl. Those results are correlated with additional coordination of chlorides in the first coordination sphere and with changes in coordination geometry. In the presence of 0.001 M NaCl, five-coordinate complex anion [ZnCl₃(en)]^- is formed initially, and then substitution reaction with imidazole occurred. In the presence of 0.010 M NaCl the octahedral complex anion [ZnCl₄(en)]^2- formed.

The kinetics of ligand substitution reactions between complex and relevant nitrogen nucleophiles such as imidazole, 1,2,3-triazole and L-histidine were investigated at pH 7.2 as a function of nucleophile concentration in the presence of 0.001 M and 0.010 M NaCl. The reactions were followed under pseudo-first-order conditions by UV-vis spectrophotometry. The substitution reactions included two steps of consecutive displacement of chlorido ligands and changes in coordination geometry of [ZnCl₂(en)] complex. Results are discussed in terms of mechanisms of interactions between potential antitumor zinc-based drugs and biomolecules.

Aim: To evaluate relationship between histamine (HIST), serotonin (5-HT), dopamine (DA), gamma-amino-butyric acid (GABA) and IGF-1 in 20 GH-deficient boys.                                  

Research design and methods: This study included 20 boys (5-14 years) with GH deficit clinically established and a 10 matched normal group with no endocrine dysfunction. All of GH deficient patients underwent GH replacement therapy. In 2017, all subjects were tested by analytical methods for blood: HIST,GABA,DA,5-HT,IGF-1.                                                           

Results: We divided this study group into a low HIST lot 1 (10 subjects): HIST median: 3.48 nM/L and a high HIST lot 2 (10 subjects): HIST median: 11nM/L. Median parameters in lot 1 vs. lot 2 were: 5-HT: 212.5 vs. 370ng/mL, DA: 30 vs. 45pg/ml, GABA: 30 vs. 56.5ng/mL, IGF-1: 373.5 vs. 200ng/mL. Median values in normal subjects were as it follows: HIST: 5.55nM/L; 5-HT: 235.5ng/mL; DA: 31.5pg/mL; GABA: 81ng /mL. T-Test revealed a statistical significance between HIST in lot 1 vs. lot 2 (P<0.001), HIST in lot 1 vs. normal group (P<0.01) or HIST in lot 2 vs. normal group (P<0.01).We can also underline a statistical significance between 5-HT in lot 1 vs. lot 2 (P<0.05) or in lot 2 vs. normal group (P=0.01).                                                                

Conclusion: Our study underlined a HIST/5-HT positive relationship in low HIST group vs. a negative relationship HIST/5-HT in high HIST group, with small IGF-1 increments under r-GH therapy.

Aim: To quantify the effect of 1 year r-GH therapy on blood gamma-aminobutyric acid (GABA), serotonin (5-HT), dopamine (DA) and IGF-1 in 15 growth-hormone (GH) deficient children.       

Research design and methods: This retrospective study included 8 boys (7-14 years) and 7 girls (7-14 years) with clinically established GH deficit and under GH replacement therapy. In 2016 they were quantified for GABA, DA, 5-HT and IGF-1.After 1 more year of GH therapy, they were again tested for the same parameters using analytical methods.                               

Results: Median plasma parameters in 8 boys pre- vs. post-GH therapy was: GABA: 59.44 vs. 105.83ng/mL; 5-HT: 269.66 vs.196.55ng/mL; DA: 46.66 vs.91.5pg/mL; IGF-1: 367.38 vs. 445.5ng/mL. The same parameters were tested in 7 girls as median pre- vs. post-GH therapy: GABA: 45 vs.96ng/mL; 5-HT: 215 vs. 200ng/mL; DA: 40 vs. 60pg/mL; IGF-1: 284 vs.420ng/mL. We established statistical significant differences in boys group pre-and post-treatment in: plasma GABA(P<0.001), serum 5-HT (P<0.01), plasma DA (P<0.02), serum IGF-1(P=0.02). In girls group we calculated statistical significant differences in plasma GABA pre- vs. post-therapy (P<0.001) and in plasma DA pre- vs. post-therapy.                                                           

Conclusions: In fact replacement GH-therapy improved GABA/5-HT, GABA/DA, GABA/IGF-1, 5-HT/IGF-1 correlations in boys group. In girls group we estimated improved correlations between GABA/DA, 5-HT/DA, 5-HT/IGF-1.These observations could be translated in general improvement of health state in growth-deficient children under GH- therapy.

In Trypanosoma brucei, a parasite that causes African trypanosomiasis in humans (sleeping sickness) and in livestock (nagana) throughout sub-Saharan Africa, the trypanosome alternative oxidase (TAO) is essential for the respiration of bloodstream form parasites (i.e. the human-infective form). Since TAO has no counterpart in mammalian cells and it is conserved among T. brucei subspecies, it has been validated as a promising target for the chemotherapy of African trypanosomiasis.

We present here a successful approach to boost the activity of TAO inhibitors based on the conjugation of the inhibitor with lipophilic cations (LC) that can cross lipid bilayers by non-carrier mediated transport, and thus accumulate specifically into mitochondria, driven by the plasma and mitochondrial transmembrane potentials (negative inside). This design afforded several LC–TAO inhibitor conjugates active in the submicromolar to low nanomolar range against wild type and resistant strains of African trypanosomes (T. b. brucei, T. congolense), with selectivity over human cells >500.

Introduction

Medical imaging is a dynamic area of research whose one of the goal is the elaboration of more efficient contrast agents. Those agents need to be improved to optimize the detection of affected tissues such as cancers or tumours while decreasing the injected quantity of agents. The paramagnetic contrast agents containing fluorine atoms can be used both on proton and fluorine MRI.

This research field is therefore promising thanks to the ability to map the anatomy by ¹H MRI and locate exactly the agents by ¹⁹F MRI.  In this domain, one of the challenges is to synthesize a molecule containing several chemically equivalent fluorine atoms characterized by a short relaxation time to allow the record of fluorine MR images in good conditions.

In that aim, we propose to synthesize a compound containing a paramagnetic ion and nine chemically equivalent fluorine atoms by a cycloaddition reaction between two previously synthesized products.

Methods

In a first time, a derivative of DOTAGA macrocyclic ligand has been synthesized. This macrocycle has been obtained by a multistep synthesis during which an azide function was added. Then, the ligand has been complexed with GdCl₃.

In a second time, a nonafluorinated compound containing an alkyne function has been synthesized in order to allow the use of the contrast agent in fluorine MRI. Finally, these two molecules were combined via a click chemistry reaction.

Results

The fluorinated paramagnetic contrast agent has been characterized by relaxometry which shows an increase of the agent efficiency in comparison with the parent compound Gd-DOTA.

A ¹⁹F NMR study has also shown a significant decrease of the fluorine-19 relaxation times (from about 2 s for the single molecule to about 10 ms for the molecule conjugated to the paramagnetic macrocycle) which is promising for a future use in 19F MRI.

Conclusions

The targeted compound has been successfully synthesized and the preliminary characterizations are very promising. It will be now essential to perform ¹⁹F MRI in vitro and in vivo tests to evaluate the diagnosis potential of the synthesized contrast agent.

Furthermore, possible perspectives are envisaged. A modification of the synthesis strategy will allow an active targeting of the compound via the grafting of a biovector, or will also allow to increase the number of chemically equivalent fluorine atoms via a dendrimeric structure, which could be benefit to increase the sensitivity.