Interference of MI‐D, a new mesoionic compound, on artificial and native membranes

Cadena, Sílvia Maria Suter Correia; Carnieri, Eva Gunilla Skare; Echevarrı́a, Aurea; Oliveira, Maria Benigna Martinelli de

doi:10.1002/cbf.932

Cited by 24 publications

(16 citation statements)

References 32 publications

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“…Different classes of mesoionic compounds have demonstrated a wide range of biological activities such as anti-inflammatory and analgesic, 5 antiparasitic, 6,7 antibacterial, 8,9 antiplatelet, fibrinolytic, thrombolytic and broncholytic effects, 10 as well as anticancer potency. [11][12][13][14][15][16][17] The promising therapeutic applications have led us to study these interesting compounds in our laboratory. We have previously described the survival enhancement of Ehrlich and Sarcoma 180 tumor-bearing mice treated with 4-phenyl-5-(4'-X-styryl)-1,3,5-thiadiazolium-2-phenylamine chlorides.…”

Section: Introductionmentioning

confidence: 99%

“…12 Respiratory chain inhibition, transmembrane potential collapse, and ATPase activity in intact rat liver mitochondria were observed when the 4-phenyl-5-(4'-X-styryl)-1,3,5-thiadiazolium-2-phenylamine chlorides were used. 13,14 In addition, Senff-Ribeiro et al 15 showed that 4-phenyl-5-(4'-nitro-styryl)-1,3,5-thiadiazolium-2-phenylamine chloride displays an important antitumor activity against murine melanoma B16F10. This compound was cytotoxic in vitro, decreasing cell viability and proliferation, and was able to inhibit tumor growth by ca.…”

Section: Introductionmentioning

confidence: 99%

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Improved synthesis of 1,3,4-thiadiazolium-2-phenylamines using microwave and ultrasound irradiation and investigation of their cytotoxic activity

Reis¹,

Echevarria-Lima²,

Miranda³

et al. 2011

J. Braz. Chem. Soc.

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Uma nova e eficiente síntese de oito derivados da classe 1,3,4-tiadiazolio-2-fenilaminas (1-8, sendo o derivado 8 inédito na literatura) foi realizada utilizando cloreto de tionila ou cloreto de trimetilsilano como catalisadores sob irradiação de microondas ou ultra-som. Os compostos alvos foram obtidos em bons rendimentos e em tempo extraordinariamente curtos, 5 min sob irradiação de microondas e 10 min sob irradiação de ultra-som, quando comparados com a metodologia tradicional (24 a 48 h em repouso a temperatura ambiente). Os melhores rendimentos foram obtidos usando irradiação de microondas e, de maneira geral, usando o cloreto de tionila ao invés de cloreto de trimetilsilano. A citotoxicidade foi avaliada frente à linhagem de leucemia humana K562 e do linfoma Daudi, apresentando resultados promissores para o derivado cloreto de 4-fenil-5-(4'-nitro-estiril)-1,3,4-tiadiazolio-2-fenilamina.A new and efficient synthesis of eight 1,3,4-thiadiazolium-2-phenylamine derivatives (1-8, where 8 is novel in the literature) was performed using thionyl chloride or trimethylsilyl chloride as catalysts under microwave or ultrasound irradiation. The target compounds were obtained in good yields and remarkably short times, 5 min under microwave irradiation and 10 min under ultrasound irradiation, where compared to traditional methodology (24 to 48 h at room temperature standing). The best yields were obtained using the microwave irradiation and, in general way, using thionyl chloride instead trimethylsilyl chloride. The cytotoxicity against K562 human leukemia and Daudi lymphoma lines was evaluated and showed promising results from the 4-phenyl-5-(4'-nitro-styryl)-1,3,4-thiadiazolium-2-phenylamine chloride derivative.Keywords: mesoionic heterocycle compounds, microwave, ultrasound, cytotoxic activity IntroductionMesoionic compounds are a special class of heterocycles with potential therapeutic applications due to their unique chemical properties. They possess a betaine-like character with a partial positive charge on the heterocyclic ring that is balanced by a negative charge located on an exocyclic atom or group.1,2 The large separation between the charged regions leads to large dipole moments of about 4-5 D.3,4 These properties suggest the possibility of interacting with biomolecules such as proteins and DNA. Additionally, the overall neutral character of these compounds enables them to cross biological membranes. Different classes of mesoionic compounds have demonstrated a wide range of biological activities such as anti-inflammatory and analgesic, 5 antiparasitic, 6,7 antibacterial, 8,9 antiplatelet, fibrinolytic, thrombolytic and broncholytic effects, 10 as well as anticancer potency.11-17 The promising therapeutic applications have led us to study these interesting compounds in our laboratory. We have previously described the survival enhancement of Ehrlich and Sarcoma 180 tumor-bearing mice treated with 4-phenyl-5-(4'-X-styryl)-1,3,5-thiadiazolium-2-phenylamine chlorides.12 Respiratory chain inhibition, transmembrane ...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Improved synthesis of 1,3,4-thiadiazolium-2-phenylamines using microwave and ultrasound irradiation and investigation of their cytotoxic activity

Reis¹,

Echevarria-Lima²,

Miranda³

et al. 2011

J. Braz. Chem. Soc.

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“…Finally, previous studies (16,50) showed that structural characteristics of mesoionic compounds enable them to cross cellular membranes and can strongly interact with biomolecules (2). Thus we can hypothesize that the relaxation induced by CMMTT may probably due to a direct intracellular effect on the endothelial NOS and consequent activation of the NO cascade; nevertheless, additional experiments are necessary to clearly elucidate the action mechanisms involved in this response.…”

Section: Discussionmentioning

confidence: 99%

Endothelium-Derived Nitric Oxide Contributes to the Vasorelaxant Response Induced by Mesoionic 2-(4-Chlorophenyl)-3-methyl-4-(4-methoxyphenyl)-1;3-thiazolium-5-thyolate (CMMTT) in Rats

et al. 2009

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Abstract. This study was performed to investigate the mechanisms involved in the vasorelaxation induced by mesoionic 2-(4-chlorophenyl)-3-methyl-4-(4-methoxyphenyl)-1;3-thiazolium-5-thyolate (CMMTT), a newly synthesized mesoionic compound, in rat superior mesenteric arteries. In phenylephrine (10 μM)-pre-contracted mesenteric rings, CMMTT (10 −14 -10 −6 M) induced a concentration-dependent relaxation [pD 2 = 10.26 ± 0.05, E max = 80.8 ± 5.8%], and this effect was almost abolished after either removal of the vascular endothelium [E max = 17.7 ± 4.2%, P<0.001], removal of the vascular endothelium plus100 μM N ω -nitro-L-arginine methyl esther (L-NAME) [E max = 21.0 ± 2.0 %, P<0.001], or after pre-treatment of the rings with 100 μM L-NAME [E max = 13.3 ± 2.4%, P<0.001] or 10 μM 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) [E max = 13.6 ± 4.8%, P<0.001]. However, endothelium-dependent relaxation induced by CMMTT was not significantly modified after 1 μM indomethacin plus 1 nM atropine [pD 2 = 11.12 ± 0.08, E max = 73.8 ± 5.15%] or 100 nM charybdotoxin (ChTX) plus 100 nM apamin [pD 2 = 10.89 ± 0.08, E max = 58.91 ± 9.8%]. In mesenteric rings, CMMTT (10 −6 M) was able to increase nitric oxide (NO) x levels, and this effect was abolished after removal of the vascular endothelium. In conclusion, the present study, using combined functional and biochemical approaches, demonstrated that CMMTT induced a significant vasorelaxant effect, almost completely mediated by the endothelium, likely via NO release and activation of the NO-cGMP pathway.

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“…Dimyristoylphosphatidylcholine (DMPC) membranes were prepared as described by AntunesMadeira & Madeira (1984) and Cadena et al (2001). Native mitochondrial membranes were prepared as described by Antunes-Madeira & Madeira (1989).…”

Section: Preparation Of Membranesmentioning

confidence: 99%

Effects of natural flavones on membrane properties and citotoxicity of HeLa cells

Herrerias¹,

Oliveira²,

Belem³

et al. 2010

Rev. bras. farmacogn.

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RESUMO: "Efeitos de flavonas naturais em propriedades de membranas e em citotoxicidade de células HeLa". O objetivo deste estudo foi avaliar se eupafolina e hispidulina, flavonas extraídas do Eupatorium littorale Cabrera, Asteraceae, possuíam a capacidade de alterar propriedades das membranas biológicas e promover efeitos citotóxicos. Eupafolina (50-200 µM) reduziu em aproximadamente 30% a velocidade e amplitude do inchamento mitocondrial induzido por valinomicina e 60-100% o inchamento mitocondrial dependente de substrato. Além disso, eupafolina na dose de 200 µM reduziu a transição de permeabilidade mitocondrial em 35% entretanto, a hispidulina não alterou este parâmetro em todas as doses testadas. A avaliação da transição de fase dos lipossomas de DMPC com a sonda DPH demonstrou que ambas as flavonas afetam a fase gel e fluida. Quando lipossomas de membranas mitocondriais e a sonda DPH-PA foram utilizados, houve aumento da polarização de fluorescência promovido pela hispidulina. Eupafolina e hispidulina, na dose de 100 µM, promoveram 40% de redução da viabilidade de células HeLa em 24 h. Nossos resultados sugerem que eupafolina e hispidulina têm efeitos citotóxicos que podem ser explicados em parte pelas alterações promovidas por estas flavonas sobre propriedades de membranas biológicas e sobre a bioenergética mitocondrial.Unitermos: Eupafolina, hispidulina, células HeLa, inchamento mitocondrial. ABSTRACT:The aim of this study was to determine whether eupafolin and hispidulin, flavones extracted from Eupatorium littorale Cabrera, Asteraceae, have the ability to change properties of biological membranes and promote cytotoxic effects. Eupafolin (50-200 µM) decreased approximately 30% the rate and total amplitude of valinomycin induced swelling and 60-100% the energy-dependent mitochondrial swelling. Moreover, eupafolin (200 µM) reduced 35% the mitochondrial permeability transition, and hispidulin did not change this parameter in any of the doses tested. The evaluation of phase transition of DMPC liposomes with the probe DPH demonstrated that hispidulin and eupafolin affect gel and fluid phase. With mitochondrial membrane as model, hispidulin increased the polarization of fluorescence when used DPH-PA probe. Eupafolin and hispidulin (100 µM) promoted a reduction of 40% in cellular viability of HeLa cells in 24 h. Our results suggest that eupafolin and hispidulin have cytotoxic effects that can be explained, in part, by alterations promoted on biological membranes properties and mitochondrial bioenergetics.

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Interference of MI‐D, a new mesoionic compound, on artificial and native membranes

Cited by 24 publications

References 32 publications

Improved synthesis of 1,3,4-thiadiazolium-2-phenylamines using microwave and ultrasound irradiation and investigation of their cytotoxic activity

Improved synthesis of 1,3,4-thiadiazolium-2-phenylamines using microwave and ultrasound irradiation and investigation of their cytotoxic activity

Endothelium-Derived Nitric Oxide Contributes to the Vasorelaxant Response Induced by Mesoionic 2-(4-Chlorophenyl)-3-methyl-4-(4-methoxyphenyl)-1;3-thiazolium-5-thyolate (CMMTT) in Rats

Effects of natural flavones on membrane properties and citotoxicity of HeLa cells

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