[Show abstract][Hide abstract] ABSTRACT: Phosphodiesterase 10A (PDE10) is a cGMP and cAMP degrading PDE isozyme that is highly expressed in the brain striatum where it appears to play an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, possibly because of low expression levels in most peripheral tissues. We recently reported high levels of PDE10 in colon tumors and that genetic silencing of PDE10 by siRNA or inhibition with small molecule inhibitors can suppress colon tumor cell growth with a high degree of selectivity over normal colonocytes (Li et al., Oncogene 2015). These observations suggest PDE10 may have an unrecognized role in tumorigenesis. Here we report that the concentration range by which the highly specific PDE10 inhibitor, Pf-2545920 (MP-10), inhibits colon tumor cell growth parallels the concentration range required to increase cGMP and cAMP levels, and activates PKG and PKA, respectively. Moreover, PDE10 knockdown by shRNA reduces the sensitivity of colon tumor cells to the growth inhibitory activity of Pf-2545920. Pf-2545920 also inhibits the translocation of β-catenin to the nucleus, thereby reducing β-catenin mediated transcription of survivin, resulting in caspase activation and apoptosis. PDE10 mRNA was also found to be elevated in colon tumors compared with normal tissues. These findings suggest that PDE10 can be targeted for cancer therapy or prevention whereby inhibition results in cGMP elevation and PKG activation to reduce β-catenin-mediated transcription of survival proteins leading to the selective apoptosis of cancer cells.
[Show abstract][Hide abstract] ABSTRACT: A series of novel pyridazin-6-one-1-acetylhydrazone hybrids were rationally designed to inhibit phosphodiesterase 4 (PDE4B). The prepared compounds were evaluated for their in vitro ability to inhibit the PDE4B enzyme; several of these compounds showed moderate activity compared to the reference drug, rolipram. Compounds 6, 12, and 14 emerged as the most potent inhibitors in this series. The [3-(4-methoxyphenyl)-6-oxo-5,6-dihydro-4H-pyridazin-1-yl]acetic acid [1-(3,4,5-trimethoxyphenyl)ethylidene]hydrazide (12) showed an IC50 value of 13 μM against PDE4B. Docking of 6, 12, and 14 into the active site of PDE4B illustrates their possible binding mode and provides insights for further optimization of this drug scaffold.
No preview · Article · Dec 2015 · Archiv der Pharmazie
[Show abstract][Hide abstract] ABSTRACT: In view of the emerging clinical indications for Phosphodiesterase 9 inhibitors e.g. treatment of Alzheimer, diabetes, cancer, and the limited number of its selective inhibitors which possess a single chemical scaffolds, a structure-based approach was undertaken to mine the ZINC database by virtual screening to identify novel PDE9 inhibitors. The database, which was never reported to have been used before for discovery of PDE9 inhibitors, was screened against the ligand binding pocket of the PDE9 complex (PDB:4GH6) using molecular docking programs, MOE and AutoDock Vina in PyRx. Three different scoring functions were used to evaluate the docking poses and scores of the compounds, and the compounds were selected through consensus selection, thus reducing the margin of error in docking. The highest scoring compounds were then selected and purchased for in vitro testing as PDE9 inhibitors and cancer growth inhibitory agents. This led to the discovery of three previously unreported potent PDE 9 inhibitory compounds with two unique chemical scaffolds. Consistent with the role of PDE9 in cancer cell growth, the compounds also inhibited the growth of breast tumor cell lines, MCF-7 and MDA-468 at concentrations comparable to those that inhibited PDE9.
No preview · Article · Dec 2015 · Medicinal chemistry (Shāriqah (United Arab Emirates))
[Show abstract][Hide abstract] ABSTRACT: Previous studies suggest the anti-inflammatory drug, sulindac inhibits tumorigenesis by a COX independent mechanism involving cGMP PDE inhibition. Here we report that the cGMP PDE isozymes, PDE5 and 10, are elevated in colon tumor cells compared with normal colonocytes, and that inhibitors and siRNAs can selectively suppress colon tumor cell growth. Combined treatment with inhibitors or dual knockdown suppresses tumor cell growth to a greater extent than inhibition from either isozyme alone. A novel sulindac derivative, ADT-094 was designed to lack COX-1/-2 inhibitory activity but have improved potency to inhibit PDE5 and 10. ADT-094 displayed >500 fold higher potency to inhibit colon tumor cell growth compared with sulindac by activating cGMP/PKG signaling to suppress proliferation and induce apoptosis. Combined inhibition of PDE5 and 10 by treatment with ADT-094, PDE isozyme-selective inhibitors, or by siRNA knockdown also suppresses β-catenin, TCF transcriptional activity, and the levels of downstream targets, cyclin D1 and survivin. These results suggest that dual inhibition of PDE5 and 10 represents novel strategy for developing potent and selective anticancer drugs.
[Show abstract][Hide abstract] ABSTRACT: Cyclic nucleotide phosphodiesterases (PDE) regulate cyclic nucleotides, cAMP and cGMP, blocking signaling by hydrolyzing the 3′,5′-phosphodiester bond resulting in their degradation to inactive forms. We have previously reported that certain PDE isozymes (e.g. PDE5) are elevated in several types of cancer, which can disrupt cyclic nucleotide signaling to suppress apoptosis. The inhibition of PDE5 by agents such as sulindac sulfide (SS) results in increased cGMP levels and reduced β-catenin/TCF/LEF mediated transcription leading to the selective inhibition of colon cancer cell proliferation and induction of apoptosis. Currently, little is known regarding the transcriptional regulation of PDE5 in cancer cells. We therefore analyzed the promoter regions of PDE5, as well as PDE10, for transcription factor binding sites using the Matinspector Genomatix Software. Matinspector analysis predicted that both PDE5 and PDE10 promoters contain binding sites for TCF/LEF-1, an important transcriptional factor that is regulated by Wnt/β-catenin signaling, which plays an important role in colorectal cancer. To determine if Wnt/β-catenin signaling can regulate PDE5 and PDE10 expression, human HCT116 colon tumor cells and normal colonic epithelial cell line NCM-460 were treated with the GSK-3β inhibitor, lithium chloride (LiCl) to inhibit β-catenin degradation and stimulate TCF/LEF transcriptional activity. TCF/LEF transcriptional activity was measured by mRNA levels of genes (e.g. survivin, cyclin D1 and c-myc) that are known to be regulated by Wnt/β-catenin signaling. Survivin, cyclin D1 and c-myc mRNA were confirmed to be significantly increased after LiCl treatment in comparison to control cells treated with NaCl. Translocation of β-catenin to the nucleus was also evident after treatment with LiCl. Levels of PDE5 and 10 mRNA were found to be significantly elevated after LiCl treatment in comparison to NaCl treated cells. Inhibitors such as SS, the novel derivative SS-D1 and a tadalafil (a selective PDE5 inhibitor) derivative TA-D1 demonstrated selective inhibition of colon cancer cell growth in comparison to normal colonocytes. The potential mechanism of these selective inhibitors may be through the inhibition of Wnt/β-catenin signaling and thus the inhibition of β-catenin/TCF/LEF mediated transcription. This study demonstrates a novel regulatory mechanism of PDE5 and PDE10 expression by the β-catenin-dependent TCF/LEF transcription factor in colon cancer cells and identifies a potential mechanism for novel chemopreventive agents. Defining the role of this regulatory mechanism in cancer progression may provide valuable insight into targeting PDE5 and/or PDE10 by small molecules for cancer chemoprevention.
[Show abstract][Hide abstract] ABSTRACT: A series of novel spirooxindole derivatives have been synthesized through a highly efficient and
green one-pot multicomponent reaction. The synthesized compounds were evaluated for their growth
inhibitory activity against two cancer cell lines, the human colorectal cancer cell line HT-29 and the triplenegative breast cancer cell line MDA-231. Compound 5, methyl 2-amino-2',5-dioxo-5,7-dihydrospiro[furo[3,4-b]pyran-4,3'-indoline]-3-carboxylate was the most active compound towards HT-29 cell line with IC50 of 20 μM. Compound 22, isopropyl 2-amino-5'-chloro-7,7-
dimethyl-2',5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3'-indoline]-3-carboxylate was the most potent
towards MDA-231 cell line with IC50 11 μM. The SAR studies on the synthesized compounds have shown a
reversed pattern of activity towards the two cell lines indicating different mechanisms of action.
[Show abstract][Hide abstract] ABSTRACT: A structure-based medicinal chemistry strategy was applied to design new naproxen derivatives that show growth inhibitory activity against human colon tumor cells through a cyclooxygenase (COX)-independent mechanism.
In vitro testing of the synthesized compounds against the human HT-29 colon tumor cell line revealed enhanced growth inhibitory activity compared to the parent naproxen with 3a showing IC50 of 11.4 μM (two orders of magnitude more potent than naproxen). Selectivity of 3a was investigated against a panel of three tumor and one normal colon cell lines and showed up to six times less toxicity against normal colonocytes. Compound 3a was shown to induce dose-dependent apoptosis of HT116 colon tumor cells as evidenced by measuring the activity of caspases-3 and 7. None of the synthesized compounds showed activity against COX-1 or COX-2 isozymes, confirming a COX-independent mechanism of action. Compound 3k was found to have no ulcerogenic effect in rats as indicated by electron microscope scanning of the stomach after oral administration. A pharmacophore model was developed for elucidating structure–activity relationships and subsequent chemical optimization for this series of compounds as colorectal cancer chemopreventive drugs.
No preview · Article · Sep 2014 · Medicinal Chemistry Research
[Show abstract][Hide abstract] ABSTRACT: A novel series of quinazolin-4(3H)-one/Schiff base hybrids was rationally designed and synthesized. The prepared compounds were evaluated for in vitro activity to inhibit phosphodiesterase 4 (PDE4), where several of them showed good-to-moderate activity compared to rolipram. Compound 7 showed potent PDE4 inhibition in this series, with an IC50 of 1.60 µM. Compounds that showed PDE4 inhibition were further assessed for antiproliferative activity using different human tumor cell lines. Compound 10 exhibited significant antiproliferative activity with IC50 values of 140, 79, and 320 nM in breast, lung, and colon tumor cells, respectively. Docking of compound 7 in the active site of PDE4B illustrates its possible binding mode and provides insight for further optimizations of this novel scaffold for inhibiting PDE4.
No preview · Article · Sep 2014 · Archiv der Pharmazie
[Show abstract][Hide abstract] ABSTRACT: Triple-negative breast cancer (TNBC) is a highly diverse group that is associated with an aggressive phenotype. Its treatment has been challenging due to its heterogeneity and absence of well-defined molecular targets. Thus, there is an urgent need to identify novel agents with therapeutic application. NF-κB is over-expressed in many breast cancers; thus, inactivation of the NF-κB pathway could serve as a therapeutic target. Here we report for the first time the anti-tumor activity of panepoxydone (PP), a NF-κB inhibitor isolated from an edible mushroom, in several breast cancer cell lines.
[Show abstract][Hide abstract] ABSTRACT: The cyclic nucleotide phosphodiesterase 10A (PDE10) has been mostly studied as a therapeutic target for certain psychiatric and neurological conditions, although a potential role in tumorigenesis has not been reported. Here we show that PDE10 is elevated in human colon tumor cell lines compared with normal colonocytes, as well as in colon tumors from human clinical specimens and intestinal tumors from Apc(Min/+) mice compared with normal intestinal mucosa, respectively. An isozyme and tumor-selective role of PDE10 were evident by the ability of small-molecule inhibitors and small interfering RNA knockdown to suppress colon tumor cell growth with reduced sensitivity of normal colonocytes. Stable knockdown of PDE10 by short hairpin RNA also inhibits colony formation and increases doubling time of colon tumor cells. PDE10 inhibition selectively activates cGMP/cGMP-dependent protein kinase signaling to suppress β-catenin levels and T-cell factor (TCF) transcriptional activity in colon tumor cells. Conversely, ectopic expression of PDE10 in normal and precancerous colonocytes increases proliferation and activates TCF transcriptional activity. These observations suggest a novel role of PDE10 in colon tumorigenesis and that inhibitors may be useful for the treatment or prevention of colorectal cancer.Oncogene advance online publication, 7 April 2014; doi:10.1038/onc.2014.94.
[Show abstract][Hide abstract] ABSTRACT: Two series of 2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-1-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitriles 5a-h and 4-(4-chlorophenyl)-2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitriles 6a-h were synthesized via a cyclocondensation reaction of the corresponding 2-hydrazinopyrimidines 3a,b with the appropriate 2-propen-1-ones 4a-h. The target compounds were screened for their antiproliferative activity against A 549 (lung), HT 29 (colon), MCF 7 and MDA-MB 231 (breast) cell lines. The two most susceptible cell lines were the colon (HT 29) and breast (MDA-MB 231). Generally, the 4-unsubstitutedphenylpyrimidine derivatives 5a-h were more active than their 4-chlorophenylpyrimidine analogs 6a-h. Compounds 5e and 5g, showed high activity against three of the cell lines. The most active compound 5c possessed IC50 = 1.76 μM against A 549 cell line.
No preview · Article · Oct 2013 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Derivatives with scaffolds of 1,3,5-tri-substituted pyrazoline and 1,3,4,5-tetra-substituted pyrazoline were synthesized and tested for their inhibitory effects versus the p53(+/+) HCT116 and p53(-/-) H1299 human tumor cell lines. Several compounds were active against the two cell lines displaying IC50 values in the low micromolar range with a clearly more pronounced effect on the p53(+/+) HCT116 cells. The compound class shows excellent developability due to the modular synthesis, allowing independent optimization of all three to four key substituents to improve the properties of the molecules.
No preview · Article · Oct 2013 · Bioorganic & medicinal chemistry