In vitro and in vivo anti-tumoral activities of imidazo[1,2-a]quinoxaline, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline derivatives

Moarbess, Georges; Deleuze‐Masquéfa, Carine; Bonnard, Vanessa; Gayraud-Paniagua, Stéphanie; Vidal, Jean-Rémi; Bressolle, Françoise; Pinguet, Frédèric; Bonnet, Pierre-Antoine

doi:10.1016/j.bmc.2008.05.022

Cited by 112 publications

(94 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We develop imidazo[1,2-a]quinoxaline drugs with interesting antitumoral activity against lymphoma [15] and melanoma [16]. On melanoma, the first lead compound (EAPB0203, IC 50 = 1.57 lM) has an in vitro activity 110 times higher than fotemustine (IC 50 = 173 lM) and 45 times higher than imiquimod (IC 50 = 70 lM) used as references [16].…”

Section: Discussionmentioning

confidence: 99%

“…On melanoma, the first lead compound (EAPB0203, IC 50 = 1.57 lM) has an in vitro activity 110 times higher than fotemustine (IC 50 = 173 lM) and 45 times higher than imiquimod (IC 50 = 70 lM) used as references [16]. In mice model, EAPB0203 is more potent than fotemustine.…”

Section: Discussionmentioning

confidence: 99%

“…EAPB0203 also has a potential therapeutic role in the treatment of malignant melanoma [16]. In a mouse model, EAPB0203 treatment schedules caused a signifi- cant decrease in tumor size compared to vehicle control and fotemustine treatment [16].…”

Section: Introductionmentioning

confidence: 99%

“…In a mouse model, EAPB0203 treatment schedules caused a signifi- cant decrease in tumor size compared to vehicle control and fotemustine treatment [16]. The chemical structure of this lead molecule has been modulated to optimize its effect [17].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Quantitation of imidazo[1,2‐a]quinoxaline derivatives in human and rat plasma using LC/ESI‐MS

Khier

Moarbess²,

Deleuze‐Masquéfa³

et al. 2009

J of Separation Science

Self Cite

View full text Add to dashboard Cite

Original PaperQuantitation of imidazo[1,2-a]quinoxaline derivatives in human and rat plasma using LC/ESI-MS Since several years, our group developed quinoxalinic compounds. Among the synthesized compounds, in the imidazo[1,2-a]quinoxaline series, EAPB0203 has shown interesting activities both on melanoma and lymphoma. The structure of EAPB0203 has been modulated and a new compound, EAPB0503, exhibits an in vitro cytotoxic activity on melanoma cancer cell line 7 -9 times higher than EAPB0203. We validated an LC/ESI-MS method to simultaneously quantify EAPB0503 and its metabolite EAPB0603 in human and rat plasma. Chromatography was performed on a C8 Zorbax eclipse XDB column with a mobile phase consisting of acetronitrile and formate buffer gradient elution. LC-MS data were acquired in SIM mode at m/z 305, 291, and 303 for EAPB0503, EAPB0603, and the internal standard, respectively. The drug/ internal standard peak area ratios were linked via quadratic relationships to concentrations (low range: 5 -300 lg/L, high range: 100 -1000 lg/L). The method is precise (precision, f14%) and accurate (recovery, 92 -113%). Mean extraction efficiencies, A72% for each analyte, were obtained. The lower LOQs were 5 lg/L. This highly specific and sensitive method was successfully used to investigate plasma concentrations of EAPB0503 and EAPB0603 in a pharmacokinetic study carried out in rat and would also be useful in clinical trials at a later stage.Keywords: Human and rat matrices / Imidazo[1,2-a]quinoxaline / LC/ESI-MS / Lymphoma / Melanoma /

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Quantitation of imidazo[1,2‐a]quinoxaline derivatives in human and rat plasma using LC/ESI‐MS

Khier

Moarbess²,

Deleuze‐Masquéfa³

et al. 2009

J of Separation Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…The cytotoxic activities of the compounds synthesized by our group have been evaluated in vitro against human cancer cell lines (Moarbess et al, 2008a;Khier et al, 2009Khier et al, , 2010. The highest cytotoxic efficacies were obtained with the imidazo[1,2-a]quinoxaline series.…”

Section: Introductionmentioning

confidence: 99%

Metabolism and Pharmacokinetics of EAPB0203 and EAPB0503, Two Imidazoquinoxaline Compounds Previously Shown to Have Antitumoral Activity on Melanoma and T-Lymphomas

Khier

Gattacceca²,

Messaoudi³

et al. 2010

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

ABSTRACT:For several years, our group has been developing quinoxalinic compounds. Two of them, N-methyl-1-(2-phenethyl)imidazo[1,2-a]quinoxalin-4-amine (EAPB0203) and 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine (EAPB0503), have emerged as the most promising anticancer drugs. In the present work, we determined metabolism pathways using liver microsomes from four mammalian species including human. We identified the cytochrome P450 isoform(s) involved in the metabolism and then investigated the pharmacokinetics and metabolism of EAPB0203 and EAPB0503 in rat after intravenous and intraperitoneal administration. Biotransformation of the compounds involved demethylation and hydroxylation reactions. Rat and dog metabolized the compounds at a higher rate than mouse and human. In all species, CYP1A1/2 and CYP3A isoforms were the predominant enzymes responsible for the metabolism. From human liver microsomes, unbound intrinsic clearances were approximately 56 ml/(min ⅐ g) protein. EAPB0203 and EAPB0503 were extensively bound to human plasma proteins, mainly human serum albumin (HSA) (ϳ98-99.5%). Thus, HSA could act as carrier of these compounds in human plasma. Scatchard plots showed patterns in which the plots yielded upwardly convex hyperbolic curves. On the basis of the Hill coefficients, there appears to be interaction between the binding sites of HSA, suggesting positive cooperativity. The main in vitro metabolites were identified in vivo. Total clearances of EAPB0203 and EAPB0503 [3.2 and 2.2 l/(h ⅐ kg), respectively] were notably lower than the typical cardiac plasma output in rat. The large volumes of distribution of these compounds (4.3 l/kg for EAPB0203 and 2.5 l/kg for EAPB0503) were consistent with extensive tissue binding. After intraperitoneal administration, bioavailability was 22.7% for EAPB0203 and 35% for EAPB0503 and a significant hepatic first-pass effect occurred.

show abstract

(Hetero)Aryl CH Amination via Organic Electrochemistry

Shah¹,

Ngai²

2022

Handbook of CH-Functionalization

View full text Add to dashboard Cite

Aromatic amines are essential compounds found in various natural products, drugs, and materials. Their widespread presence has motivated scientists worldwide to explore new avenues for the development of aromatic CN bond formation methodologies. Since the turn of the century, there has been a growing impetus to develop sustainable molecular syntheses. Having been recognized as an effective tool to control the redox events and flow of electrons between reactive species, organic electrocatalysis has been revived after being somewhat dormant for decades in industry and academia. This article provides an overview of electrocatalyzed aromatic CN bond formation reactions, which involve dehydrogenative coupling between aromatic CH bonds and amines through electrocatalysis. We present mechanistic insights and the scope of the methodology in terms of various substrates. We also have provided an outlook for future synthetic applications and different technologies that can merge with electrosynthesis.

show abstract

In vitro and in vivo anti-tumoral activities of imidazo[1,2-a]quinoxaline, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline derivatives

Cited by 112 publications

References 13 publications

Quantitation of imidazo[1,2‐a]quinoxaline derivatives in human and rat plasma using LC/ESI‐MS

Quantitation of imidazo[1,2‐a]quinoxaline derivatives in human and rat plasma using LC/ESI‐MS

Metabolism and Pharmacokinetics of EAPB0203 and EAPB0503, Two Imidazoquinoxaline Compounds Previously Shown to Have Antitumoral Activity on Melanoma and T-Lymphomas

(Hetero)Aryl CH Amination via Organic Electrochemistry

Contact Info

Product

Resources

About