Synthesis of (R)-Dihydropyridones as Key Intermediates for an Efficient Access to Piperidine Alkaloids

The efficient transformation of D-glucal to (2R)-hydroxymethyldihydro-pyridinone 5 in seven steps and 35 % overall yield is reported. Dihydropyridone 5 constitutes a versatile chiral building block for the synthesis of various piperidine alkaloids. In this regard, 5 was converted to piperidinol 13 and piperidinone 15, that may be further elaborated for the syntheses of (+)-desoxoprosophylline (1) and deoxymannojirimycin (3) or D-mannolactam (4), respectively

Synthesis of novel molecules with anticancer activity

The significant biological/pharmaceutical interest of azaheterocyclic compounds has initiated a vigorous research activity towards the development of methodologies for the efficient synthesis of novel bioactive molecules containing in their structural frameworks diverse azaheterocyclic rings. The endeavor herein falls within this initiative, focusing on the development of several novel derivatives of pyrazoles and isoxazoles, molecules containing the azaheterocyclic ring residue and displaying multidimensional biological activities. Final goal was the development of novel molecules with potent anticancer and/or antiangiogenic activities.In this respect, we designed, synthesized and determined the bioactivities of novel derivatives of: 1)pyrazoles, synthesized via the condensation of 1,3-diketones with hydrazines,2)isoxazoles, prepared by the condensation of 1,3-diketones with hydroxylamines,3)pyrazole[1,5a]pyrimidines, analogues of the bioactive molecule dorsomorphinSubsequently, the biological activities of the novel compounds, along with their chemical structures were utilized for the development and validation of an in silico model, used for the design, synthesis and bioactivity determination of several additional target molecules with anticipated anticancer activities. The structures of all novel molecules were elucidated using NMR spectroscopy (1H, 13C, 2D, etc) experiments, while their anticancer activity was evaluated through several in vitro assays determing the inhibition of endothelial and cancer cells proliferation. Finally, their antiangiogenic activity was evaluated by in vitro assays of the inhibition of cell tubes formation and cell migration.In particular, during the implementation of this thesis the following activities were performed: a) Synthesis of 59 novel molecules, which had been set as the target compounds. Amongst them, 23 are pyrazole derivatives, 20 isoxazole and 16 are analogues of dorsomorphin.b) Development, validation and utilization of novel in silico model for the discovery of potentially bioactive molecules. The model was used for the design and synthesis of novel derivatives of isoxazole.c) Determination of the anticancer activities of all novel molecules synthesized herein. The results pointed out the pyrazolic compound Π-9 as the most active against the MCF-7 cells, displaying IC50 = 1.5 ± 0.4 µM, while isoxazoles Π-35 and Π-38 (developed using the classification model) exhibited the best antiproliferative activities, with IC50 values below 1μM against most cell lines tested. d) Synthesis of novel dorsomorphine analogues, with compounds Π-46, Π-50 and Π-57 showing the most potent antiproliferative activity with IC50 values below 10 μM against most cancer cell lines.e) Evaluation of all novel compounds as inhibitors of angiogenesis through the assessment of their tube formation inhibition potencies, highlighting as the most actives the derivatives of pyrazole Π-12 and isoxazole Π-35 and Π-38. In addition, the antiangiogenic mechanism of compounds Π-22, Π-23, Π-36 and Π-38 was found to proceed through the deactivation of VEGF pathway.f) It was found that the novel pyrazolo[1,5a]pyrimidine derivative Π-46 exhibits significant antiviral activity against a variety of herpes viruses.Το σημαντικό βιολογικό/φαρμακευτικό ενδιαφέρον που παρουσιάζουν οι αζαετεροκυκλικές ενώσεις έχει αποτελέσει έναυσμα για τη διενέργεια πλήθους ερευνητικών εργασιών με αντικείμενο το σχεδιασμό και την ανάπτυξη μεθοδολογιών σύνθεσης νέων βιοδραστικών μορίων που εμπεριέχουν στη δομή τους ποικίλους αζαετεροκυκλικούς δακτυλίους. Η παρούσα διατριβή εντάσσεται στην προσπάθεια αυτή και επικεντρώνεται στην ανάπτυξη μιας σειράς νέων παραγώγων των πυραζολίων και ισοξαζολίων, μορίων με αζαετεροκυκλικούς δακτύλιους και πολυδιάστατη βιολογική δράση. Απώτερος στόχος ήταν η ανάπτυξη νέων μορίων με αντικαρκινική ή/και αντιαγγειογενετική δράση. Στο πλαίσιο εκπόνησης της διατριβής, σχεδιάστηκαν, συντέθηκαν και αξιολογήθηκαν νέα παράγωγα των: πυραζολίων, που συντέθηκαν με συμπύκνωση υδραζινών με ποικίλες 1,3-δικετόνεςισοξαζολίων, τα οποία παρασκευάστηκαν μέσω της συμπύκνωσης της υδροξυλαμίνης με ποικίλες 1,3-δικετόνες, πυραζολο[1,5a]πυριμιδινών, μορίων που είναι ανάλογα της ντορσομορφίνηςστη συνέχεια, τα αποτελέσματα των βιοδοκιμών των παραπάνω μορίων –σε συνδυασμό με τη χημική τους δομή– χρησιμοποιήθηκαν για την ανάπτυξη & πιστοποίηση ενός νέου in silico μοντέλου για τον περαιτέρω σχεδιασμό, σύνθεση και μελέτη βιοδραστικότητας μιας επιπλέον σειράς νέων μορίων-στόχων με προσδόκιμη αντικαρκινική δραστικότητα. Οι δομές όλων των νέων μορίων διαλευκάνθηκαν με σειρά πειραμάτων φασματοσκοπίας NMR (1Η, 13C, 2D, κλπ), ενώ η αντικαρκινική τους ικανότητα αξιολογήθηκε μέσω ποικίλων in vitro δοκιμασιών προσδιορισμού της ανασταλτικής τους δράσης κατά του πολλαπλασιασμού διαφόρων ενδοθηλιακών και καρκινικών κυτταρικών σειρών. Τέλος, η αντι-αγγειογενετική τους δράση πιστοποιήθηκε σε δοκιμασίες αναστολής του σχηματισμού μικροσωληνίσκων και του βαθμού της κυτταρικής μετανάστευσης. Αναλυτικότερα, κατά τη διενέργεια της διατριβής υλοποιήθηκαν οι παρακάτω δράσεις: α) Σύνθεση 59 νέων μορίων-στόχων. Από αυτά, τα 23 είναι παράγωγα του πυραζολίου, τα 20 ισοξαζολίου και τα 16 είναι νέα ανάλογα της ντορσομορφίνης. β) Αναπτύχθηκε, επικυρώθηκε και δοκιμάστηκε ένα νέο in silico μοντέλο για τον εντοπισμό-επιλογή νέων μορίων με πιθανή βιοδραστικότητα. Στη συνέχεια, το μοντέλο αυτό χρησιμοποιήθηκε για το σχεδιασμό και τη σύνθεση των νέων ισοξαζολικών παραγώγων.γ) Προσδιορίστηκε η αντικαρκινική δράση όλων των μορίων που συντέθηκαν. Οι δοκιμές ανέδειξαν το πυραζολικό παράγωγο Π-9 ως το πλέον δραστικό κατά της καρκινικής σειράς μαστού MCF-7, με τιμή IC50 = 1.5 ± 0.4, ενώ τα ισοξαζολικά παράγωγα Π-35 και Π-38 (προήλθε από την εφαρμογή του in silico μοντέλου επιλογής), εμφάνισαν τις καλύτερες αντι-πολλαπλασιαστικές δράσεις με τιμές IC50 μικρότερες από 1μM έναντι των περισσότερων κυτταρικών σειρών που μελετήθηκαν. δ) Συντέθηκαν νέα ανάλογα της ντορσομορφίνης, από τα οποία τα Π-46, Π-50 και Π-57 εμφάνισαν την καλύτερη αντι-πολλαπλασιαστική δράση με τιμές IC50 κάτω από 10 μM εναντίον σειράς καρκινικών κυτταρικών σειρών. ε) Μελετήθηκε η αντιαγγειογενετική δράση όλων των παραπάνω μορίων σε πειράματα αναστολής σχηματισμού μικροσωληνίσκων, αναδεικνύοντας ως πλέον δραστικά τα παράγωγα πυραζολίου Π-12 και ισοξαζολίου Π-35 και Π-38. Επίσης, επιβεβαιώθηκε ότι ο τα μόρια Π-22, Π-23, Π-36 και Π-38 αναστέλλουν την αγγειογένεση μέσω της απενεργοποίησης του VEGF.στ) Προσδιορίστηκε ότι το νέο ανάλογο της ντορσομορφίνης Π-46 διαθέτει μια αξιοσημείωτη αντιϊκή δράση εναντίον ποικίλων ιών έρπητα

A Comprehensive Review of Organochlorine Pesticide Monitoring in Agricultural Soils: The Silent Threat of a Conventional Agricultural Past

Soil constitutes the central environmental compartment that, primarily due to anthropogenic activities, is the recipient of several contaminants. Among these are organochlorine pesticides (OCPs), which are of major concern, even though they were banned decades ago due to their persistence and the health effects they can elicit. In this review, an overview of monitoring studies regarding OCPs in soils published over the last 30 years along with the development of analytical methods and extraction procedures for their determination in soil are presented. The presented synopsis verifies the soil contamination by OCPs during the last several decades. Soil pollution by OCPs should be an essential aspect of the characterization of whole soil quality, considering that a significant percent of soils on a global scale are in the borderline of suitability for cultivation and pertinent activities. The latter, to an extent, is attributed to the presence of organic contaminants, especially those of persistent chemical natures

Pyrazoles as potential anti-angiogenesis agents: a contemporary overview

Angiogenesis is a mulit-step process by which new blood vessels are formed from preexisting vasculature. It is a key rate limiting factor in tumor growth since new blood vessels are necessary to increase tumor size. In this context it has been shown that anti-angiogenic factors can be used in cancer therapy. Among the plethora of heterocyclic compounds administered as anti-angiogenesis agents, pyrazoles constitute one of the bottlenecks of this category. Currently several pyrazole based compounds are administered or are in Phase II and III trials and new targets emerge. It is highly possible that the advent of the next two decades will lead to the discovery and use of additional pyrazoles whose anti-angiogenic profile will position them in the forefront of the battle of various malignancies. The present review is an attempt to focus on those pyrazoles that arise as anti-angiogenesis agents commenting both on the chemistry and bioactivity that these exhibit aiming to contribute to the perspectives that they hold for future research

A Dieldrin Case Study: Another Evidence of an Obsolete Substance in the European Soil Environment

Soil constitutes a central environmental compartment that, due to natural and anthropogenic activities, is a recipient of several contaminants. Among them, organochlorine pesticides are of major concern, even though they have been banned decades ago in the European Union, due to their persistence and the health effects they can elicit. In the presented work, a gas chromatographic tandem mass spectrometric (GC-MS/MS) developed method was applied to soil samples after the suspected and potential use of formulations containing organochlorine active substance. One soil sample was positive to dieldrin at 0.018 mg kg−1. Predicted environmental concentration in soil (PECsoil) considering a single application of this active substance potentially attributed the finding in its past use. The subsequent health risk assessment showed negligible non-carcinogenic risk and tolerable carcinogenic risk. The latter signifies that repetitive and prolonged sampling can unveil the pragmatic projection of persistent chemicals’ residues in the soil

Synthesis of (R)-Dihydropyridones as Key Intermediates for an Efficient Access to Piperidine Alkaloids

Abstract: The efficient transformation of D-glucal to (2R)-hydroxymethyldihydropyridinone 5 in seven steps and 35 % overall yield is reported. Dihydropyridone 5 constitutes a versatile chiral building block for the synthesis of various piperidine alkaloids. In this regard, 5 was converted to piperidinol 13 and piperidinone 15, that may be further elaborated for the syntheses of (+)-desoxoprosophylline (1) and deoxymannojirimycin (3) or D-mannolactam (4), respectively

Novel pyrazole and indazole derivatives: synthesis and evaluation of their anti-proliferative and anti-angiogenic activities

The synthesis of several new pyrazole and indazole derivatives from acetophenone and tetralone substrates is reported. The bioactivities of the new compounds were evaluated through in vitro assays for endothelial cell proliferation and tube formation. Results herein indicate that the easily prepared compounds containing the indazole structural framework exhibit potent cytostatic properties against all cell lines tested, with compounds 13 and 14 being the most active displaying IC(50) values of 1.5 ± 0.4 µM and 5.6 ± 2.5 µM, respectively, against MCF-7 cells. In addition, the indazole derivative 16 was assessed as a competent inhibitor of endothelial tube formation at 30 µM.status: publishe

Novel Carbonyl Analogs of Tamoxifen: Design, Synthesis, and Biological Evaluation

Aim of this work was to provide tamoxifen analogs with enhanced estrogen receptor (ER) binding affinity. Hence, several derivatives were prepared using an efficient triarylethylenes synthetic protocol. The novel compounds bioactivity was evaluated through the determination of their receptor binding affinity and their agonist/antagonist activity against breast cancer tissue using a MCF-7 cell-based assay. Phenyl esters 6a,b and 8a,b exhibited binding affinity to both ERα and ERβ higher than 4-hydroxytamoxifen while compounds 13 and 14 have shown cellular antiestrogenic activity similar to 4-hydroxytamoxifen and the known ER inhibitor ICI182,780. Theoretical calculations and molecular modeling were applied to investigate, support and explain the biological profile of the new compounds. The relevant data indicated an agreement between calculations and demonstrated biological activity allowing to extract useful structure-activity relationships. Results herein underline that modifications of tamoxifen structure still provide molecules with substantial activity, as portrayed in the inhibition of MCF-7 cells proliferation

Antiproliferative novel isoxazoles: Modeling, virtual screening, synthesis, and bioactivity evaluation

A series of novel isoxazole derivatives were efficiently synthesized through the adaptation/modification of an in situ synthetic procedure for pyrazoles. All novel compounds were tested against four different cell lines to evaluate their antiproliferative activity. Based on the Hela cells results of this study and previous work, a classification model to predict the anti-proliferative activity of isoxazole and pyrazole derivatives was developed. Random Forest modeling was used in view of the development of an accurate and reliable model that was subsequently validated. A virtual screening study was then proposed for the design of novel active derivatives. Compounds 9 and 11 demonstrated significant cytostatic activity; the fused isoxazole derivative 18 and the virtually proposed compound 2v, were proved at least 10 times more potent as compared to compound 9, with IC50 values near and below 1 μM. In conclusion, a new series of isoxazoles was exploited with some of them exhibiting promising cytostatic activities. Further studies on the substitution pattern of the isoxazole core can potentially provide compounds with cytostatic action at the nM scale. In this direction the in silico approach described herein can also be used to screen existing databases to identify derivatives with anticipated activity.publisher: Elsevier articletitle: Antiproliferative novel isoxazoles: Modeling, virtual screening, synthesis, and bioactivity evaluation journaltitle: European Journal of Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.ejmech.2014.05.011 content_type: article copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.status: publishe