Browsing by Author "Laronze-Cochard M."

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    5-Arylisothiazol-3(2H)-one-1,(1)-(di)oxides: A new class of selective tumor-associated carbonic anhydrases (hCA IX and XII) inhibitors
    (2019-08-01) Cornelio B.; Laronze-Cochard M.; Miambo R.; De Grandis M.; Riccioni R.; Borisova B.; Dontchev D.; Machado C.; Ceruso M.; Fontana A.; Supuran C.T.; Sapi J.
    Sixteen 5-aryl-substituted isothiazol-3(2H)-one-1,(1)-(di)oxide analogs have been prepared from the corresponding 5-chloroisothiazol-3(2H)-one-1-oxide or −1,1-dioxide by a Suzuki-Miyaura cross-coupling reaction and screened for their inhibition potency against four human carbonic anhydrase isoenzymes: the transmembrane tumor-associated hCA IX and XII and the cytosolic off-target hCA I and II. Most of the synthesized derivatives inhibited hCA IX and XII isoforms in nanomolar range, whereas remained inactive or modestly active against both hCA I and II isoenzymes. In the N-tert-butylisothiazolone series, the 5-phenyl-substituted analog (1a) excelled in the inhibition of tumor-associated hCA IX and XII (Ki = 4.5 and Ki = 4.3 nM, respectively) with excellent selectivity against off target hCA I and II isoenzymes (S > 2222 and S > 2325, respectively). Since the highest inhibition activities were observed with N-tert-butyl derivatives, lacking a zinc-binding group, we suppose to have a new binding mode situated out of the active site. Additionally, three free-NH containing analogs (3a, 4a, 3i) have also been prepared in order to study the impact of free-NH containing N-acyl-sulfinamide- (-SO-NH-CO-) or N-acyl-sulfonamide-type (-SO2-NH-CO-) derivatives on the inhibitory potency and selectivity. Screening experiments evidenced 5-phenylisothiazol-3(2H)-one-1,1-dioxide (4a), the closest saccharin analog, to be the most active derivative with inhibition constants of Ki = 40.3 nM and Ki = 9.6 nM against hCA IX and hCA XII, respectively. The promising biological results support the high potential of 5-arylisothiazolinone-1,(1)-(di)oxides to be exploited for the design of potent and cancer-selective carbonic anhydrase inhibitors.
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    Synthesis and analgesic activity of new analogs of FELL tetrapeptide containing D-Phe in the first position
    (2024-01-01) Borisova B.; Nocheva H.; Iliev I.; Laronze-Cochard M.; Gérard S.; Petrin S.; Danalev D.
    Pain, whether acute or chronic, is one of the most unpleasant experiences. It can have different origins and long-term effects on the body starting from the trivial once such as physical discomfort, accompanying by emotional distress and going to the more serious like depression, anxiety, and social isolation. The removal and proper treatment of the pain is a problem highly dependent on both the source and the individual features of each organism. Herein the view is turned on investigation of activity of new analogs of natural FELL peptide as a promising alternative of the existing antipain molecules. All targeted compounds are obtained by means of conventional peptide synthesis on solid support using standard Fmoc/OtBu approach and their analgesic activity was evaluated by Paw-pressure (Randall-Selitto) test. Determination of the in vivo analgesic activity of the newly synthesized substances showed that the substitution of both Leu (BB11) with Val residues (BB8) increased PPT of the experimental animals on the 10th min, compared to the values after the nonmodified parent molecule injection. On the 20th and the 30th min, BB8 analgesic activity was comparable to BB11 and further a decrease in the PPT was observed. In addition, compared to the controls, analgesia exists until the end of the monitored period of 50 min. The other three newly synthesized substances including Nle (BB6), Ile (BB7) and triple Leu (BB5) instead of double Leu residues showed time-varying short-term analgesic activity, which did not reach that of the parent molecule BB11. Final results show that D-Phe in a first position of the molecule, combined with both Leu residues in the third and fourth positions are the best combination concerning analgesic activity. In addition, lengthening the peptide chain by adding one more hydrophobic residue has also a positive effect on the obtained analgesia. Cytotoxicity of final molecules is significantly lower than those of the positive control SLS, combined with complete hydrolytic stability, which allows their safety use in pharmacy.
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    Synthesis, Hydrolytic Stability and In Vivo Biological Study of Bioconjugates of the Tetrapeptides FELL Containing Pyrrole Moiety
    (2023-12-01) Borisova B.; Vladimirova S.; Nocheva H.; Laronze-Cochard M.; Gérard S.; Petrin S.; Danalev D.
    Background: Bioconjugates are promising alternatives for the multiple targeting of any disease. Pyrrole heterocycle is well known with many activities and is a building block of a lot of medical drugs. On the other hand, peptides are short molecules with many advantages such as small size, ability to penetrate the cell membrane and bond-specific receptors, vectorizing potential, etc. Thus, hybrid molecules between peptide and pyrrole moiety could be a promising alternative as an anti-pain tool. Methods: New bioconjugates with a general formula Pyrrole (α-/β-acid)-FELL-OH (NH2) were synthesized using Fmoc/OtBu peptide synthesis on solid support. HPLC was used to monitor the purity of newly synthesized bioconjugates. Their structures were proven by electrospray ionization mass spectrometry. The Paw Pressure test (Randall–Selitto test) was used to examinate the analgesic activity. Hydrolytic stability of targeted structures was monitored in three model systems with pH 2.0, 7.4 and 9.0, including specific enzymes by means of the HPLC-UV method. Results: The obtained results reveal that all newly synthesized bioconjugates have analgesic activity according to the used test but free pyrrole acids have the best analgesic activity. Conclusions: Although free pyrrole acids showed the best analgesic activity, they are the most unstable for hydrolysis. Combination with peptide structure leads to the hydrolytic stabilization of the bioconjugates, albeit with slightly reduced activity.
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    Synthesis, In Silico Logp Study, and In Vitro Analgesic Activity of Analogs of Tetrapeptide FELL
    (2023-08-01) Borisova B.; Nocheva H.; Gérard S.; Laronze-Cochard M.; Dobrev S.; Angelova S.; Petrin S.; Danalev D.
    Background: The inflammatory process represents a specific response of the organism’s immune system. More often, it is related to the rising pain in the affected area. Independently of its origin, pain represents a complex and multidimensional acute or chronic subjective unpleasant perception. Currently, medical doctors prescribe various analgesics for pain treatment, but unfortunately, many of them have adverse effects or are not strong enough to suppress the pain. Thus, the search for new pain-relieving medical drugs continues. Methods: New tetrapeptide analogs of FELL with a generaanalgesic-Glu-X3-X4-Z, where X = Nle, Ile, or Val and Z = NH2 or COOH, containing different hydrophobic amino acids at positions 3 and 4, were synthesized by means of standard solid-phase peptide synthesis using the Fmoc/OtBu strategy in order to study the influence of structure and hydrophobicity on the analgesic activity. The purity of all compounds was monitored by HPLC, and their structures were proven by ESI-MS. Logp values (partition coefficient in octanol/water) for FELL analogs were calculated. Analgesic activity was examined by the Paw-pressure test (Randall-Selitto test). Results: The obtained results reveal that Leu is the best choice as a hydrophobic amino acid in the FELL structure. Conclusions: The best analgesic activity is found in the parent compound FELL and its C-terminal amide analog.