Hand-Ground Nanoscale ZnII -Based Coordination Polymers Derived from NSAIDs: Cell Migration Inhibition of Human Breast Cancer Cells.

Increased levels of intracellular prostaglandin E2 (PGE2 ) have been linked with the unregulated cancer cell migration that often leads to metastasis. Non-steroidal anti-inflammatory drugs (NSAIDs) are known inhibitors of cyclooxygenase (COX) enzymes, which are responsible for the increased PGE2 concentration in inflamed as well as cancer cells. Here, we demonstrate that NSAID-derived ZnII -based coordination polymers are able to inhibit cell migration of human breast cancer cells. Various NSAIDs were anchored to a series of 1D ZnII coordination polymers through carboxylate-Zn coordination, and these structures were fully characterized by single-crystal X-ray diffraction. Hand grinding in a pestle and mortar resulted in the first reported example of nanoscale coordination polymers that were suitable for biological studies. Two such hand-ground nanoscale coordination polymers NCP1 a and NCP2 a, which contained naproxen (a well-studied NSAID), were successfully internalized by the human breast cancer cells MDA-MB-231, as was evident from cellular imaging by using a fluorescence microscope. They were able to kill the cancer cells (MTT assay) more efficiently than the corresponding mother drug naproxen, and most importantly, they significantly inhibited cancer cell migration thereby displaying anticancer activity.

Exploiting supramolecular synthons in designing gelators derived from multiple drugs.

A simple strategy for designing salt-based supramolecular gelators comprised of various nonsteroidal anti-inflammatory drugs (NSAIDs) and amantadine (AMN) (an antiviral drug) has been demonstrated using a supramolecular synthon approach. Single-crystal and powder X-ray diffraction established the existence of the well-studied gel-forming 1D supramolecular synthon, namely, primary ammonium monocarboxylate (PAM) synthon in all the salts. Remarkably five out of six salts were found to be capable of gelling methyl salicylate (MS)-an important ingredient in commercially available topical gels; one such selected biocompatible salt displayed an anti-inflammatory response in prostaglandin E2 (PGE2 ) assay, thereby indicating their plausible biomedical applications.

A novel naproxen derivative capable of displaying anti-cancer and anti-migratory properties against human breast cancer cells.

BACKGROUND: Increasingly, the role of chronic inflammation and its mediators in tumor generation and progression is gaining importance in the field of cancer research. In this context, candidature of non steroidal anti-inflammatory drugs (NSAIDs) as potential anti-tumor therapeutic agent is being evaluated globally. In the present study we have evaluated the anti-cancer effect of a series of newly synthesized naproxen derivatives on human breast cancer cell lines. METHODS: MCF-7 (poorly invasive) and MDA-MB-231 (highly invasive) cells were treated with different concentrations of naproxen sodium and its derivatives in vitro, and the underlying mechanism of action was monitored by employing studies related to induction of apoptosis, activation of caspases, cell-cycle progression, synthesis of PGE2 and cellular migration. RESULTS: After a preliminary screening using MCF-7 and MDA-MB-231 cells, it was evident that naproxen derivative 4 has a better killing property compared to its parent compound naproxen sodium (NS). On further investigation, it was apparent that the observed growth inhibitory activity on MDA-MB-231 cells after treatment with 4, was not due to cell cycle arrest but due to an early induction of apoptosis and subsequent induction of caspases 3 and 9. Derivative 4 could also inhibit COX activity in MDA-MB-231 cells as evidenced by reduction in prostaglandin E2 secretion. Moreover, 4 was capable of delaying the overall migration rate of MDA-MB-231 cells in vitro. CONCLUSION: In this study we report that a naproxen-derivative (4) has powerful anti-inflammatory and anti-tumor properties as it induces appreciable amount of apoptosis in breast cancer cell line, and can also delay migration of cancer cells (MDA-MB-231) which would in turn delay cancer cell invasion and formation of secondary tumours in primary breast cancer patients. Thus, we propose that 4 is worthy of further investigation due to its potential as a therapeutic agent in anti-tumor treatment regimen.

Hydrogen-bonding-induced chain folding and vesicular assembly of an amphiphilic polyurethane.

We have reported synthesis and vesicular assembly of a novel amphiphilic polyurethane with hydrophobic backbone and hydrophilic pendant carboxylic acid groups which were periodically grafted to the backbone via a tertiary amine group. In aqueous medium the polymer chain adopted a folded conformation which was stabilized by intrachain H-bonding among the urethane groups. Such a model was supported by concentration and solvent-dependent FT-IR, powder XRD, and urea-mediated "denaturation" experiments. Folded polymer chains further formed vesicular assembly which was probed by dynamic light scattering, TEM, AFM, SEM, and fluorescence microscopic studies, and dye encapsulation experiments. pH-dependent DLS and fluorescence microscopic studies revealed stable polymersome in entire tested pH window of 3.5-11.0. Zeta potential measurements showed a negatively charged surface in basic pH while a charge-neutral surface in neutral and acidic pH. MTT assay with CHO cell line indicated good cell viability.

ß-Amino acid and amino-alcohol conjugation of a nonsteroidal anti-inflammatory drug (NSAID) imparts hydrogelation displaying remarkable biostability, biocompatibility, and anti-inflammatory properties.

A well-known nonsteroidal anti-inflammatory drug (NSAID), namely, naproxen (Np), was conjugated with ß-alanine and various combinations of amino alcohols and l-alanine. Quite a few bioconjugates, thus synthesized, were capable of gelling pure water, NaCl solution (0.9 wt %), and phosphate-buffered saline (PBS) (pH 7.4). The hydrogels were characterized by rheology and electron microscopy. Hydrogelation was probed by FT-IR and temperature-variable (1)H NMR studies. Single-crystal X-ray diffraction (SXRD) of a nonhydrogelator and a hydrogelator in the series established a useful structure-property (gelation) correlation. MTT assay of the hydrogelators in the mouse macrophage RAW 264.7 cell line showed excellent biocompatibility. The prostaglandin E2 (PGE2) assay of the hydrogelators revealed their anti-inflammatory response, which was comparable to that of the parent NSAID naproxen sodium (Ns).

Mechanistic studies of in vitro anti-proliferative and anti-inflammatory activities of the Zn(ii)-NSAID complexes of 1,10-phenanthroline-5,6-dione in MDA-MB-231 cells.

Two zinc(ii)-NSAID complexes [(phendione)ZnII(NPR)2(H2O)2] (1) and [(phendione)ZnII(MFN)2] (2) (HNPR = naproxen and HMFN = mefenamic acid) of 1,10-phenanthroline-5,6-dione (phendione) were isolated and characterized to evaluate their potential as anti-cancer agents. Each of the complexes contains two equivalents of NSAID per zinc(ii)-phendione unit. The complexes are stable in solution under cell culture conditions. Cytotoxic assay on the human breast cancer cell line (MDA-MB-231) reveals that the anti-proliferative activity of phendione is retained in both the complexes. The anti-inflammatory properties of NSAIDs are also preserved in the metal complexes as evident from the PGE2 assay. Both 1 and 2 exhibit selective COX-1 inhibition at a low concentration. Furthermore, the zinc(ii)-naproxen complex (1) disrupts the intercellular bridges displaying in vitro delay in cellular migration and down-regulation of EMT-related genes. The mechanistic studies indicate that the ternary complexes are more active compared to cisplatin and have the potential to overcome cisplatin resistance in MDA MB 231 cells. These findings demonstrate that the zinc(ii)-NSAID complexes are worthy of further in vivo studies for their promising anti-tumor potential.

Anti-inflammatory activity and enhanced COX-2 selectivity of nitric oxide-donating zinc(ii)-NSAID complexes.

Zinc(ii)-NSAID complexes supported by NO-donating 1,10-phenanthrolinefuroxan exhibit anti-inflammatory activities through selective inhibition of the COX-2 pathway. The strategy represents a general procedure to convert non-selective or COX-1 selective NSAIDs to selective COX-2 inhibitors.

Cetirizine derived supramolecular topical gel in action: rational design, characterization and in vivo self-delivery application in treating skin allergy in mice.

A conventional drug delivery system requires a delivery vehicle which often faces various problems such as inefficient drug loading into the delivery vehicle and its release, cytotoxicity and biodegradability of the delivery vehicle, etc., whereas a supramolecular gel based self-delivery system delivers a gelator drug at the target site without using any vehicle thereby getting rid of such problems. Here, a simple salt formation strategy has been employed to convert a well known anti-allergic drug (cetirizine) to a supramolecular gelator for the purpose of making a topical gel for in vivo self-delivery applications. The salt of cetirizine and tyramine (salt 3) displays excellent gelation properties in methylsalicylate/menthol. The gels are characterised by electron microscopy, and table top- and dynamic rheology. The gelator salt 3 displays excellent physiological stability in phosphate buffer saline (PBS) and it is biocompatible in mouse macrophage RAW 264.7 and mouse myoblast C2C12 cell lines. A methylsalicylate/menthol topical gel of salt 3 is successfully self-delivered in treating the 2,4-dinitrochlorobenzene (DNCB)-induced allergic skin condition in mice.

Peptide conjugates of a nonsteroidal anti-inflammatory drug as supramolecular gelators: synthesis, characterization, and biological studies.

Indomethacin (IND), which is a well-known nonsteroidal anti-inflammatory drug (NSAID), was conjugated with various naturally occurring amino acids. Most of these bioconjugates were capable of gelling pure water, a solution of NaCl (0.9 wt%), and phosphate-buffered saline (pH 7.4), as well as a few organic solvents. The gels were characterized by table-top and dynamic rheology, and electron microscopy. Variable-temperature (1)H NMR spectroscopy studies on a selected gel were performed to gain insights into the self-assembly process during gel formation. Both 1D and 2D hydrogen-bonded networks were observed in the single-crystal structures of two of the gelators. Plausible biological applications of the hydrogelators were evaluated with the ultimate aim of drug delivery in a self-delivery fashion. All hydrogelators were stable in phosphate-buffered saline at pH 7.4 at 37 °C, and biocompatible in mouse macrophage RAW 264.7 cell line (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). Two of the most biocompatible hydrogelators displayed an anti-inflammatory response comparable to that of the parent drug IND in prostaglandin E2 assay. Release of the bioconjugates into the bulk solvent interfaced with the corresponding hydrogels indicated their plausible future application in drug delivery.

Designing a simple organic salt-based supramolecular topical gel capable of displaying in vivo self-delivery application.

The supramolecular synthon approach has been exploited to design simple salt-based supramolecular gelators derived from a non-steroidal anti-inflammatory drug (NSAID) - naproxen; one such biocompatible anti-inflammatory gelator salt was converted into a topical gel that showed excellent in vivo self-delivery application in treating imiquimod (IMQ)-induced skin inflammation in mice.

Activity of aspirin analogues and vanillin in a human colorectal cancer cell line.

Colorectal cancer is the third most common cancer and is associated with significant morbidity and mortality. Epidemiological and animal studies indicate that regular acetylsalicylic acid (aspirin) intake is associated with a reduction in the incidence of colorectal cancer. Acetylsalicylic acid (ASA) has also been shown to inhibit colorectal cancer cell proliferation in vitro. The molecular basis for this specific cytotoxicity is an area of considerable debate. To investigate the toxicity of salicylates, the sensitivity of the DNA mismatch repair proficient SW480 human colorectal cancer cell line to four categories of compounds with varying degrees of structural similarity to acetylsalicylic acid was tested. These compounds were: i) salicylic acid analogues with substituents at the 5-position; ii) ASA analogues with extended chain lengths in the acyl group; iii) vanillin (4-hydroxy-3-methoxybenzaldehyde; and iv) bis(2-carboxyphenyl) succinate (BCS) and structurally similar derivatives thereof. It was found that compounds with amino and acetamido substituents at the salicylate 5-position were less toxic than ASA itself. Modifications to the length of the hydrocarbon chain in the acyl groups of ASA analogues also marginally reduced toxicity. Vanillin exhibited relatively limited toxicity against the SW480 colorectal cancer cell line. Commercially available and in-house synthesised BCS (diaspirin) were notably more inhibitory to cell growth than ASA itself, yet retained substantial specificity against colorectal cancer cell lines vs. non-colorectal cancer cell lines. BCS and ASA were toxic to SW480 cells through initiation of necrotic and apoptotic pathways. Fumaroyldiaspirin and benzoylaspirin exhibited greater toxicity than ASA against the SW480 cell line. A novel method for synthesis of BCS, a compound that has erratic commercial availability, is described. We propose that the anti-inflammatory and anticancer capacity of BCS and the other analogues described herein is worthy of investigation.

NFATc1 affects mouse splenic B cell function by controlling the calcineurin--NFAT signaling network.

By studying mice in which the Nfatc1 gene was inactivated in bone marrow, spleen, or germinal center B cells, we show that NFATc1 supports the proliferation and suppresses the activation-induced cell death of splenic B cells upon B cell receptor (BCR) stimulation. BCR triggering leads to expression of NFATc1/αA, a short isoform of NFATc1, in splenic B cells. NFATc1 ablation impaired Ig class switch to IgG3 induced by T cell-independent type II antigens, as well as IgG3(+) plasmablast formation. Mice bearing NFATc1(-/-) B cells harbor twofold more interleukin 10-producing B cells. NFATc1(-/-) B cells suppress the synthesis of interferon-γ by T cells in vitro, and these mice exhibit a mild clinical course of experimental autoimmune encephalomyelitis. In large part, the defective functions of NFATc1(-/-) B cells are caused by decreased BCR-induced Ca(2+) flux and calcineurin (Cn) activation. By affecting CD22, Rcan1, CnA, and NFATc1/αA expression, NFATc1 controls the Ca(2+)-dependent Cn-NFAT signaling network and, thereby, the fate of splenic B cells upon BCR stimulation.