Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: Synthesis and stability of N-acylamino acid derivatives of triazenes

Perry, Maria de Jesus; Carvalho, E.; Rosa, Eduarda; Iley, Jim

doi:10.1016/j.ejmech.2008.06.022

Cited by 15 publications

(7 citation statements)

References 31 publications

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“…Compound extraction was performed using 1 mL of ice-cold acetonitrile. The organic phase was separated, filtered through PVDF syringe filters (Millex: 0.22 μm pore size), and analyzed by HPLC-PDA. ,, The stability profile was evaluated based on the comparison with samples not incubated at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive N-Sulfonylhydrazones

et al. 2022

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Sulfonylhydrazones are privileged structures with multifaceted pharmacological activity. Exploring the hypoglycemic properties of these organic compounds, we previously revealed a new series of Nsulfonylhydrazones (NSH) as antidiabetic drug candidates. Here, we evaluated the microsomal metabolism, chemical stability, and permeability profile of these NSH prototypes, focusing on the pharmacokinetic differences in N-methylated and non-N-methylated analogs. Our results demonstrated that the N-methylated analogs (LASSBio-1772 and LASSBio-1774) were metabolized by CYP, forming three and one metabolites, respectively. These prototypes exhibited chemical stability at pH 2.0 and 7.4 and brain penetration ability. On the other hand, non-Nmethylated analogs (LASSBio-1771 and LASSBio-1773) were hydrolyzed in acid pH and could not cross the artificial blood−brain barrier. The cyano group in LASSBio-1771 was postulated as a possible site of interaction with the heme group, potentially inhibiting CYP enzymes. Moreover, prototypes with the methyl ester group were metabolized by carboxylesterase, and non-N-methylated analogs did not show oxidative metabolism. The prototypes (except LASSBio-1774) showed excellent gastrointestinal absorption. Altogether, our data support the idea that the methyl effect on NSH strongly alters their pharmacokinetic profile, enhances the recognition by CYP enzymes, promotes brain penetration, and plays a protective effect upon acid hydrolysis.

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Section: Methodsmentioning

confidence: 99%

Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive N-Sulfonylhydrazones

et al. 2022

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“…A lot on antitumor drugs posses a limited bioavailability due to low chemical stability limited oral absorption or rapid metabolism [33], because of these is advantage, several prodrug models that can be activated into antitumor drugs have been designed. An important aspect of prodrug design in the need for converting rapidly to the active therapeutic agent in vivo [34], the two nitrogen atoms of co-ligand 4,4 ' -dimethyl-2,2 ' -bipyridyl may be due to cytotoxic activity of this ligand, the results reflect the complexes with (SMX) as a ligand alone is perfect than mixed ligand and the PtL1 is the highest inhibition rates this is may be attributed that the sulfonamide to through exchanges of different functional groups without modification of the structural−S(O) 2 N(H)− features and this is make a novel drug as antitumor [3], and from inorganic side many factors may be responsible in the activity of these prepared complexes in pharmacological composition field like size of metal, charge distribution, geometry shape, and polarity [35],from these results this highest data for this complexes may be attrbuited to the gold (III) complex have square planner geometry and high charge of gold (III) may be reduced inside the cell into low charge gold(I) and make more stable complex which may be due to increasing the inhibition rates on Hep-2 cell line. While the platinum (IV) complex has octahedral geometry and the high charge (IV) may be reduced inside the cell into low charge (II) and this makes more stable complex and increase from inhibition rates on cell line, and the dimer structure of Pd(II) and Cu(II)complex give it the highest inhibition rates (Fig.2).…”

Section: B-cytotoxicity Assaymentioning

confidence: 99%

Synthesis and Characterization of Some Metal Complexes with their Sulfamethoxazoleand 4,4'-dimethyl-2,2'-bipyridyl and study Cytotoxic Effect on Hep-2 Cell Line

Journal¹

2015

Baghdad Sci.J

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The ligand 4-amino-N-(5-methylisoxazole-3-yl)-benzene-sulfonamide(L1) (as a chelating ligand) was treated with Pd(II),Pt (IV) and Au(III) ions in alcoholic medium in order to prepare a series of new metal complexes. Mixed ligand complexes of this primary ligand were prepared in alcoholic medium in presence of the co-ligand 4,4'-dimethyl-2,2'-bipyridyl(L2) with Cu(II) ,Pd(II) and Au(III) ions. The complexes were characterized in solid state using flame atomic absorption, elemental analysis C.H.N.S, FT-IR, UV-Vis Spectroscopy, conductivity and magnetic susceptibility measurements. The nature of some complexes formed in ethanolic solution has been studied following the molar ratio method, also stability constant was studied and the complexes found to be stable in molar ratio1:1.an octahedral geometry was suggested for PdL1L2, PtL1and AuL1L2 complexes, square planar was suggested for AuL1 and PdL1complexes,while CuL1L2 complex has a square pyramidal geometry. Cytotoxic effect of theprepared complexes as well as ligands was evaluated against Hep-2 cell line using four different concentrations (625, 1250, 2500&5000 µg/ml) respectively in an exposure time 48 hrs comparing this effect with control positive Cis-Pt as reference drug. The obtained results refers to the higher inhibition rates of all complexes and their ligands and ligand (L1) and its complexes give more activity against tested cell than ligand (L2) and its complexes comparable with control positive .

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“…An important aspect of prodrug design is the need for converting rapidly to the active therapeutic agent in vivo. Some triazene derivatives provide a potential prodrug system for anticancer activity (9). On the other hand, some researchers synthesize a range of triazene derivatives and investigate as a prodrug candidates for melanocyte-directed enzyme prodrug therapy (10).…”

Section: Prontosil 4-[(24-diaminophenyl)azo]benzenesulfonamidementioning

confidence: 99%

Synthesis and characterization of triazenes derived from sulfonamides

Ünsalan¹

2011

mpj

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Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: Synthesis and stability of N-acylamino acid derivatives of triazenes

Cited by 15 publications

References 31 publications

Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive N-Sulfonylhydrazones

Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive N-Sulfonylhydrazones

Synthesis and Characterization of Some Metal Complexes with their Sulfamethoxazoleand 4,4'-dimethyl-2,2'-bipyridyl and study Cytotoxic Effect on Hep-2 Cell Line

Synthesis and characterization of triazenes derived from sulfonamides

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