Phosphodiesterase 10A is overexpressed in lung tumor cells and inhibitors selectively suppress growth by blocking β-catenin and MAPK signaling.

Phosphodiesterase 10A (PDE10) is a cyclic nucleotide (e.g. cGMP) degrading enzyme highly expressed in the brain striatum where it plays an important role in dopaminergic neurotransmission, but has limited expression and no known physiological function outside the central nervous system.

Design and Synthesis of Substituted Pyridazinone-1-Acetylhydrazones as Novel Phosphodiesterase 4 Inhibitors.

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.

Mining ZINC Database to Discover Potential Phosphodiesterase 9 Inhibitors Using Structure-Based Drug Design Approach.

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.

Structure-Based Design of Novel Tetrahydro-Beta-Carboline Derivatives with a Hydrophilic Side Chain as Potential Phosphodiesterase Inhibitors.

Tadalafil is a clinically approved phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction and pulmonary arterial hypertension. It contains two chiral carbons, and the marketed isomer is the , isomer with a methyl substituent on the terminal nitrogen of the piperazinedione ring. In this report, tadalafil analogues with an extended hydrophilic side chain on the piperazine nitrogen were designed to interact with particular hydrophilic residues in the binding pocket.

Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10.

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.

Macrolide-peptide conjugates as probes of the path of travel of the nascent peptides through the ribosome.

Despite decades of research on the bacterial ribosome, the ribosomal exit tunnel is still poorly understood. Although it has been suggested that the exit tunnel is simply a convenient route of egress for the nascent chain, specific protein sequences serve to slow the rate of translation, suggesting some degree of interaction between the nascent peptide chain and the exit tunnel. To understand how the ribosome interacts with nascent peptide sequences, we synthesized and characterized a novel class of probe molecules.

Novel quinazolin-4(3H)-one/Schiff base hybrids as antiproliferative and phosphodiesterase 4 inhibitors: design, synthesis, and docking studies.

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.

Synthesis of some dihydropyrimidine-based compounds bearing pyrazoline moiety and evaluation of their antiproliferative activity.

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).

Dual-acting histone deacetylase-topoisomerase I inhibitors.

Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands that can modulate multiple targets while avoiding the toxicity of a single-targeted agent. Two attractive targets, histone deacetylase (HDAC) and topoisomerase I (Topo I), are cellular modulators that can broadly arrest cancer proliferation through a range of downstream effects.

Dual targeting of histone deacetylase and topoisomerase II with novel bifunctional inhibitors.

Strategies to ameliorate the flaws of current chemotherapeutic agents, while maintaining potent anticancer activity, are of particular interest. Agents which can modulate multiple targets may have superior utility and fewer side effects than current single-target drugs. To explore the prospect in cancer therapy of a bivalent agent that combines two complementary chemo-active groups within a single molecular architecture, we have synthesized dual-acting histone deacetylase and topoisomerase II inhibitors.

Design and synthesis of novel histone deacetylase inhibitor derived from nuclear localization signal peptide.

We describe herein the synthesis and characterization of a new class of histone deacetylase (HDAC) inhibitors derived from conjugation of a suberoylanilide hydroxamic acid-like aliphatic-hydroxamate pharmacophore to a nuclear localization signal peptide. We found that these conjugates inhibited the histone deacetylase activities of HDACs 1, 2, 6, and 8 in a manner similar to suberoylanilide hydroxamic acid (SAHA). Notably, compound 7b showed a threefold improvement in HDAC 1/2 inhibition, a threefold increase in HDAC 6 selectivity and a twofold increase in HDAC 8 selectivity when compared to SAHA.

Interaction of anthracyclines with iron responsive element mRNAs.

Double-stranded sections of mRNA are often inviting sites of interaction for a wide variety of proteins and small molecules. Interactions at these sites can serve to regulate, or disrupt, the homeostasis of the encoded protein products. Such ligand target sites exist as hairpin-loop structures in the mRNAs of several of the proteins involved in iron homeostasis, including ferritin heavy and light chains, and are known as iron responsive elements (IREs).