Synthesis and biological evaluation of 4-nitro-substituted 1,3-diaryltriazenes as a novel class of potent antitumor agents

Čimbora‐Zovko, Tamara; Brozović, Anamaria; Piantanida, Ivo; Fritz, Gerhard; Virag, Andrej; Alič, Branko; Majce, Vita; Kočevar, Marijan; Polanc, Slovenko; Osmak, Maja

doi:10.1016/j.ejmech.2011.04.024

Cited by 26 publications

(24 citation statements)

References 33 publications

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“…1) because it was highly cytotoxic against different tumor cell lines, including a cisplatin-resistant human laryngeal carcinoma cell line. Moreover, its antiproliferative activity against tumor cells was significantly higher than against normal cells [15]. We showed that compound 8b did not bind to DNA, unlike the alkyltriazenes (dacarbazine and temozolomide) or the diaryltriazene derivative, berenil.…”

Section: Introductionmentioning

confidence: 84%

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3-Acetyl-bis(2-chloro-4-nitrophenyl)triazene is a potent antitumor agent that induces oxidative stress and independently activates the stress-activated protein kinase/c-Jun NH2-terminal kinase pathway

et al. 2014

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Previously, we described the synthesis and biological activity of a new class of anticancer molecules that preferentially target malignant cells and may serve as potential antitumor agents. Among several synthesized agents, we selected 3-acetyl-1,3-bis(2-chloro-4-nitrophenyl)-1-triazene (8b) as a representative of the group of 4-nitro-substituted 1,3-diaryltriazenes. The aim of this study was to further investigate the mechanism of cell response to the 8b compound. The HeLa human cervical carcinoma cell line was used as an experimental model to further investigate the mechanism of cell response to the 8b compound. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay was used to address cell survival, and western blot (immunoblotting) was used for the expression of relevant proteins after 8b drug exposure. The pretreatment of HeLa cells with salubrinal, a specific inhibitor of endoplasmic reticulum (ER) stress, confirmed the importance of ER stress in apoptosis induced by 8b. We also demonstrate that 8b triggers the activation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) in a time-dependent and dose-dependent manner. Moreover, the inhibition of SAPK/JNK activity by JNK II before 8b treatment increased the survival rate of HeLa cells relative to survival in the presence of 8b alone, indicating the importance of this kinase in cell death. The simultaneous inhibition of ER stress induction and SAPK/JNK activation increased the survival of HeLa cells upon 8b treatment more than inhibition of both pathways independently, suggesting the separate triggering of both signaling pathways. Our data indicate that cytotoxic activity of the novel compound 8b is based on its ability to induce ER stress and SAPK/JNK signaling pathways independently, driving cells to cell death.

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Section: Introductionmentioning

confidence: 84%

“…We showed that compound 8b did not bind to DNA, unlike the alkyltriazenes (dacarbazine and temozolomide) or the diaryltriazene derivative, berenil. Instead, 8b induces reactive oxygen species (ROS) and the endoplasmic reticulum (ER) stress response resulting in apoptosis [15].…”

Section: Introductionmentioning

confidence: 99%

3-Acetyl-bis(2-chloro-4-nitrophenyl)triazene is a potent antitumor agent that induces oxidative stress and independently activates the stress-activated protein kinase/c-Jun NH2-terminal kinase pathway

et al. 2014

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“…INH is a highly specific first-line TB prodrug, which after activation couples isonicotinoyl radical to NADPH and binds irreversibly to enoylAcpM reductase, blocking cell wall synthesis. 14 In addition to nicotinoyl (14) and isonicotinoyl (15) derivatives, some other acyl analogues 2-13 were considered. Since alkyl triazenes are well known as DNA alkylating agents, 11,12 17 For a key of substituents, see Figure 1.…”

Section: Chemistrymentioning

confidence: 99%

Diaryltriazenes as antibacterial agents against methicillin resistant Staphylococcus aureus (MRSA) and Mycobacterium smegmatis

Vajs

Proud

Brozović

et al. 2017

European Journal of Medicinal Chemistry

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Antibiotic resistance poses a critical threat to global health care. Alkyl-and aryltriazene compounds have found utility as DNA-modifying agents and have been previously 2 assessed as potential anti-cancer therapeutics. However, their potential utility as antimicrobials has only recently been appreciated. Therefore, to further investigate the efficacy of these compounds as antibiotics, we synthesized a series of forty six diaryltriazene derivatives and evaluated their antimicrobial properties. Initial experiments showed activity of some diaryltriazene compounds against both methicillin-resistant strains of Staphylococus aureus (MRSA) and against Mycobacterium smegmatis with MICs of less than 0.02 and 1 μg/mL. Those diaryltriazene compounds with potent anti-staphylococcal and anti-mycobacterial activity were inactive as growth inhibitors of mammalian cell lines and yeast. Furthermore, we demonstrated that one of the most active anti-MRSA diaryltriazene derivatives was subject to very low frequencies of resistance at < 10 -9 . Whole genome sequencing of resistant isolates identified mutations in the enzyme that lysylates phospholipids. This could result in the modification of phospholipid metabolism and consequently the characteristics of the staphylococcal cell membrane, ultimately modifying the sensitivity of these pathogens to triazene challenge. Our work has therefore extended the potential range of triazenes, which could yield novel antimicrobials with low levels of resistance.

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“…In view of the biological activities of the triazenes with mentioned scaffold [31,47], considering the information obtained from ADME properties of the synthesized ligand would be valuable. In this study, the pharmacokinetic features of the five synthesized triazenes were predicted through projection on some predefined models provided by volSurf.…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

Synthesis, Crystal Structure, Solution Study and In Silico ADME Profiling of Various Asymmetric Functionalized Triazenes

Gharamaleki

Goodarzi

Bolouhari

et al. 2015

J Inorg Organomet Polym

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Syntheses of some ligands based on asymmetric triazenes consisting 1-(2-methoxycarbonylphenyl)-3-(2-methylphenyl)triazene (1), 1-(2-methoxycarbonylphenyl)-3-(3-methylphenyl)triazene (2), 1-(2-methoxycarbonylphenyl)-3-(4-methylphenyl)triazene (3), 1-(2-methoxycarbonylphenyl)-3-(3,5-dichlorophenyl)triazene (4), 1-(4-chlorophenyl)-3-(4-methylphenyl)-triazene (5) and their related Hg II complexes were reported. The characterizations were performed by FT-IR, 1 H NMR and 13 C NMR spectroscopies. In (3) and (4), both triazenes possess trans-conformation around the (-N=N-) bond and monomeric moieties are linked to pairs and wave-like chains through C-HÁÁÁO and C-HÁÁÁN hydrogen bonds which are further assembled by stacking through secondary pÁÁÁp interactions [3.829(1) and 3.736(1) Å ]. The reaction of (1) and Hg(NO 3 ) 2 in methanol produces the corresponding Hg II complex (6) where each triazenide binds to the Hg II atom through two nitrogen atoms of triazenide and one oxygen atom of pendant methoxycarbonyl group forming distorted MN 4 O 2 octahedral around the Hg II atom. The stoichiometry and formation of complex (6) and (8) in methanol solution were investigated by UV-Vis titration. Moreover, Reaction of substituted 1,3-diaryltriazenes (2) and (5) with Hg II salts afford a family of orange complexes (7) and (8), respectively. Finally, the chemical structures of the investigated ligands were correlated to their pharmacokinetic behaviour using five pre-calculated models implemented in VolSurf program. Graphical Abstract Polyhedron around HgII atom coordinated by two triazenide ligands in an octahedron fashion.

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Synthesis and biological evaluation of 4-nitro-substituted 1,3-diaryltriazenes as a novel class of potent antitumor agents

Cited by 26 publications

References 33 publications

3-Acetyl-bis(2-chloro-4-nitrophenyl)triazene is a potent antitumor agent that induces oxidative stress and independently activates the stress-activated protein kinase/c-Jun NH2-terminal kinase pathway

3-Acetyl-bis(2-chloro-4-nitrophenyl)triazene is a potent antitumor agent that induces oxidative stress and independently activates the stress-activated protein kinase/c-Jun NH2-terminal kinase pathway

Diaryltriazenes as antibacterial agents against methicillin resistant Staphylococcus aureus (MRSA) and Mycobacterium smegmatis

Synthesis, Crystal Structure, Solution Study and In Silico ADME Profiling of Various Asymmetric Functionalized Triazenes

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