Research paperSynthesis of 5-(4-(1H-phenanthro[9,10-d]imidazol-2-yl)benzylidene)thiazolidine-2,4-dione as promising DNA and serum albumin-binding agents and evaluation of antitumor activity
Graphical abstract
Introduction
The development of diverse and novel small scaffold is causing higher attention in the medicinal and biological systems [[1], [2], [3]]. This may attribute to growing necessity in assembling libraries of complex substances, to be evaluated as lead compounds in drug discovery and development. Polycyclic aromatic hydrocarbon (PAH) heterocycles are extremely important structural units in a variety of pharmaceutically active substances [[4], [5], [6], [7], [8]] owing to rigid structures that have a role in the progress of antitumor agents due to their ability to insert between stacked base pairs of DNA and thus act as intercalators [9].
Introduction of appropriate side chains to these planar polycyclic heterocycles further increase the interactions with important macromolecules [10]. Many heterocyclic compounds have been synthesized using the phenanthroline as core moiety, some of which having substituted and unsubstituted aryl rings at C2- and/or NH-position(s) of imidazole ring (A-C) that have been identified as potent antitumor agents [11,12] (Fig. 1). Li and co-workers have designed and synthesized a series of polyglycol side chain substituted phenanthro-imidazole (D) as anticancer agent [13]. Moody and co-workers have synthesized a series of phenanthro[9,10-d]imidazoles (E) that showed in vitro potency against human melanoma, breast and colon cancer cell lines as well as inhibition of pathway of molecular chaperone heat shock protein 70 (Hsp70) in cells [14].
Phenanthrene-imida-/oxa-zole also showed favourable properties such as high extinction coefficient, ease of synthesis, stability and superior absorption and emission properties [15], which was commonly utilized in various optical sensors and probes. To the best of our knowledge, only few literature reports are available for anticancer activity of phenanthrene-imida-/oxa-zole moieties. In the framework of our program to develop the potentially bioactive heterocyclic compounds and in continuation with our on-going interests in this field [[16], [17], [18]], here, we have designed and synthesized a series of compounds with different substitution of aromatic rings at C2 position which can able to form H-bonds and π-interactions with various biomacromolecules, that may increase the binding affinity with DNA and thus, improve the antiproliferative activity. The planarity of this series of compounds is important to intercalate into the base pairs of DNA double helix, causing miscoding that resulting in cell death.
A facile procedure has been trailed for synthesis of 2-(aryl)-1H-phenanthro[9,10-d]imidazole/oxazole via condensation of 9,10-phenanthrenedione with aryl aldehydes followed by substitution with various heterocyclic moieties. In addition to these compounds, 7H-acenaphtho[1,2-d]imidazol-8-yl derivatives have also been synthesized that emerged as a promising chemical scaffold for the anticancer activity. Synthesized compounds were subjected to cytotoxic assay in 60 various human cancerous cell lines. The interactions of these compounds were further studied with human and calf thymus (Ct) DNA for intercalation mode of binding as well as BSA and HSA for protein transport. Moreover, molecular modelling was used to gain further understanding into the binding mode and binding affinity of phenanthroline derivative in the active site of DNA.
Section snippets
Chemistry
A series of 1H-phenanthro[9,10-d]imidazole/oxazole and 7H-acenaphtho[1,2-d]imidazole derivatives has been synthesized with substitution at C2 position possessing aromatic rings like thiazolidine, phenol, salicylaldehyde, pyrene, naphthalimide etc (Scheme 1, Scheme 2, Scheme 3, Scheme 4). Accordingly, series of 2-substituted 1H-phenanthro[9,10-d]imidazole (3) and phenanthro[9,10-d]oxazole (4) were synthesized by heating the phenanthrene-9,10-dione (1) and substituted aromatic aldehydes (2a-h) at
Conclusion
A series of 1H-phenanthro[9,10-d]imidazole/oxazole and 7H-acenaphtho[1,2-d]imidazole were synthesized and evaluated for antiproliferative activity. Compound 8 with thiazolidine moiety at C-2 position of 1H-phenanthro[9,10-d]imidazole exhibited better growth inhibitory activity for most of the cancer cell panels than other derivatives. In addition, an MTT assay used for the evaluation of the cytotoxicity effects of the compound 8 which showed 90% inhibition to cancer cell lines and only 15%
Chemistry
Melting points were observed in open capillaries and were uncorrected. All commercially available compounds (Spectrochem, Aldrich, Merck etc.) were used without further purification. 1H and 13C NMR spectra were performed on Jeol ECS 400 NMR spectrometer, operated at 400 MHz for 1H nuclei and 100 MHz for 13C nuclei, using CDCl3 and DMSO‑d6 as solvents. Chemical shifts are reported in parts per million (ppm) with TMS as an internal reference. Mass spectra of the synthesized compounds were
Acknowledgments
KP thanks DST-SERB, New Delhi (EMR/2014/000669). IS is grateful for CSIR, New Delhi (Project No. 09/677(0033)/2018-EMR-I) for SRF. NIH, Bethesda, USA for anticancer activities and SAI labs, Thapar Institute of Engineering and Technology, Patiala are also acknowledged.
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