Potential antitumor agents. 51. Synthesis and antitumor activity of substituted phenazine-1-carboxamides

Zaid

et al. 2014

J. Electrochem. Soc.

The electrochemical response of two biologically important phenazine derivatives was examined by using cyclic, differential pulse and square wave voltammetry in a wide pH range of 2.0 -12.0. Cyclic voltammetry was employed for the determination of heterogeneous electron transfer rate constant and diffusion coefficient of the analytes. The value of electron transfer rate constant was used for evaluation of Gibbs free energy, enthalpy and entropy changes of redox reactions of the compounds. Differential pulse voltammetry was used for the determination of number of protons and electrons involved in the redox processes. Limits of detection and quantification were assessed by square wave voltammetry. The detailed pH dependent redox mechanisms of the compounds were proposed on the basis of experimental results which were further supported by theoretical calculations. These redox mechanistic pathways are expected to play a key role in understanding the necessary aspects of structure-activity relationships and exploring the hidden routes by which this class of compounds exert its biochemical actions. Phenazines have broad range applications in biology and chemistry.1 This class constitutes a large group of nitrogen containing heterocyclic compounds, the members of which differ in their chemical and physical properties on the basis of type and position of functional groups present. Naturally, phenazines are produced by limited genera of bacteria including Pseudomonas, Burkholderia and Brevibacterium.2 Starting from different parent materials, phenazines can be synthesized by various reactions including oxidative condensation, electrochemical reduction, reductive cyclization and photochemical reactions.From the last 50 years, phenazines are the subject of extensive research investigations because of their broad range applications in pharmaceutical and clinical research.3 Such compounds have been reported for their wide variety of biological activities such as antitumor, anti-parasitic and antibiotic activities. Benzo [a] phenazine acts as efficient DNA intercalating ligand with antitumor activity in leukaemia and solid tumors. 4 1-Hydroxyphenazine has been reported to have promising antifungal activity against various microbes such as aspergillus fumigatus and candida albicans.5 Macrolactone synthesized from benzo [a] phenazine shows good activity against mycobacterium tuberculosis. 6 In general, natural and synthetic phenazines find useful applications against malaria 7 and hepatitis C viral replication. 8The biological activity of phenazines is due to their redox reactions leading to the formation of toxic radicals. 9 Different functional groups attached to phenazine determine their redox potential and solubility. The redox behavior and concomitant modulation of biological activities of phenazines by changing the nature and position of substituents attached to their aromatic rings have been reported by several research groups.10-12 Phenazines can alter cellular redox states and act as transporters of electrons to altern...

mentioning

confidence: 99%

pH Dependent Electrochemical Characterization, Computational Studies and Evaluation of Thermodynamic, Kinetic and Analytical Parameters of Two Phenazines

Zaid

et al. 2014

J. Electrochem. Soc.

“…Some of the bis-intercalators were found to possess high selective toxicity against human colon carcinoma (Yong et al, 2005;Denny, 2003). In addition to DNA intercalation, the bis-heterocyclic molecules were also shown to exhibit such diverse pharmacological activity as anti-microbial (Holla et al, 1998), anti-protozoal (Coro et al, 2005), anti-inflammatory (Sondhi et al, 2007), anti-HIV (Pomarnacka and Kornicka, 2001), and cytotoxicity (Antonini et al, 2008;Brana et al, 1997;Rewcastle et al, 1987;Gamage et al, 1999;Spicer et al, 2000;Dabholkar and Ansari, 2008). Many of the bis-1,2,4-triazoles have also been reported to possess wide spectrum of biological activity (Holla et al, 2000;Holla et al, 2002;Ghorab et al, 2000;Al-Soud and Al-Masoudi, 2004).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, in vitro cytotoxicity, and anti-microbial studies of 1,4-bis(4-substituted-5-mercapto-1,2,4-triazol-3-yl)butanes

Purohit

Mayur

2010

Med Chem Res

Synthesis and evaluation of cytotoxicity and anti-microbial activity of a series of 1,4-bis(4-substituted-5-mercapto-1,2,4-triazol-3-yl)butane derivatives comprising thioether functionality and other pharmacophore modifications are described. All the newly synthesized compounds were characterized by IR, NMR, elemental analyses, and mass spectral studies. The compounds 4a-f, 5a-f, and 6a-f were evaluated for in vitro cytotoxicity potential using the standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against a panel of three human cancer cell lines: Lung carcinoma A-549, Colon carcinoma HT-29, and Breast Cancer MDA MB-231. All the compounds were subjected to in vitro antibacterial activity against Bacillus subtilus (ATCC 6633), Staphylococcus aureus (ATCC-25923), Escherichia coli (ATCC-25922), and Pseudomonas aeruginosa (ATCC-27853) and their minimal inhibitory concentrations were determined.

“…6 Benzo[a]phenazines are also efficient DNA intercalating ligands, exhibiting antitumor activity in leukaemia and solid tumors. 7 They have also been described as dual inhibitors of topoisomerase I and II. 8 In our search for preparing new derivatives, for synthetic purposes and biological screening, we recently reported 9 that peroxidation of the b-lapachone-derived benzophenazine, named lapazine (1), with m-ClC 6 H 4 CO 2 H/CH 2 Cl 2 generated, unexpectedly, a macrocyclic lactone 2 with a rigid 10-membered ring (27% yield), the corresponding N-oxide 3 (13% yield), and the dihydrobenzophenazine-5-one 4 (35% yield) (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

The preparation of a 10-membered ring macrolactone by selective ozonolysis and the role of the dihydropyran-substituent on the MCPBA-oxidation reaction profile of beta-lapachone phenazines

Silva¹,

Guimarães²,

Teixeira³

et al. 2005

J. Braz. Chem. Soc.

A benzofenazina derivada da β-lapachona foi submetida a ozonólise em condições que forneceram seletivamente a lactona macrocíclica 7,7-dimetil-7,8,9,10-tetrahidro-5H-benzo[3,4]oxecino [5,6-b]quinoxalina-5,10-diona, com rendimento de 52%. O efeito de substituintes localizados no anel diidropirânico das fenazinas, no caso C2'-OH, C2'-Br e C2'-I, em reações de oxidação com MCPBA, foi também investigado.The benzophenazine from β-lapachone was submitted to ozonolysis under conditions that selectively furnished the corresponding rigid macrocyclic lactone 7,7-dimethyl-7,8,9,10-tetrahydro-5H-benzo [3,4]oxecino [5,6-b]quinoxaline-5,10-dione in an yield of 52%. The effect of substituents located at the dihydropyrane moiety of the phenazines, namely C2'-OH, C2'-Br and C2'-I, in the oxidation with MCPBA, was also investigated.Keywords: β-lapachone, ozonolysis, 10-membered ring macrolide, selectivity, effect of substituent IntroductionIn general, natural and synthetic phenazines have attracted considerable attention because of their interesting biological activities, 1 including broad-spectrum antibiotic, 2 antimalarial, 3,4 trypanocidal 5 along with anti hepatitis C viral replication activities.6 Benzo[a]phenazines are also efficient DNA intercalating ligands, exhibiting antitumor activity in leukaemia and solid tumors.7 They have also been described as dual inhibitors of topoisomerase I and II. 8 In our search for preparing new derivatives, for synthetic purposes and biological screening, we recently reported 9 that peroxidation of the b-lapachone-derived benzophenazine, named lapazine (1), with m-ClC 6 H 4 CO 2 H/CH 2 Cl 2 generated, unexpectedly, a macrocyclic lactone 2 with a rigid 10-membered ring (27% yield), the corresponding N-oxide 3 (13% yield), and the dihydrobenzophenazine-5-one 4 (35% yield) (Figure 1). Macrocyclic compounds 2 and 3 were formed via oxidative cleavage of the aromatic double bond at the site of fusion of the dihydropyran moiety with the phenazine component. This region (rings C/E, in 1) (Figure 1) would behave as a conjugated enol ether, which, after the expected epoxide formation and fragmentation would lead to 2 and 3 (further oxidation). An acid-catalysed epoxide-acetal or α-hydroxy hemiacetal would furnish 4. 9Compounds 2 and 3 belong to the class of macrolides, an important group of biologically active compounds, especially recognized as antibiotics. 10Among 10-membered macrolactones, the antibiotic activity of apicularen A and B was reported. 11In the present work, considering 2 and 3, the presence of diaza heterocyclic groups close to the ion-binding macrolactone moiety constitutes attractive molecular features.In searching for a more general application of the oxidative cleavage by MCPBA, 9 we have analysed the role of substituent, at C-2', in the dihydropyrane moiety of lapazine, namely -OH (5), -Br (6) and -I (7) (Figure 1). 1075 The Preparation of a 10-Membered Ring Macrolactone Vol. 16, No. 5, 2005 Additionally, in an attempt to develop a more selective and simpler method by...