Microwave assisted synthesis of pyrido[2,3-a]carbazoles; investigation of in vitro DNA binding/cleavage, antioxidant and cytotoxicity studies

doi:10.1016/j.jphotobiol.2014.02.020

Journal of Photochemistry and Photobiology B: Biology

Volume 133, 5 April 2014, Pages 145-152

https://doi.org/10.1016/j.jphotobiol.2014.02.020 Get rights and content

Highlights

•
The pyrido[2,3-a]carbazoles were synthesized by p-TsOH catalyzed microwave reaction.
•
The structure of all the compounds was established by spectroscopic method.
•
The compounds interact with CT-DNA, intercalatively.
•
The compounds possess significant antioxidant property against DPPH radical.
•
The compound 3e shows higher IC₅₀ value than the other compounds against tumor cell.

Abstract

We have developed an effective microwave assisted p-TsOH catalyzed synthesis of pyrido[2,3-a]carbazoles via a one pot reaction of ethanolamine and 1-chloro-2-formyl carbazoles. The structure has been characterized by spectroscopic methods. The electronic spectroscopic experimental evidence strongly showed that the compounds could interact with calf thymus DNA (CT-DNA) through intercalation with a binding constant value of 1.2–3.0 × 10⁴ M⁻¹. All the compounds showed weak to moderate capacity of scavenging with DPPH. The cytotoxicity has been evaluated by MTT assay against MCF-7 cell line and compared with standard drug cisplatin.

Graphical abstract

Introduction

Carbazole and its derivatives are an important type of nitrogen containing aromatic heterocyclic compounds endowed with various pharmacological activities such as anti-cancer, antimicrobial, antiviral, anti-inflammatory and antioxidant activity [1], [2], [3]. Carbazole scaffold is present in many drugs such as carvedilol and carproten. Carvedilol is an antihypertensive drug act as a non-specific β-adrenergic antagonist. Carproten is a non-steroidal anti-inflammatory drug (NSAID) and a selective COX-2 inhibitor [4], [5]. Also, carbazole ring is present in a variety of naturally occurring medicinal active substances, such as ervatamine [6], 20-epiervatamine [7], 16-episilicine [8], eruistine [9], caulersine [10], homoarcyriaflavin [11], and are having highly interesting pharmacological properties.

In particular, several pyridocarbazole derivatives has been reported to exhibit anti-cancer and anti-HIV activities [12], [13], [14], [15], [16]. In addition ellipticine and its regioisomeric annulated indole and carbazole derivatives with pyrido[4,3-b]carbazole framework constitute an interesting class of antitumor activity drugs [17], [18], [19], [20]. Among the ellipticine compounds, the 9-methoxyellipticine shows activity against a verity of human tumor cell lines, especially agaius leukaemia where as the quaternary pyridinium salt ellipticinium acetate was developed against metastatic breast cancer [19], [21]. Apart from their utility for several disease targets, pyrido[2,3-a]carbazole derivatives has shown an enormous synthetic value in the preparation of various bio-active molecules.

To encourage by the varied biological activities of pyrido carbazole derivatives, we used an alternative green reaction (Microwave) for the synthesis of pyrido carbazole derivatives. On the other hand, for the stringent and growing environmental regulations, organic chemists are requested to develop environmentally benign synthetic methodologies. Microwave-assisted heating has been shown to be an invaluable technology in synthesis since it highly reduces reaction times, typically from days or hours to minutes or even seconds. It can also provide pure products in quantitative yields. Solvent-free reaction techniques were successfully coupled with the microwave method because they avoid the use of the low boiling point and high vapour pressure solvents, which may sometimes lead to explosions. Additionally, it can also avoid the use of poisonous and expensive solvents, and as such can be environmentally benign, and make manipulations much easier [22], [23].

Considering the above mentioned fact, herein we wish to report a simple, convenient microwave assisted synthesis of pyrido[2,3-a]carbazoles from the reaction of ethanolamine and 1-chloro-2-formyl carbazoles in the presence of p-TsOH as the catalyst with shorter reaction times and good yield. The structures of the products were deduced from their elemental analysis data, and from their IR, mass, ¹H and ¹³C NMR spectra. Furthermore, the newly synthesized compounds were evaluated for their in vitro DNA binding/cleavage affinity, antioxidant assay and cytotoxicity against MCF-7 breast cancer cell line.

Section snippets

Materials, instruments and methods

All the chemicals used were chemically pure and AR grade. Solvents were purified and dried according to the standard procedure [24]. Elemental analysis (C, H and N) was performed on a vario EL 111 CHN analyzer. IR spectra were recorded by KBr pellet technique in the range 400–4000 cm⁻¹ region using a Perkin Elmer FT-IR 8000 spectrophotometer model. ¹H and ¹³C NMR spectra were recorded on a Bruker AV 111 500 MHz instrument using TMS as internal reference. Electron ionization mass spectra of the

Chemistry

The focus of this work is on the synthesis of pyrido[2,3-a]carbazoles by microwave assisted synthetic method. The reactants 1-chloro-2-formyl carbazole 1a and ethanolamine 2 were reacted in the presence of p-TsOH as the catalyst with shorter reaction time and good yield. The reaction was attempted in the presence of various catalysts like tin chloride, zinc chloride, aluminium chloride and ferric chloride (Table 1) in micro oven, when these metal chlorides were replaced by p-TsOH

Conclusions

We have synthesized pyrido[2,3-a]carbazoles by p-TsOH catalyzed microwave reaction of 1-chloro-2-formyl carbazole with ethanolamine. The structure of the newly synthesized compounds is established by spectroscopic methods. The DNA binding ability of the compounds were assessed by absorption spectra which inferred an intercalative mode of binding the experimental result suggested that the compound 3e can bind to DNA more strongly than the other compounds. The binding constant value of 3e is 3.0 ×

Acknowledgement

This work was carried out with financial support from the University Grants Commission (UGC), New Delhi. (Project F. No. 41-279/2012 (SR)).

References (35)

E. Yamuna et al.
Eur. J. Med. Chem.
(2012)
T. Indumathi et al.
Eur. J. Med. Chem.
(2011)
N. Noguchi et al.
Biochem. Pharmacol.
(2000)
A. Zall et al.
Bioorg. Med. Chem.
(2011)
M. Andriantsiferana et al.
Tetrahedron Lett.
(1977)
G.H. Svoboda et al.
J. Pharm. Sci.
(1968)
K. Hirata et al.
Bioorg. Med. Chem. Lett.
(1999)
Microwaves in Organic Synthesis
M. Munde et al.
J. Mol. Biol.
(2010)
S.C. Jain et al.
J. Mol. Biol.
(1979)

A. Wolfe et al.

Biochemistry

(1987)

B.N. Ames

Science

(1983)

H.J. Knolker et al.

Chem. Rev.

(2002)

M.L. Bennasar et al.

J. Org. Chem.

(1997)

J.R. Knox et al.

Aus. J. Chem.

(1975)

J.-M. Yue et al.

Helv. Chim. Acta

(2005)

J.Y. Su et al.

J. Nat. Prod.

(1997)

Cited by (12)

Microwave-assisted synthesis of bioactive heterocycles: An overview
2022, Tetrahedron
Citation Excerpt :
Annulated pyridines, a subclass of pyridines containing fused cyclic/aryl moieties, are a type of biologically active compounds that have been explored for antitumor and antifungal characteristics in medicinal chemistry. Quiroga group synthesized pyrazolo[3,4-g] [1,8]napthyridine-5-amine derivatives which showed potential antitumor and antifungal activity (Scheme 9) [87]. Under 300 W microwave irradiation, ortho-aminonitrile 44 reacted with excess cyclic ketone 45 in presence of 10 mol % zinc chloride in ethanol in one pot at 120 °C for 5–10 min and produced the desired derivatives 46 with 55–80%.
Microwave-assisted synthesis of numerous bioactive scaffolds has gained much attention of late in organic chemistry. Most of the heterocyclic rings can be synthesized using the microwave irradiation method. This application is further used in the synthesis of active pharmaceutical ingredients containing heterocycle moiety. These bioactive heterocyclic derivatives synthesized by microwave-assisted one-pot multicomponent reaction, have significant anticancer, antibacterial, and antimicrobial properties. Herein, we summarize significant advances in the microwave-assisted synthesis of heterocycles and their useful bioactive properties.
Synthesis and biological activity of pyrrolidine/piperidine substituted 3-amido-9-ethylcarbazole derivatives
2021, Journal of Molecular Structure
Citation Excerpt :
Upon addition of increased amount of ct-DNA, a significant hypochromism and a red shift of about 3–5 nm was observed in the band at the range of 228–315 nm. This can be attributed to a strong interaction between DNA and compounds, and it also likely that these compounds bind to the DNA helix via intercalation [52]. The synthesized compounds showed comparable DNA binding activity with such activitiy reported in the literature [8].
In this study, pyrrolidine/piperidine substituted 3-amido-9-ethylcarbazole derivatives were synthesized and characterized by FT-IR, ¹H NMR, ¹³C NMR spectroscopic and HRMS techniques. Acetylcholinesterase inhibition activity of the compounds were determined. Also, total antioxidant capacity, DPPH radical scavenging and metal chelating activity methods were used to evaluate the antioxidant effects of the compounds. In addition, the antiproliferative effect of the compounds on HT-29 and SH-SY5Y cells were assessed by the MTT assay. In addition, gel electrophoresis was utilized to determine DNA cleavage and topoisomerase II inhibition activities of 2a and 2b. Moreover, the features of the interaction between the compounds and calf thymus DNA (ct-DNA) were evaluated using UV–Vis absorption spectroscopic titration method. The biological activitiy demonstrated an acetylcholinesterase inhibition activity, antioxidant activity, and antiproliferative effect of the compounds on HT-29 and SH-SY5Y cells. The compounds also augmented DNA cleavage from the supercoiled form (SC, Form I) to the nicked circular form (NC, Form II), a process free of simultaneous Form III formation, which indicated the cleavage of single-strand DNA. The compounds prevented topoisomerase II functions at varying concentrations, and are connected to ct-DNA through the intercalation mode. Therefore, the compounds may be offered as anti-cancer drug candidate for use in cancer treatment.
Spectroscopic and spectrophotometric studies on hydrogen bonded charge transfer complex of 2-amino-4-methylthiazole with chloranilic acid at different temperatures
2018, Journal of Molecular Liquids
Citation Excerpt :
The study of the molecular interaction between donor and acceptor is due to wide applications [30–37]. These organic molecules exist in different isomeric forms, having enormous synthetic and biological importance such as antibacterial, antifungal, antioxidant, anticancer, DNA-binding/cleavage and ion transfer through lipophilic membranes [30,38–47]. Charge transfer complexes also play an important role in the field of magnetic, electrical conductivity and optical properties [48,49].
The synthesized hydrogen bonded charge transfer (CT) complex between 2-amino-4-methylthiazole (AMT) and chloranilic acid (CLA) was characterized using various spectral techniques such as UV–visible, FTIR, ¹H NMR, ESI-MS, P-XRD and TG/DTA analysis. The CT complexes act as an intermediate in a variety of reactions involving electron rich and electron deficient molecules. The spectral analysis of the CT complex suggests that N and NH₂ groups play a major role in determining the orientation in the reaction mechanism. The fluorescence studies show that Ct-DNA interacted with CT complex and quenched its intrinsic fluorescence in a static quenching process. Stern-Volmer equation was used to determine the binding ability of the CT complex with in vitro calf thymus DNA. The different physical parameters such as the association constant (K_CT), molar extinction coefficient (ε), energy of interaction (E_CT), ionization potential (I_D), resonance energy (R_N), free energy (∆G), oscillator strength (f) and transition dipole moment (μ_EN) were determined using Benesi-Hildebrand equation. The Van't Hoff equation was used to calculate the various thermodynamic parameters such as enthalpy (ΔH), entropy (ΔS) and free energy (ΔG). The nature of interaction between donor and acceptor moieties can also be visualized by calculating thermodynamic parameters. The molecular interaction between AMT and CLA has been established through N⁺—H∙∙∙∙O^– hydrogen bonding. The straight line method was established by the 1:1 stoichiometry of the CT complex. TG/DTA analysis provided information about changes in material properties as a function of temperature. The various fragmentation of the CT complex was evaluated using ESI-mass spectroscopy.
Anticancer Tetrahydrocarbazoles: A Wide Journey from 2000 till Date
2024, Letters in Drug Design and Discovery
Synthesis of Pyrazole, Pyridine, and Pyrimidine Derivatives Incorporating Glucaminoid Moiety and Their Antioxidant, Antitumor Activities and Docking Study
2023, ChemistrySelect
An Insight into the Synthesis and Pharmacological Activities of Indoles, Isoindoles and Carbazoles
2022, N-Heterocycles: Synthesis and Biological Evaluation

View all citing articles on Scopus

View full text