Introduction: In chemoinformatics, stereochemical attributes are commonly taken into account only by direct description of spatial structures via 3D-QSAR approaches.  Usually these models are applied for one fixed conformer of each molecule. That can be undesirable if we don’t know the spatial structure of the molecule interacting with a biological target. In this study we show how to solve this problem in terms of simplex representation of the molecular structure (SiRMS).

Methods: In the SiRMS approach, every molecule is represented as a system of different simplexes (tetratomic fragments with fixed composition and structure). The advantages of that approach are the absence of "molecular alignment" problems, consideration of different physical-chemical properties of atoms (e.g. charge, lipophilicity, etc.), the high adequacy and good interpretability of obtained models and clear ways for  further molecular design. In this study, all molecular fragments which don’t determine stereochemistry of a molecule are described in terms of 2D molecular representation (structural formula). Structural elements which determine molecular stereoisomerism are described by  respective 3D chiral  conformation-independent simplexes  It should be noted that chiral simplexes allow us to describe the molecular system of any stereochemical complexity. In the proposal (2.0+0.X)D - QSAR approach parameter (0.X) is determined by the ratio of 2D achiral and 3D chiral simplexes included in the appropriate QSAR model. 

Results:To evaluate applicability of this approach, we had to solve some QSAR tasks with sets of compounds containing chirality. This approach allowed us to get valid QSAR models for data sets consisting of only compounds with one or more centers of chirality, of chiral and achiral compounds and of compounds with central and axial chirality as well. Use of simplex descriptors also allowed us to get structural and functional interpretation for those models. There was no situation where consensus QSAR model did not include some chiral descriptors, so, all of the studied properties are chirality-dependent.

Conclusion: Quality of those models is an evidence that  application of Simplex Representation of the Molecular Structure with described modification considering chirality is relatively simple and universal approach for obtaining adequate QSAR-models of chirality-dependent properties.

Introduction

AGuIX^® nanoparticles are small platforms of polysiloxane recently developed for various applications of medical imaging. These nanoparticles contain on their surface several amine functions used for the fixation of DOTA ligands. Approximately 70 percents of these ligands are complexed with Gd³⁺ ions [1]. These paramagnetic platforms have a diameter less than 5 nm and a low transmetalation [2]. Different studies have been achieved in the biomedical domain, showing that they allow to combine multimodal and theranostic properties. A passive tumoral targeting has already been observed by EPR effect (Enhanced Permeation Effect). Otherwise, their small size allows a quick elimination by the kidney [3]. Previous phage display studies showed that TLVSSL peptide has a high affinity for phosphatidylserine, a phospholipid overexpressed on the membrane of apoptotic cells. Apoptosis is a natural process of cell death [4]. The targeting of apoptotic cells is interesting to follow the efficiency of an antitumoral therapy and for diagnosis of diseases related to this process. In this work, AGuIX nanoparticles have thus been grafted with this peptide and characterized.

Methods

The TLVSSL peptide has been grafted on nanoparticles AGuIX^® by activation with EDC of carboxylic functions available on nanoparticle surface. Furthermore, previous addition of an optical dye allows their applications in optical imaging. Different techniques such as PCS, fluorescence spectroscopy, HPLC and proton relaxometry were used to characterize this platform.

Results

Relaxometric studies by NMRD profiles confirm the increase of the rotational correlation time after linking of the peptide and allow to study the time stability of the platform. The biological efficiency of this novel bimodal agent to target apoptotic cells was evaluated by fluorescence microscopy on lymphablastic human T cell line. In vitro cell apoptosis was chemically induced by incubation with campthothecin. Biological experiments has been checked by fluorescence microscopy and flow cytometry on incubated cells with labelled and grafted-AGuIX nanoparticles. RITC fluorescence intensity detection allowed to confirm the probe efficiency to target apoptosis.

Conclusion

These characterizations and biological tests confirm the binding of the peptide and the efficient targeting of apoptotic cells. Further in vivo tests will be achieved to confirm the efficiency of grafted-nanoparticles on apoptotic mouse model.

References

[1] F. Lux et Al., Angew. Chem. Int. Ed. 2011, 50, 1-6.

[2] A. Mignot et Al., Chem. Eur. J., 2013, 19, 6122-6136.

[3] G. Le Duc et Al., ACS Nano, 2011, 5, 9566-9574.

[4] C. Laumonier, thesis, 2005, Université de Mons-Hainaut, « Imagerie moléculaire : recherche de vecteurs peptidiques spécifiques de l'apoptose par la méthode du phage display ».

The precise biological function of elevated chromogranin A (CgA) in neuroendocrine and nonneuroendocrine neoplasms remains unclear. Limited studies in cell and animal models have provided contradictory evidence as to whether CgA promotes or inhibits tumorigenesis. In a neuroendocrine tumor (NET)-derived cell line a study demonstrated that cyclooxygenase-2 (Cox-2) up-regulates both CgA expression and bioactivity with implications of this polypeptide in neuroendocrine cancer.                      

In our study, we indirectly tested the link between Cox-2 and CgA  in  a  lot of 15 patients clinically suspected of pheochromocytoma by comparison with a lot of 15 matched controls without endocrine dysfunction. Biochemical diagnosis of pheochromocytoma was realized by differentially Elisa assay of plasma free normetanephrines (NMNp) /free metanephrines (MNp) and by plasma Elisa assay of CgA. Plasma Cox-2 was assayed by an Elisa research kit. All four parameters were assayed both in tumoral and normal subjects.We calculated means and standard errors in pheo group vs control subjects and we established statistically significant differences between all parameters assayed. Multiple regression showed important correlation coefficients between: NMNp/CgA: 0.86; NMNp/MNp:0.70; CgA/Cox-2:0.56. Practically,we proved the traffic control of the noradrenergic metabolite NMNp by CgA and Cox-2.Using Relative Operating Curve Analysis (ROC) we compared sensitivity and specificity of all four assayed parameters. Cox-2,CgA,NMNp proved the best sensitivity and a great specificity.                                                                                                                                                      

We can conclude that Cox-2 could be used as a prediction marker in pheochromocytoma pathology together with CgA/NMNp/MNp.

Bibliography

1-Cox-2 promotes CgA expression and bioactivity:evidence for a Prostaglandin E2 dependent  mechanism and bioactivity:evidence for a Prostaglandin E2 dependent mechanism and the    involvement of a proximal cyclic Adenosine 5'-Monophosphate-Responsive Element-Endocrinology 148(9):4310-4317,2007 - Connolly R et al.                                                                

2-Increased expression of cyclooxygenase-2 in malignant pheochromocytomas-J Clin Endocrinol Metab 86:5615-5619-2001- Salmenkiwi K. et al.

3-Pheochromocytoma-Lancet 366:665-675-2005 -Lenders JWM et al.

Our group is focused on the synthesis of C,N,S- or C,N,O-containing heterocyclic precursors of bioactive molecules able to modulate the activity of kinases involved to some extent in Alzheimer's disease.¹ Previous biological results lead us to intensively study thiazoloquinazolin-4-one backbone especially modulations of positions 1 and 2. Following our effort for the construction of a broad range of substituted thiazoloquinazolin-4-one derivatives as potential kinase inhibitors,² modulating the position 3 was further explored. As an efficient and versatile approach in complex molecules synthesis palladium-catalyzed, C–H functionalization of heteroarenes³ represents an extremely attractive approach.

Our presentation describes the first extensive study of palladium-catalyzed direct C-H (hetero)-arylation of quinazolin-4(3H)-ones with aryl iodides, bromides and chlorides under microwave irradiation.⁴ This innovative methodology tolerates a broad range of heteroaryl and aryl halides substituted by electronically different groups. The scope of substrates was extended to pyridinopyrimidin-4-ones. This method provides an efficient, versatile, and rapid access to 2-arylquinazolin-4-one backbone and will be extended to our thiazoloquinazolin-4-one derivatives.

References

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4. (a) Laclef, S.; Harari, M.; Godeau, J.; Schmitz-Afonso, I.; Bischoff, L.; Hoarau, C.; Levacher, V.; Fruit, C.; Besson, T. Org. Lett. 2015, 17, 1700. (b) Godeau, J.; Harari, M.; Laclef, S.; Deau, E.; Fruit, C.; Besson, T. Eur. J. Org. Chem. 2015, in press.

The expiration date is the final day that the manufacturer guarantees the full potency and safety of a medication. In general, most drug products are not toxic when expired but they can lose their effectiveness over time. The decrease in the concentration of the drug in a drug product from 100% to 90% is known as its shelf life. When a medication is used within its shelf life, it shows maximum efficacy and safety.  Recently studies conducted by the U.S. Food and Drug Administration over 100 drugs, prescriptions and over-the-counter products, showed that about 90% of them were effective and safe as long as 15 years past their expiration dates. India's pharmaceutical industry is losing around Rs 500 corer annually on account of destruction of expired drugs, hitting the bottom line of drug manufacturers, especially the small and medium ones. In our present communication, we made an attempt to study different methodologies for recycling active drugs from expired drug products or pharmaceutical dosage forms. It is admitted that when a drug product gets expired, it may contain 90% or even above of the Active Pharmaceutical Ingredient(s). Suitable chromatographic methods and analytical techniques could therefore be adopted for isolation and eventual quantification of active ingredients for the purpose of successful recycling (especially if manufacturers are mandated to blister-package and bar-code for individual tablets and capsules) into useful synthetic intermediates or active drugs. This approach would remain cost-effective as well as eco-friendly from the point of view of its industrial applicability.