Intramolecular Cyclization of N-phenyl N'(2-chloroethyl)ureas leads to Active N-phenyl-4,5-dihydrooxazol-2-amines Alkylating β-Tubulin Glu198 and Prohibitin Asp40

International audienceThe cyclization of anticancer drugs into active intermediates has been reported mainly for DNA alkylating molecules including nitrosoureas. We previously defined the original cytotoxic mechanism of anticancerous phenyl '(2-chloroethyl)ureas (CEUs) that involves their reactivity towards cellular proteins and not against DNA; two CEUs subsets have been shown to alkylate β-tubulin and prohibitin leading to inhibition of cell proliferation by G/M or G/S cell cycle arrest. In this study, we demonstrated that cyclic derivatives of CEUs, -phenyl-4,5-dihydrooxazol-2-amines (Oxas) are two to threefold more active than CEUs and share the same cytotoxic properties in B16F0 melanoma cells. Moreover, the CEU original covalent binding by an ester linkage on β-tubulin Glu198 and prohibitin Asp40 was maintained with Oxas. Surprisingly, we observed that Oxas were spontaneously formed from CEUs in the cell culture medium and were also detected within the cells. Our results suggest that the intramolecular cyclization of CEUs leads to active Oxas that should then be considered as the key intermediates for protein alkylation. These results could be useful for the design of new prodrugs for cancer chemotherapy

A“Proteoglycan Targeting Strategy” for the Scintigraphic Imaging and Monitoring of the Swarm Rat Chondrosarcoma Orthotopic Model

Our lab developed 99mTc-NTP 15-5 radiotracer as targeting proteoglycans (PGs) for the scintigraphic imaging of joint. This paper reports preclinical results of 99mTc-NTP 15-5 imaging of an orthotopic model of Swarm rat chondrosarcoma (SRC). 99mTc-NTP 15-5 imaging of SRC-bearing and sham-operated animals was performed and quantified at regular intervals after surgery and compared to bone scintigraphy and tumoural volume. Tumours were characterized by histology and PG assay. SRC exhibited a significant 99mTc-NTP 15-5 uptake at very early stage after implant (with tumour/muscle ratio of 1.61 ± 0.14), whereas no measurable tumour was evidenced. As tumour grew, mean tumour/muscle ratio was increased by 2.4, between the early and late stage of pathology. Bone scintigraphy failed to image chondrosarcoma, even at the later stage of study. 99mTc-NTP 15-5 imaging provided a suitable set of quantitative criteria for the in vivo characterization of chondrosarcoma behaviour in bone environment, useful for achieving a greater understanding of the pathology

Targeting cyclic nucleotide phosphodiesterase 5 (PDE5) in brain: Toward the development of a PET radioligand labeled with fluorine-18

International audienceWith the aim to develop a specific radioligand for imaging the cyclic nucleotide phosphodiesterase 5 (PDE5) in brain by positron emission tomography (PET), seven new fluorinated inhibitors (3-9) were synthesized on the basis of a quinoline core. The inhibitory activity for PDE5 together with a panel of other PDEs was determined in vitro and two derivatives were selected for IC50 value determination. The most promising compound 7 (IC50 = 5.92 nM for PDE5A), containing a 3-fluoroazetidine moiety, was further radiolabeled by aliphatic nucleophilic substitution of two different leaving groups (nosylate and tosylate) using [18F]fluoride. The use of the nosylate precursor and tetra-n-butyl ammonium [18F]fluoride ([18F]TBAF) in 3-methyl-3-pentanol combined with the addition of a small amount of water proved to be the best radiolabeling conditions achieving a RCY of 4.9 ± 1.5% in an automated procedure. Preliminary biological investigations in vitro and in vivo were performed to characterize this new PDE5 radioligand. Metabolism studies of [18F]7 in mice revealed a fast metabolic degradation with the formation of radiometabolites which have been detected in the brain

Synthesis under moderate pressure of 3-imidazo[1,2- a ]pyridinylidene pyrrol-2-ones

International audienceConversion of 3-imidazo[1,2-a]pyridinylidene furan-2-ones into their pyrrol-2-one analogues was achieved efficiently with high yields, using a solution of ammonium hydroxide under moderate pressure conditions. A NMR study showed that the compounds are mainly isolated as E isomers

Melanoma-targeted delivery system (part 1): Design, synthesis and evaluation of releasable disulfide drug by glutathione

International audienc

Synthesis and Biological Evaluation of Indoloquinolines and Pyridocarbazoles: A New Example of Unexpected Photoreduction Accompanying Photocyclization

International audienceIndoloquinoline alkaloid cryptolepine and pyridocarbazole alkaloid ellipticine are of great interest because in vitro and in vivo studies revealed their good cytotoxic properties. In order to obtain some biologically active analogs of these compounds, we developed a synthesis based on the photocyclization of tertiary N-substituted enaminones derived from 1,3-cyclohexandione and 3 or 6-aminoquinoline. The angular cyclized compounds thus obtained were tested in vitro on K 562 cells and A 2780 doxorubicin sensitive and resistant cells. All compounds were less effective than doxorubicin in sensitive cells but their activity wasn’t decreased by MDR resistance

A Photochemical Approach to Pyridopyrroloquinoline Derivatives as New Potential Anticancer Agents

International audienceIndoloquinoline alkaloid cryptolepine and pyridocarbazole alkaloid ellipticine are of great interest becausein vitro and in vivo studies revealed their good cytotoxic properties. In order to obtain some biologically activeanalogs of these compounds, we developped a synthesis based on the photocyclisation of tertiary N-methylatedenaminones derived from cyclopentane-1,3-dione and 3 or 6-aminoquinoline. The angular cyclised compoundsthus obtained were submitted to Beckmann rearrangement, preceded by the formation of a Z oxime. Finally, thed -lactame ring was oxidized using 10% palladium/carbon in diphenylether and pyridopyrroloquinolines wereobtained. These compounds and the intermediate lactams and cyclopentanopyrroloquinolines were tested in vitroon K 562 cells and A 2780 doxorubicine sensitive and resistant cells. All compounds were less effective than doxorubicine in sensitive cells but their activity wasn’t decreased by MDR resistance

Design, synthesis and in vitro drug release investigation of new potential 5-FU prodrugs

International audienc

Synthesis and in Vitro Cytotoxic Evaluation of New Derivatives of Pyrido[1,2-a]benzimidazolic Ring System: The Pyrido[1,2:1,2]imidazo[4,5-h]quinazolines

International audienceAccess to the original series of pyrido[1',2':1,2]imidazo[4,5-h]quinazoline was developed from a 1,3-dicarbonyl unit with some “N-C-N” bisnucleophilic reagents and the derivatives obtained were evaluated for in vitro cytotoxic activities against HL60 and A2780 cells. All compounds exhibited cytotoxic activitise on resistant cell lines (MDR+; HL60R and A2780R) with no resistance phenomena

Macrocyclic complexes, their process of preparation and use as PET imaging agents

The present invention concerns compounds of formula (I):their process of preparation and compositions thereof. The present invention also concerns their use as diagnostic agent in PET imaging