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This article shows how milling can be used to explore the phase diagram of pharmaceuticals. This process has been applied to sulindac. A short milling has been found to trigger a polymorphic transformation between form II and form I upon heating which is not seen in the nonmilled material. This possibility was clearly demonstrated to result from crystalline microstrains induced by the mechanical shocks. A long milling has been found to induce a total amorphization of the material. Moreover, the amorphous fraction produced during milling appears to have a complex recrystallization upon heating which depends on the milling time. The investigations have been mainly performed by differential scanning calorimetry and powder X-ray diffraction., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Sulindac sulfone is a metabolite of sulindac, a non-steroidal anti-inflammatory drug (NSAID), without anti-inflammatory ability. However, sulindac sulfone has been reported to significantly reduce polyps in patients with colorectal adenomatous polyposis in clinical trials. Thus, sulindac sulfone is expected to be useful for the chemoprevention of neoplasia with few side effects related to anti-inflammatory ability. To date, the molecular targets of sulindac sulfone have not yet fully investigated. Therefore, in order to newly identify sulindac sulfone-binding proteins, we generated sulindac sulfone-fixed FG beads and purified sulindac sulfone-binding proteins from human colon cancer HT-29 cells. we identified mitochondrial outer membrane proteins voltage-dependent anion channel (VDAC) 1 and VDAC2 as novel molecular targets of sulindac sulfone, and sulindac sulfone directly bound to both VDAC1 and VDAC2. Double knockdown of VDAC1 and VDAC2 by siRNA inhibited growth and arrested the cell cycle at G1 phase in HT-29 cells. Depletion of VDAC1 and VDAC2 also inhibited the mTORC1 pathway with a reduction in cyclin D1. Interestingly, these effects were consistent with those of sulindac sulfone against human colon cancer cells, suggesting that sulindac sulfone negatively regulates the function of VDAC1 and VDAC2. In the present study, our data suggested that VDAC1 and VDAC2 are direct targets of sulindac sulfone which suppresses the mTORC1 pathway and induces G1 arrest., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis (RA). Reactive oxygen species (ROS) are produced in the course of cellular oxidative phosphorylation and by activated phagocytic cells during oxidative bursts, exceed the physiological buffering capacity and result in oxidative stress. ROS result in oxidation of serum albumin, which causes a number of structural changes in the spatial structure, may influence the binding and cause significant drug interactions, particularly in polytherapy. During the oxidation modification of amino acid residues, particularly cysteine and methionine may occur. The aim of the study was to investigate the influence of oxidative stress on human serum albumin (HSA) structure and evaluate of possible alterations in the binding of the drug to oxidized human serum albumin (oHSA). HSA was oxidized by a chloramine-T (CT). CT reacts rapidly with sulfhydryl groups and at pH 7.4 the reaction was monitored by spectroscopic techniques. Modification of free thiol group in the Cys residue in HSA was quantitatively determined by the use of Ellman's reagent. Changes of albumin conformation were examined by comparison of modified (oHSA) and nonmodified human serum albumin (HSA) absorption spectra, emission spectra, red-edge shift (REES) and synchronous spectroscopy. Studies of absorption spectra indicated that changes in the value of absorbance associated with spectral changes in the region of 200-250 nm involve structural alterations in peptide backbone conformation. Synchronous fluorescence spectroscopy technique confirmed changes of position of tryptophanyl and tyrosyl residues fluorescent band caused by CT. Moreover analysis of REES effect allowed to observe structural changes caused by CT in the region of the hydrophobic pocket containing the tryptophanyl residue. Effect of oxidative stress on binding of anti-rheumatic drugs, sulfasalazine (SSZ) and sulindac (SLD) in the high and low affinity binding sites was investigated by spectrofluorescence, ITC and (1)H NMR spectroscopy, respectively. SSZ and SLD change the affinity of each other to the binding site in non- and modified human serum albumin. The presence of SLD causes the increase of association constant (Ka) of SSZ-oHSA system and the strength of binding and the stability of the complexes has been observed while in the presence of SSZ a displacement of SLD from the SLD-HSA has been recorded. The analysis of (1)H NMR spectral parameters i.e. changes of chemical shifts of the drug indicate that the presence of SSZ and SLD have a mutual influence on changes in the affinity of human serum albumin binding site and this competition takes place not only due to the additional drug but also to the oxidation of HSA., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Retinoid X receptor-alpha (RXRα), an intriguing and unique drug target, can serve as an intracellular target mediating the anticancer effects of certain nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac. We report the synthesis and characterization of two sulindac analogs, K-8008 and K-8012, which exert improved anticancer activities over sulindac in a RXRα-dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXRα (tRXRα) with the p85α subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRα ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRα LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXRα modulators and define a binding mechanism for regulating the nongenomic action of tRXRα., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A potentiometric sulindac sensitive sensor based on tetraoctylammonium (Z)-5-fluoro-2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate (TOA-SUL) was described. The electrode responded with sensitivity of 57.5±1.6mV decade(-1) over the linear range 5×10(-5)-1×10(-2)mol L(-1) at pH6.0-9.0. It had the limit of detection 1.4×10(-5)mol L(-1), a fast response time of 13s and showed clear discrimination of sulindac ions from several inorganic and organic compounds and also amino acids. This electrode did not contain any inner solutions, so it was easy and comfortable to use. The proposed sensor was used to determine sulindac in clear solution and in urine sample solution., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this paper, we explore the use of Neusilin, an inorganic magnesium aluminometasilicate, to stabilize the amorphous form of an acidic drug Sulindac. Both cryomilling and ball milling of the drug with Neusilin were found to produce the amorphous phase. However, the ball-milled (BM) material exhibited superior physical stability when compared with the cryomilled material at 40°C/75% relative humidity. (13) C solid-state nuclear magnetic resonance investigation of the BM material revealed an acid-base reaction between Sulindac and Neusilin. Optimal milling conditions and the kinetics of salt formation were also established. As benchtop milling is a laboratory-scale process, a scalable process was developed to make Sulindac-Neusilin amorphous drug complex using hot-melt extrusion (HME). The dissolution properties of the resulting HME material was found to have been improved over the material made by benchtop milling while maintaining similar physical stability. The HME material was used to make tablets using a direct compression method. The HME tablets were found to have better dissolution properties than tablets made from crystalline Sulindac. For the broad class of acidic drugs containing the carboxyl moiety, inorganic silicates such as Neusilin would offer a better choice than organic polymers to stabilize the amorphous phase., (Copyright © 2011 Wiley-Liss, Inc.)

The selection and discovery of new crystalline forms is a longstanding issue in solid-state chemistry of critical importance because of the effect molecular packing arrangement exerts on materials properties. Polymer-induced heteronucleation has recently been developed as a powerful approach to discover and control the production of crystal modifications based on the insoluble polymer heteronucleant added to the crystallization solution. The selective nucleation and discovery of new crystal forms of the well-studied pharmaceuticals flurbiprofen (FBP) and sulindac (SUL) has been achieved utilizing this approach. For the first time, FBP form III was produced in bulk quantities and its crystal structure was also determined. Furthermore, a novel 3:2 FBP:H(2)O phase was discovered that nucleates selectively from only a few polymers. Crystallization of SUL in the presence of insoluble polymers facilitated the growth of form I single crystals suitable for structure determination. Additionally, a new SUL polymorph (form IV) was discovered by this method. The crystal forms of FBP and SUL are characterized by Raman and FTIR spectroscopies, X-ray diffraction, and differential scanning calorimetry., (Copyright 2007 Wiley-Liss, Inc.)

Sulindac is a known anti-inflammatory drug that functions by inhibition of cyclooxygenases 1 and 2 (COX). There has been recent interest in Sulindac and other non-steroidal anti-inflammatory drugs (NSAID) because of their anti-tumor activity against colorectal cancer. Studies with sulindac have indicated that it may also function as an anti-tumor agent by stimulating apoptosis. Sulindac is a pro-drug, containing a methyl sulfoxide group, that must be reduced to sulindac sulfide to be active as a COX inhibitor. In the present studies we have developed a simple assay to measure sulindac reduction and tested sulindac as a substrate for 6 known members of the methionine sulfoxide reductase (Msr) family that have been identified in Escherichia coli. Only MsrA and a membrane associated Msr can reduce sulindac to the active sulfide. The reduction of sulindac also has been demonstrated in extracts of calf liver, kidney, and brain. Sulindac reductase activity is also present in mitochondria and microsomes.

The polymorphism of sulindac was investigated. Two polymorphs (I and II) and a new crystalline form (form III) of sulindac were prepared by recrystallization in different solvents. In addition, three new pseudopolymorphs (solvates) from acetone, chloroform, and benzene were obtained, with each containing 1 mol of solvent to 2 mol of sulindac. Different sulindac polymorphs and pseudopolymorphs were characterized by X-ray diffractometry, infrared spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot-stage microscopy. The transition behavior of the crystalline forms of sulindac, their melting points, and their enthalpies were investigated by DSC. The melting of form II was observed at 184 degrees C, and form I subsequently recrystallized from this melt. Similarly, form III melts at 145 degrees C and then recrystallizes to form I. We also investigated the influence of the crystallization solvent on sulindac crystal shape.