Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin ...synthesis limits their use for chemoprevention. Previous studies have concluded that the mechanism responsible for their antineoplastic activity may be COX independent. To selectively design out the COX inhibitory activity of sulindac sulfide (SS), in silico modeling studies were done that revealed the crucial role of the carboxylate moiety for COX-1 and COX-2 binding. These studies prompted the synthesis of a series of SS derivatives with carboxylate modifications that were screened for tumor cell growth and COX inhibitory activity. A SS amide (SSA) with a N,N-dimethylethyl amine substitution was found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of human colon tumor cell lines, HT-29, SW480, and HCT116 with IC(50) values of 2 to 5 micromol/L compared with 73 to 85 micromol/L for SS. The mechanism of growth inhibition involved the suppression of DNA synthesis and apoptosis induction. Oral administration of SSA was well-tolerated in mice and generated plasma levels that exceeded its in vitro IC(50) for tumor growth inhibition. In the human HT-29 colon tumor xenograft mouse model, SSA significantly inhibited tumor growth at a dosage of 250 mg/kg. Combined treatment of SSA with the chemotherapeutic drug, Camptosar, caused a more sustained suppression of tumor growth compared with Camptosar treatment alone. These results indicate that SSA has potential safety and efficacy advantages for colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy.
Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients ...with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activity
and demonstrating
xenograft activity.
Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities.
A series of sulindac amine analogs were designed and synthesized and then further modified in a "libraries from libraries" approach to produce amide, sulfonamide and N,N-disubstituted sulindac amine sub-libraries. All analogs were screened against three cancer cell lines (prostate, colon and breast).
Several active compounds were identified
cancer cell line screening with the most potent compound (
) in the nanomolar range.
Compound
and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds.
Replacement of the neuraminyl residue by a wide range of aryl rings in transition-state analogs of CMP-Neu5Ac led to readily accessible and potent inhibitors of α-(2→6)- and ...α-(2→3)-sialyltransferases. The synthesis of a series of potential sialyltransferase inhibitors in which the neuraminyl residue is replaced by hetaryl methylphosphonate residues (thiazole, benzothiazole, benzoxazole, benzothiophene and thiophene) is described in this paper.
Abstract
Many colon cancers harbor APC mutations that prevent the proteosomal degradation of oncogenic β-catenin. Previous studies have found that certain nonsteroidal anti-inflammatory drugs ...(NSAIDs) have the ability to reduce nuclear levels of β-catenin and inhibit tumor cell growth through a cyclooxygenase (COX)-independent mechanism, which might be responsible for their cancer chemopreventive activity. A potential mechanism may involve cGMP phosphodiesterase (PDE) inhibition and the activation of protein kinase G (PKG). In this study we evaluated over 500 novel sulindac derivatives for colon tumor cell growth inhibitory activity. Select compounds were also evaluated for COX and cGMP PDE inhibitory activity to determine which activity is associated with colon tumor cell growth inhibition and ability to suppress nuclear β-catenin levels. A subset of derivatives was identified that displayed reduced COX-1 and COX-2 inhibitory activity, yet increased potency to inhibit the growth of several colon tumor cell lines (HT29, HCT116, SW480, and COLO741) with IC50 values of 2-10 µM compared with IC50 values of 80-110 µM for the parent compound, sulindac sulfide (SS). Certain derivatives also displayed increased potency to inhibit recombinant phosphodiesterase 5 (PDE5), which appears to be the isozyme responsible for the cGMP PDE inhibitory activity of SS. Treatment of colon tumor cells with such compounds also increased the phosphorylation of vasoactive stimulated protein (VASP), a known PKG substrate. Furthermore, nuclear levels of β-catenin decreased within the same time period as PKG activation, which is consistent with previous reports suggesting that PKG can phosphorylate β-catenin to induce proteosomal degradation. Together, these data indicate that sulindac can be chemically modified to eliminate COX inhibitory activity while enhancing its ability to inhibit colon tumor cell growth. We conclude that the suppression of nuclear β-catenin levels by SS is independent of COX inhibition and that novel derivatives can be developed with improved antineoplastic activity while reducing the toxicities associated with COX inhibition. Funding provided by NIH/NCI grants CA131378 and CA148817.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 837. doi:10.1158/1538-7445.AM2011-837
Abstract
Previous studies have concluded that the mechanism responsible for the antineoplastic properties of NSAIDs is cyclooxygenase (COX) independent, which suggests that more selective drugs can ...be developed for cancer chemoprevention by targeting such mechanisms. With this paradigm, we are synthesizing novel sulindac derivatives that have reduced COX inhibitory activity, but enhanced tumor cell growth inhibitory activity. A prototypic dimethylethyl amide derivative referred to as sulindac sulfide amide (SSA) was previously reported to lack COX-1 or COX-2 inhibitory activity, yet have improved potency to inhibit tumor cell growth in vitro. For example, SSA inhibited the growth of human HT-29 colon tumor cells with IC50 values of 1-2 µM compared with 70-90 µM for sulindac sulfide (SS), a non-selective COX inhibitor. SSA was also appreciably more effective than SS in inhibiting HT-29 colon tumor cell growth using a 3-dimensional in vitro tumor cell model. SSA induced apoptosis of HT-29 carcinoma cells, but normal human colonocytes were insensitive to treatment, suggesting an element of tumor selectivity. The mechanism of SSA induced apoptosis is associated with cGMP phosphodiesterase (PDE) inhibition, elevation of intracellular cGMP, and activation of protein kinase G, which also appears to be an important off-target effect of SS. SSA inhibited the growth of a variety of histologically diverse tumor cell lines, an effect that is consistent with studies showing the overexpression of PDE5 in various tumor types, including colorectal adenomas and carcinomas. SSA was well tolerated in the FCCC Min mouse model in which oral administration reduced colon tumor multiplicity by approximately 80% and tumor incidence by 50%. SSA also inhibited tumor growth in the human HT-29 colon mouse xenograft model by approximately 60%, while sulindac at its maximum tolerated dose was marginally effective. The antitumor activity of SSA in the HT-29 model was accompanied by decreased numbers of proliferating cells and increased numbers of apoptotic cells as determined by immunohistochemistry. Pharmacokinetic studies in mice bearing HT-29 xenografts revealed that plasma and tumor levels of SSA from a tolerated dose of SSA appreciably exceeded the in vitro IC50 value for growth inhibition. In contrast, sulindac generated plasma and tumor levels of SS that were appreciably less than the IC50 value for tumor cell growth inhibition. These results support the feasibility of chemically modifying sulindac to design out COX associated toxicities, while increasing anticancer efficacy. Newer sulindac derivatives with higher potency and target selectivity, as well as formulations to improve oral bioavailability are being developed for colon cancer chemoprevention. Funding provided by NIH/NCI grants CA131378 and CA148817.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1865. doi:10.1158/1538-7445.AM2011-1865
Nanofibrous biocomposite scaffolds of type I collagen and nanohydroxyapatite (nanoHA) of varying compositions (wt %) were prepared by electrostatic cospinning. The scaffolds were characterized for ...structure and morphology by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), atomic force microscopy (AFM) and X-ray diffraction (XRD) techniques. The scaffolds have a porous nanofibrous morphology with random fibers in the range of 500-700 nm diameters, depending on the composition. FT-IR and XRD showed the presence of nanoHA in the fibers. The surface roughness and diameter of the fibers increased with the presence of nanoHA in biocomposite fiber as evident from AFM images. Tensile testing and nanoindendation were used for the mechanical characterization. The pure collagen fibrous matrix (without nanoHA) showed a tensile strength of 1.68 plus or minus 0.10 MPa and a modulus of 6.21 plus or minus 0.8 MPa with a strain to failure value of 55 plus or minus 10%. As the nanoHA content in the randomly oriented collagen nanofibers increased to 10%, the ultimate strength increased to 5 plus or minus 0.5 MPa and the modulus increased to 230 plus or minus 30 MPa. The increase in tensile modulus may be attributed to an increase in rigidity over the pure polymer when the hydroxyapatite is added and/or the resulting strong adhesion between the two materials. The vapor phase chemical crosslinking of collagens using glutaraldehyde further increased the mechanical properties as evident from nanoindentation results. A combination of nanofibrous collagen and nanohydroxyapatite that mimics the nanoscale features of the extra cellular matrix could be promising for application as scaffolds for hard tissue regeneration, especially in low or nonload bearing areas.
o-Benzoquinone is a unique conjugated 1,2-dione that can exhibit diverse cycloaddition modes, participating either as carbodiene, heterodiene, dienophile or heterodienophile. With electron-rich ...dienes, benzodioxins are formed in excellent yields. Pentafulvenes including 6-vinylfulvenes normally give rise to bicyclo 2.2.2 adducts. Exceptions are observed with cycloalkylfulvenes where the fulvenes undergo rearrangement to cyclopentadiene derivatives prior to cycloaddition, resulting in benzodioxins.o-Benzoquinones participate as dipolarophiles on treatment with nitrile oxides and carbonyl ylides yielding highly oxygenated novel spiro compounds. Triphenylphosphine catalyzed addition of DMAD too-benzoquinones afforded another class of novel spirolactones. The bicyclo 2.2. octene diones derived fromo-benzoquinones undergo a number of synthetically useful transformations.
Cognitive radio is a potential technique for future wireless communications to mitigate the spectrum scarcity issue. One of the most important challenge of a cognitive radio system is to identify the ...presence of primary (licensed) users over a wide range of frequency spectrum at a particular time and specific geographic location. In this paper, a spectrum sensing technique for cognitive radios based on discriminant analysis, called spectrum discriminator is studied. It is a blind detection technique where no prior knowledge about the measured signal is needed. In this paper, this spectrum sensing technique is extended to a cooperative environment using an adaptive cooperative spectrum sensing scheme based on the optimal data fusion rule. In the proposed method, secondary users efficiently cooperate to achieve superior detection accuracy with minimum cooperation overhead. The algorithm is able to detect the presence or absence of signals in any kind of spectrum. Hence, this method becomes a strong basis for a high quality operation mode of cognitive radios. Simulation results show that the proposed cooperative spectrum sensing scheme outperforms the conventional methods even under low SNR conditions.
o-Thioquinones undergo 4+2 cycloaddition reactions with pentafulvenes leading to 1,4-benzoxathiins. Reactions of 6-styrenylfulvene with
o-thioquinones also afforded similar products.
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