Sanjoy Kumar Dey

Synthesis, crystal structure, DNA interaction and in vitro anticancer activity of a Cu(II) complex of purpurin: dual poison for human DNA topoisomerase I and II

Although generation of reactive oxygen species (ROS) by anthracycline anticancer drugs is essential for anti-tumor activity, they make these drugs cardiotoxic. Metal–anthracyclines that generate relatively fewer ROS are however, effective antitumor agents. Purpurin (LH3), a hydroxy-9,10-anthraquinone, closely resembles doxorubicin, an established anthracycline drug. This molecule was chosen to study the extent to which simpler analogues are effective. A Cu(II) complex of LH3 [Cu(II)–(LH2)2] was synthesized to mimic the metal–anthracycline complexes. The crystal structure of [Cu(II)–(LH2)2] was determined by Rietveld refinement of PXRD data using an appropriate structural model developed on the basis of spectroscopic data. This is the first report on the crystal structure of any hydroxy-9,10-anthraquinone with a 3d-transition metal ion. The bond lengths and bond angles obtained by structural refinement corroborate those calculated by the DFT method. DNA binding of the complex was slightly better than purpurin. However, more importantly, unlike purpurin, binding constant values did not decrease with increasing pH of the medium. DNA relaxation assays show Cu(II)–(LH2)2 as a novel potent dual inhibitor of human DNA topoisomerase I and topoisomerase II enzymes. Cu(II)–(LH2)2 stabilizes covalent topoisomerase–DNA adducts both in vitro and within cancer cells. The cleavage assay keeps the complex well ahead of LH3 with regard to efficacy. These results paralleled those of cell growth inhibition and showed that the complex was more effective in killing ALL MOLT-4 cells than LH3, suggesting it targets topoisomerase enzymes within cells. The NADH dehydrogenase assay revealed further that the generation of superoxide was less in the case of the complex as compared to LH3.

Floating mucoadhesive alginate beads of amoxicillin trihydrate: A facile approach for H. pylori eradication.

This study investigates the design of sunflower oil entrapped floating and mucoadhesive beads of amoxicillin trihydrate using sodium alginate and hydroxypropyl methylcellulose as matrix polymers and chitosan as coating polymer to localize the antibiotic at the stomach site against Helicobacter pylori. Beads prepared by ionotropic gellation technique were evaluated for different physicochemical, in-vitro and in-vivo properties. Beads of all batches were floated for >24h with a maximum lag time of 46.3±3.2s. Scanning electron microscopy revealed that the beads were spherical in shape with few oil filled channels distributed throughout the surfaces and small pocket structures inside the matrix confirming oil entrapment. Prepared beads showed good mucoadhesiveness of 75.7±3.0% to 85.0±5.5%. The drug release profile was best fitted to Higuchi model with non fickian driven mechanism. The optimized batch showed 100% Helicobacter pylori growth inhibition in 15h in in-vitro culture. Furthermore, X-ray study in rabbit stomach confirmed the gastric retention of optimized formulation. The results exhibited that formulated beads may be preferred to localize the antibiotic in the gastric region to allow more availability of antibiotic at gastric mucus layer acting on Helicobacter pylori, thereby improving the therapeutic efficacy.

A pharmaceutical cocrystal with potential anticancer activity

The design of pharmaceutical cocrystals has become a prime thrust of crystal engineering and the pharmaceutical industry in recent times – but the use of pharmaceutical cocrystals as regular drugs is yet to be explored. Quinoxaline acts as a basic skeleton of several potential anticancer drugs. We have successfully cocrystallized quinoxaline with another organic molecule 3-thiosemicarbano-butan-2-one-oxime (TSBO, a virus replication inhibitor) and examined the anticancer activity of the cocrystal. The crystal structure of the cocrystal was determined by single crystal X-diffraction study. According to thermogravimetric study the cocrystal exhibits better thermal stability than quinoxaline. UV-Vis spectroscopic study has shown that in solution state the behavior of the cocrystal and the physical mixture of its components (mixture of quinoxaline and TSBO) are significantly different. The solubility of the cocrystal in distilled water has been found to be 31.9 mg mL−1. The cocrystal exhibits a specific cytotoxic effect on lung cancer cells (A549) at 10−7 M concentration while it shows growth inhibitory effect on normal cells. The detailed mechanistic study of the cytotoxicity of the cocrystal suggests that it follows the mitochondrial mediated cell death pathway through activation of Caspase 9 and Bax. It also shows anticancer activity on breast cancer cells (MCF-7).

CuII complex of emodin with improved anticancer activity as demonstrated by its performance on HeLa and Hep G2 cells

Emodin, a hydroxy-9,10-anthraquinone, resembles anthracycline anticancer drugs at the core and possesses anticancer activities. A CuII complex of emodin [CuII(emod)2]2− was synthesized and its crystal structure was determined by Rietveld refinement of the PXRD data by using an appropriate structural model based on spectroscopy. This is the third report on the crystal structure of a hydroxy-9,10-anthraquinone with a 3d-transition metal ion. Since the formation of reactive oxygen species (ROS) by anthracycline-based anticancer drugs is important for antitumor activity and given the fact that the generation of ROS is responsible for cardiotoxic side effects, it is essential to be able to control their formation. Complex formation decreases ROS generation and could thereby lead to a decrease in cardiotoxic side effects. However, in an attempt to decrease complications, there is also the possibility of compromising the therapeutic efficacy. For this reason, the activities of emodin and its modified form [Cu(II) complex] were studied on the carcinoma cell lines HeLa and Hep G2 to see how they compared with each other in terms of performance. Studies were also performed on WI 38 lung fibroblast normal cells. The studies revealed that, in spite of the decreased ROS formation, followed by the DCFDA assay, the Cu(II) complex showed better activity on carcinoma cell lines. This suggests that the complex has other attributes that enable it to perform better than emodin. Consequently, one such attribute, namely DNA binding, was thoroughly investigated by varying the ionic strength and the temperature of the medium. It was found that the complex was able to bind DNA better than emodin, and, more importantly, since both generate a good amount of anionic species in solution under increased ionic strength of the medium, both bind DNA better; the increase in binding with increase in ionic strength being higher for the complex. The study suggests that with a substantial decrease in ROS generation by the complex, there are likely to be less toxic side effects, which is a key advantage of the complex, leading to an improvement in the therapeutic index. The complex showed almost no activity on WI 38 normal cells.

A new multicomponent salt of imidazole and tetrabromoterepthalic acid: structural, optical, thermal, electrical transport properties and antibacterial activity along with Hirshfeld surface analysis.

Herein, we report the structural, optical, thermal and electrical transport properties of a new multicomponent salt (TBTA(2-))·2(IM(+))·(water) [TBTA-IM] of tetrabromoterepthalic acid (TBTA) with imidazole (IM). The crystal structure of TBTA-IM is determined by both the single crystal and powder X-ray diffraction techniques. The structural analysis has revealed that the supramolecular charge assisted O(-)⋯HN(+) hydrogen bonding and Br⋯π interactions play the most vital role in formation of this multicomponent supramolecular assembly. The Hirshfeld surface analysis has been carried out to investigate supramolecular interactions and associated 2D fingerprint plots reveal the relative contribution of these interactions in the crystal structure quantitatively. According to theoretical analysis the HOMO-LUMO energy gap of the salt is 2.92 eV. The salt has been characterized by IR, UV-vis and photoluminescence spectroscopic studies. It shows direct optical transition with band gaps of 4.1 eV, which indicates that the salt is insulating in nature. The photoluminescence spectrum of the salt is significantly different from that of TBTA. Further, a comparative study on the antibacterial activity of the salt with respect to imidazole, Gatifloxacin and Ciprofloxacin has been performed. Moreover, the current-voltage (I-V) characteristic of ITO/TBTA-IM/Al sandwich structure exhibits good rectifying property and the electron tunneling process governs the electrical transport mechanism of the device.

Thermally induced single crystal to single crystal transformation leading to polymorphism

The robust complex [La(1,10-phen)2(NO3)3] (1,10-phen=1,10-phenanthroline) exhibits thermally induced single crystal to single crystal transformation from one polymorphic phase to another. The complex crystallizes in monoclinic C2/c space group with C2 molecular symmetry at 293K while at 100K it shows P21/c space group with C1 molecular symmetry. Supramolecular investigation shows that at 100K the complex forms 2D achiral sheets whereas at 293K forms two different homochiral 2D sheets. Low temperature DSC analysis indicates that this structural transformation occurs at 246K and also this transformation is reversible in nature. We have shown that thermally induced coherent movement of ligands changes the molecular symmetry of the complex and leads to polymorphism. Photoluminescence property of complex has been studied in both solid state and in methanolic solution at room temperature. The effect of the presence low-lying LUMO orbital of π-character in the complex is elucidated by theoretical calculation using DFT method.