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Interaction of Zinc(II) Complexes with Relevant Nitrogen Nucleophiles under Physiological Conditions
Published: 01 November 2017 by MDPI AG in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

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.

  • Open access
  • 24 Reads
Interrelation between Histamine and Serotonin, Dopamine, GABA, IGF-1 in a Growth Hormone (GH) Deficient Group under rh-GH Replacement Therapy
Published: 01 November 2017 by MDPI AG in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

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.

  • Open access
  • 21 Reads
One Year r-GH Therapy Influence on Blood gamma-Aminobutyric acid, Serotonin, Dopamine and IGF-1 in 15 Growth-hormone Deficient Children
Published: 01 November 2017 by MDPI AG in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

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.

  • Open access
  • 37 Reads
Targeting the Trypanosome Alternative Oxidase (TAO) as Promising Chemotherapeutic Approach for African Trypanosomiasis

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.

  • Open access
  • 27 Reads
Synthesis and Physicochemical Characterizations of a Fluorinated Paramagnetic Contrast Agent
Published: 01 November 2017 by MDPI AG in 3rd International Electronic Conference on Medicinal Chemistry session Posters


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.


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.


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.


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.

  • Open access
  • 15 Reads
Application of a Multilevel Factorial Design to the Formulation of Indomethacin-loaded Nanoparticles
Published: 01 November 2017 by MDPI AG in 3rd International Electronic Conference on Medicinal Chemistry session Posters

Indomethacin, a potent nonsteroidal anti-inflammatory drug (NSAID), is typically used for chronic inflammatory arthritis. However, patients receiving Indomethacin often experience gastrointestinal side effects. Thus, the design of targeted delivery formulations to reduce side effects of NSAIDs continues to be a focus of current research. In this regard, enteric nanoparticles have been recognized as a potential system to reduce gastrointestinal irritations. The aim of this study was to apply a two-level factorial design with three factors to the formulation of indomethacin-loaded nanoparticles. The effect of the polymer matrix and the surfactant on encapsulation efficiency was estimated. Statistical analysis of multilevel factorial design has shown 7 significance effects on evaluated response (95% confidence level), while PEG had shown the greater influence due to its co-surfactant behavior. Moreover, the process yield, particle morphology, and in vitro dissolution profile of the nanoparticles have been evaluated.

  • Open access
  • 17 Reads
Small Molecule Analogues of the Immunomodulatory Protein, ES-62: Potential Anti-inflammatory Compounds and Mechanism of Action
Published: 01 November 2017 by MDPI AG in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

ES-62, a secreted product of the parasitic filarial nematode, Acanthocheilonema viteae, has been shown in several studies to be a highly effective immunomodulatory agent. It interferes with the pro-inflammatory responses of a number of immune system cells including B cells, dendritic cells (DCs), macrophages and mast cells. Consequently ES-62 has protective effects in a number of mouse models of inflammatory disease, in particular collagen-induced arthritis (CIA), ovalbumin-induced airway-hyper-responsiveness (OAH), oxazolone-induced skin hypersensitivity (OSH), the MRL/Lpr model of systemic lupus erythematosus (SLE), and the Gld.ApoE-/- model of accelerated atherosclerosis in SLE. The biological activity of ES-62 dependens upon post-translational attachment of phosphorylcholine (PC) to an N–type glycan. To obtain potentially beneficial therapeutic effects not accessible to a protein of this type a library of small molecule analogues (SMAs) based upon the active PC moiety but containing chemically stable substitutes for the phosphate ester. Phopshonates, sulfones and sulfonamides were all investigated of which the sulfones were found to have the most immunomodulatory properties. Sulfone containing SMAs have since been found to be effective in treating mouse models of inflammatory diseases noted above. In this paper, potential mechanisms of action including receptor binding and various downstream signalling modifications are considered with the most substantial evidence emerging in favour of blocking essential interactions of the scaffolding protein MyD-88 with its partners thereby reducing the effect of TLR4 activation which in turn leads to a reduction in the release of pro-inflammatory cytokines from the targeted cells.

  • Open access
  • 14 Reads
Activity of Vitamin E Phosphate (VEP) Prodrugs of Gemcitabine in a Xenograft Model of NSCLC (NCI-H460)
Published: 01 November 2017 by MDPI AG in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

VEP nucleosides bypass two mechanisms of tumor resistance: nucleoside transport and kinase downregulation.  Isoforms of VE have shown activity against solid and hematologic tumors.  Gemcitabine was conjugated at the 5’ position to either δ-tocopherol-MP (NUC050) or δ-tocotrienol-MP (NUC052).

NUC050 has been demonstrated to deliver gemcitabine-MP intracellularly.  Its half-life IV in mice is 3.9 compared to 0.28 hours for gemcitabine (European J Cancer. 2016. 61(Suppl. 1):S119).

When tumors in nude mice reached 32 to 75 mg mm3 (day 4) treatment was initiated with gemcitabine (120 mg/kg IP q3dx9), NUC050 or NUC052 (both 40 mg/kg qwkx4) and compared to saline control (SC).

Gemcitabine inhibited tumor growth but was not tolerated.  NUC050 resulted in inhibition to tumor growth on days 11-31 (p<0.05), with a nadir of -73% compared to SC.  Median survival was 25.5 days (SC) vs 33 days (NUC050) ((hazard ratio) HR=0.24, p=0.017).  NUC052 had the dose increased to 50 mg/kg after 2 doses.  NUC052 resulted in inhibition to tumor growth on days 14-27 (p<0.05), with a nadir of -45%, and median survival was 34 days (HR=0.27, p=0.033).

NUC050 and NUC052 have been shown to be safe and effective in a NSCLC xenograft.  Studies have been initiated in a pancreatic cancer xenograft.

  • Open access
  • 19 Reads
The Effect of Terpenoid Esters on Membrane Structure Investigated by Fluorescence and Fourier-transform Infrared Spectroscopy
Published: 01 November 2017 by MDPI AG in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

The influence of esters based on gamma-aminobutyric acid (GABA) and mono-/bicyclic terpenoids on membrane structure was investigated. The mechanism of action for terpenoid esters on phospholipids of artificial membranes and lipids isolated from the rat stratum corneum was studied by fluorescence and FT-IR spectroscopy. We report here, that inclusion of monocyclic terpenoid esters in phospholipid liposomes leads to growth of excimer to monomer ratio (IE/IM) indicating a decrease of membrane microviscosity. Another mechanism of influence on biomembranes was proposed for ester of bicyclic borneol ‒ in this case a high ratio of vibronic peak intensities (I1/I3) was revealed. The addition of terpenoid esters appears in the FT-IR spectra as intensity reduction of absorption bands associated with C=O, P=O and Р‒О‒С groups of lecithin phospholipids. Similar results were obtained after esters addition to lipids isolated from stratum corneum indicating a decrease of hydrogen bonds number between polar groups of lipids.

  • Open access
  • 16 Reads
Minor Groove Binders for DNA as Antitrypanosomal Agents: the Veterinary Context

Animal African trypanosomiasis (or nagana) is a wasting livestock disease found in sub-Saharan Africa and caused by protozoan parasites Trypanosoma congolense, T. vivax and T. brucei. Chemotherapy (mostly with the diamidine diminazene aceturate) and chemoprophylaxis (mostly with the phenanthridine isometamidium chloride) are essential for disease control. However, as current treatments lose efficacy due to increased drug resistance, the need for new veterinary trypanocides becomes a high-priority. Trypanosoma spp. are one of the genera of parasites that are susceptible to DNA minor groove binder drugs synthesised at the University of Strathclyde (S-MGBs). All three of the above African species are susceptible to S-MGBs and in addition, the South American species, T. cruzi has been shown to be similarly susceptible. One of the principal challenges to obtaining compounds useful in the field is to achieve activity across the range of infectious species so that characterisation of the infection is not required at diagnosis. Over 100 S-MGBs have been evaluated at the University of Glasgow and the Swiss Tropical Health Institute, Basel, and compounds with development potential have been identified. As an example, S-MGB 234 has been shown to be curative in in vivo models of trypanosome infection in mice. Importantly S-MGB 234 does not show cross resistance with other antitrypanosomal drugs such as diminazine, isometamidium, or ethidium bromide, which is consistent with a different route into the parasite’s cell. S-MGBs that contain alkene links, such as in S-MGB 234, are the most active sub-class of S-MGB and point the way towards structural optimisation.