Synthesis and antitumor activity of bis(arylsulfonyl)dihydroimidazolinone derivatives.

A series of novel bis(arylsulfonyl)dihydroimidazolinones with different aryl substitution patterns were readily synthesized and evaluated for their antitumor activities. Some of the newly synthesized compounds exhibited cytotoxicity at micromolar range against multiple cancer cell lines, including A549, HepG2, HuCCA-1, and MOLT-3. The most potent analogue contained pentafluorobenzenesulfonyl groups, which could be chemically elaborated to serve as a potential pharmacophore.

2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation.

Imidazoline-based small molecule inhibitors of p53-MDM2 interaction intended for the treatment of p53 wild-type tumors are the promising structures for design of anticancer drugs. Based on fragment approach we have investigated a key role of substituents in cis-imidazoline core for biological activity of nutlin family compounds. Although the necessity of the substituents in the phenyl rings of cis-imidazoline has been shown, there are no studies in which the replacements of a halogen by other substituents have been investigated. A series of simple cis-imidazoline derivatives containing halogen, hydroxy and alkoxy-substituents were synthesized. The biological activity of the compounds was studied using assays of cytotoxicity (MTT) and p53 level. It was found that the hydroxyl-derivatives were not cytotoxic whereas the alkoxy analogues were the same or more active as halogen-substituted compounds in cell viability test. The synthesized alkoxy derivatives induced an increase of p53 level and did not promote necrotic cell death in the concentration up to 40 µM.

Glucopyranosylidene-spiro-imidazolinones, a New Ring System: Synthesis and Evaluation as Glycogen Phosphorylase Inhibitors by Enzyme Kinetics and X-ray Crystallography.

Epimeric series of aryl-substituted glucopyranosylidene-spiro-imidazolinones, an unprecedented new ring system, were synthesized from the corresponding Schiff bases of O-perbenzoylated (gluculopyranosylamine)onamides by intramolecular ring closure of the aldimine moieties with the carboxamide group elicited by N-bromosuccinimide in pyridine. Test compounds were obtained by Zemplén O-debenzoylation. Stereochemistry and ring tautomers of the new compounds were investigated by NMR, time-dependent density functional theory (TDDFT)-electronic circular dichroism, and DFT-NMR methods. Kinetic studies with rabbit muscle and human liver glycogen phosphorylases showed that the (R)-imidazolinones were 14-216 times more potent than the (S) epimers. The 2-naphthyl-substituted (R)-imidazolinone was the best inhibitor of the human enzyme (Ki 1.7 µM) and also acted on HepG2 cells (IC50 177 µM). X-ray crystallography revealed that only the (R) epimers bound in the crystal. Their inhibitory efficacy is based on the hydrogen-bonding interactions of the carbonyl oxygen and the NH of the imidazolinone ring.

Copper-Promoted C-Se Cross-Coupling of 2-Selenohydantoins with Arylboronic Acids in an Open Flask.

The modification of Chan-Lam-Evans cross-coupling reaction for the selective Se-arylation of 2-selenohydantoins under base-free mild conditions via aryl boronic acids is described herein. This approach was used to synthesize novel 5-arylidene-3-substituted-2-(arylselanyl)-imidazoline-4-ones with high yields. The anticancer activity of the final compounds was evaluated in vitro against different cancer cells, and thus, the possibility of 5-arylidene-3-substituted-2-(arylselanyl)-imidazoline-4-ones successful application as cytotoxic agents was demonstrated.

Synthesis, antifungal and antitumor activity of two new types of imidazolin-2-ones.

Thirty-six imidazolin-2-ones, including ten pairs of benzimidazolones and sixteen imidazopyridines, were synthesized and subjected for the evaluation of antifungal and antitumor activity. Compounds 4a-01, 6-01, 6-04 and 6-06 could effectively inhibit the spore germination and mycelium growth of Botrytis cinerea. The relationship between structure and antifungal activity revealed that the introducing short-chain aliphatic acyl groups at the moiety of imidazopyridines is favorable for the antifungal activity, whereas aromatic acyl groups are much better than aliphatic acyl groups for the activity of benzimidazolones except for acetyl. Preliminary SRB assay indicated that 6-01 exerted strong antiproliferative effect against Hela and NCM460 cell lines. Further kinases assay revealed that 6-01 could specially inhibit mTOR among 114 human cancer related kinases. Elisa and Western blot analysis testified that 6-01 simultaneously inhibits the phosphorylation of Akt and 4E-BP1, and 6-01 is a novel mTOR inhibitor which targets on both mTORC1 and mTORC2. This investigation provided a valuable chemical structure for the development of antitumor drugs.

Synthesis of dihydroimidazole tethered imidazolinethiones and their activity as novel antagonists of the nuclear retinoic acid receptor-related orphan receptors (RORs).

Targeting the transcriptional activity of nuclear hormone receptors has proven an effective strategy to treat certain human diseases, and they have become a major focus point to develop novel therapies for the treatment of cancer, inflammation, autoimmune diseases, metabolic disorders, and others. One family of nuclear receptors that has attracted most interest in recent years is the retinoic acid receptor-related orphan receptors (RORs), in particular RORγ. RORγ is a critical regulator of the immune system and RORγ antagonists have shown activity in animal models of inflammatory autoimmune diseases. Here we present the synthesis and biological evaluation of dihydroimidazole tethered imidazolinethiones. We have identified several dual RORγ/α and pan-ROR antagonists with significant activity in cellular assays that could serve as starting points for future optimization efforts to generate potent and selective RORγ modulators.

Design and synthesis of fused tetrahydroisoquinoline-iminoimidazolines.

In the aim of identifying new privileged structures, we describe the 5-steps synthesis of cyclic guanidine compounds "tetrahydroisoquinoline-iminoimidazolines" derived from tetrahydroisoquinoline-hydantoin core. In order to evaluate this new minimal structure and the impact of replacing a carbonyle by a guanidine moiety, their affinity towards adenosine receptor A2A was evaluated and compared to those of tetrahydroisoquinoline-hydantoin compounds.

Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a N-(2-Aminophenyl)-benzamide Binding Unit.

A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was observed for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines.

Design and synthesis of potent 1,2,4-trisubstituted imidazolinone derivatives with dual p38αMAPK and ERK1/2 inhibitory activity.

The synthesis of new 1,2,4-trisubstituted imidazolinone derivatives was described. The new compounds were designed as dual p38αMAPK and ERK1/2 inhibitors through hybridization of pharmacophoric elements associated with inhibition of these kinases. The kinase inhibition assay revealed excellent activity in the nanomolar range; especially compounds 6d and 7h which seemed promising candidates for such dual activity with IC50 values of 4.5 and 4.7 nM against p38αMAP, 25.0 and 24.0 nM against ERK1, and 3.2 and 3.5 nM against ERK2, respectively. These compounds were further tested for their antiproliferative activity against nine cancer cell lines, where they elicited high activity in the sub-micromolar range against breast, prostate and melanoma cells.

Inhibition of the human proteasome by imidazoline scaffolds.

The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors such as bortezomib. Herein, we describe the optimization of noncompetitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound 49, IC50 130 nM) toward proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of noncompetitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors.

Inhibitors of the p53/hdm2 protein-protein interaction-path to the clinic.

A growing number of the elements identified in intracellular signaling events that affect cell growth and transformation are proteins that physically interact with each other via domains or specifically recognized amino acid sequences. Some of these intracellular protein-protein interactions are attractive targets for anticancer targeted therapy, but progress in this field has been compromised by the paucity of compounds with suitable biological profiles and pharmacological properties. This Letter covers salient achievements in the identification and development of inhibitors of the p53-hdm2 protein-protein interaction, and highlights different screening techniques and structure-based design approaches that may be brought to bear on the discovery and development of inhibitors of other therapeutically relevant intracellular protein-protein interactions.

Attenuation of collagen-induced arthritis by orally available imidazoline-based NF-κB inhibitors.

The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice.

Design, synthesis and CoMFA studies of N1-amino acid substituted 2,4,5-triphenyl imidazoline derivatives as p53-MDM2 binding inhibitors.

A series of novel N1-amino-acid substituted 2,4,5-triphenyl imidazoline derivatives was designed and synthesized based on our previous studies. All synthesized target compounds were screened for their p53-MDM2 binding inhibitory activities and anti-proliferative activities against five cancer cell lines. Among them, twelve compounds displayed improved binding inhibitory activities and most compounds showed higher cell growth inhibition activities with IC(50) values in the low micromolar range. Compound 6c exhibited marked p53-MDM2 binding inhibitory activity (IC(50)=0.59 µM) which was eightfold more potent than that of Nutlin-1 (IC(50)=4.78 µM). CoMFA analysis was performed based on obtained biological data and resulted in a statistically significant CoMFA model with high predict abilities (q(2)=0.645, r(2)=0.979).

Design, synthesis, and biological evaluation of imidazoline derivatives as p53-MDM2 binding inhibitors.

Three series of novel imidazoline derivatives were designed, synthesized, and evaluated for their p53-MDM2 binding inhibitory activities, and anti-proliferation activities against PC3, A549, KB, and HCT116 cancer cell lines. Five of the tested compounds showed enhanced p53-MDM2 binding inhibitory potency and anti-proliferation activities in comparison with that of Nutlin-1. Flow cytometric analysis indicated that compound 7c, one of the most potent p53-MDM2 binding inhibitors with a K(i) value of 0.6 µM, showed its ability to arrest cell cycle progression.

Novel imidazo[4,5-b]pyridine and triaza-benzo[c]fluorene derivatives: synthesis, antiproliferative activity and DNA binding studies.

In the present paper, we have described the synthesis and biological activity of the novel derivatives of imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes (7-21, 24-26, 28-29). A preponderance of these compounds exerted strong cytostatic effects on the panel of seven human tumour cell lines in a dose-dependent manner. In particular, imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes including 2-imidazolinyl derivatives showed the most potent antitumour activity. Similarly, triaza-benzo[c]fluorenes 18 and 20 induced strong growth inhibition of tested tumour cell lines, and showed low cytotoxicity in normal human fibroblasts. DNA interaction studies of these compounds demonstrated that N-methylated 16 and 2-imidazolinyl 28 triaza-benzo[c]fluorenes bind to DNA in an intercalative mode.

Rapid and efficient hydrophilicity tuning of p53/mdm2 antagonists.

The protein-protein interaction of p53 and mdm2 is an important anticancer target. The interface, however, is very hydrophobic and naturally results in very hydrophobic antagonists. We used the Orru three component reaction (O-3CR) along with a rapid and efficient, recently discovered amidation reaction to dramatically improve the water solubility of our recently discovered low molecular weight p53/mdm2 antagonists. Arrays of amides were synthesized with improved hydrophilicity and retainment and/or improvement of p53/mdm2 inhibitory activity.

Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists: reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect.

A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp(34)NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.

Nuclear factor-kappaB mediated inhibition of cytokine production by imidazoline scaffolds.

The mammalian nuclear transcription factor NF-kappaB is responsible for the transcription of multiple cytokines, including the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Elevated levels of pro-inflammatory cytokines play an important role in the pathogenesis of inflammatory disorders such as rheumatoid arthritis (RA). Inhibition of the pro-inflammatory transcription factor NF-kappaB has therefore been identified as a possible therapeutic treatment for RA. We describe herein the synthesis and biological activity of a series of imidazoline-based scaffolds as potent inhibitors of NF-kappaB mediated gene transcription in cell culture as well as inhibitors of TNF-alpha and IL-6 production in interleukin 1 beta (IL-1beta) stimulated human blood.

Synthesis and antiproliferative activity of imidazole and imidazoline analogs for melanoma.

We have previously reported substituted 2-aryl-thiazolidine-4-carboxylic acid amides as potent and selective antiproliferative agents for melanoma. To understand the importance of the thiazolidine ring and to reduce potential complications associated with the two chiral centers, we designed and synthesized sets of new analogs by modifying this ring. These new analogs were tested in two melanoma cell lines and fibroblast cells (negative controls). Compared with the older analogs containing the thiazolidine ring, these new analogs have lower potency in general, but some of these analogs still have very good selectivity. These structure-activity studies indicated that the thiazolidine ring is very critical for the activity for these series of compounds.

Synthesis and reactivity of copper(I) complexes with an ethylene-bridged bis(imidazolin-2-imine) ligand.

A series of copper(I) complexes with a sterically hindered, bidentate ligand, BL iPr, derived from an N-heterocyclic carbene precursor have been isolated, characterized and their reactivity studied. The ethylene-bridged bis(imidazolin-2-imine) ligand (BL iPr) provides strongly donating N-donor atoms for the stabilization of a copper(I) metal center, priming it for reactivity. The complexes [(BL iPr)Cu(XyNC)]PF6 (4) and [(BL iPr)CuCl] (5) were characterized by X-ray crystallography and exhibit trigonal coordination at the copper centers. The reactivity of [(BL iPr)Cu]SbF6 toward dioxygen was studied at low temperature, indicating formation of a thermally sensitive intermediate with intense UV/Vis features and an isotope-sensitive vibration at 625 cm(-1) (599 cm(-1) with 18 O2). The intermediate is assigned as containing the bis(mu-oxo)dicopper(III) core, [2](PF6)2, and the related, stable hydroxo form was crystallized as [{(BL iPr)Cu}2(mu-OH)2](PF6)2, [3](PF6)2. The reactivity of 5 as a catalyst for the ATR polymerization of styrene was assessed in terms of reaction kinetics and polymer properties, with low PDI values achieved for polymers with molecular weights up to 30 000 g mol(-1).