Benzylideneacetone Derivatives Inhibit Osteoclastogenesis and Activate Osteoblastogenesis Independently Based on Specific Structure-Activity Relationship.

(E)-3,4-Dihydroxybenzylideneacetone (compound 1) inhibited receptor activator of NF-κB ligand-induced osteoclastogenesis of C57BL/6 bone marrow monocyte/macrophages with IC50 of 7.8 µM (IC50 of alendronate, 3.7 µM) while stimulating the differentiation of MC3T3-E1 osteoblastic cells, accompanied by the induction of Runt-related transcription factor 2, alkaline phosphatase, and osteocalcin. (E)-4-(3-Hydroxy-4-methoxyphenyl)-3-buten-2-one (compound 2c) showed a dramatically increased osteoclast-inhibitory potency with IC50 of 0.11 µM while sustaining osteoblast-stimulatory activity. (E)-4-(4-Hydroxy-3-methoxyphenyl)-3-buten-2-one (compound 2g) stimulated alkaline phosphatase production 2-fold at 50 µM without changing osteoclast-inhibitory activity, compared with compound 1. Oral administration of compounds 1, 2c, and 2g prevented ovariectomy-induced osteoporosis in ddY mice to a degree proportional to their osteoclastogenesis-inhibitory potencies. The administration of 1 (mg/kg)/d compound 2c ameliorated histomorphometry of osteoporotic bone to a degree comparable with 10 (mg/kg)/d alendronate. Conclusively, the in vitro capacity of a few benzylideneacetone derivatives to inhibit osteoclastogenesis supported by independent osteoblastogenesis activation was convincingly reflected in in vivo management of osteoporosis, suggesting a potential novel therapeutics for osteopenic diseases.

C-cinnamoyl Glycosides: An Emerging "Tail" for the Development of Selective Carbonic Anhydrase Inhibitors.

Attachment of different tails to the well-known carbonic anhydrase (CA) pharmacophores has led to the development of several new CA inhibitors (CAIs). A very good example of such "tails" is constituted by carbohydrates, which represent a wide range of chemotypes, leading thus to a high number of new CAIs. In the last years, several C-cinnamoyl glycosides containing different scaffolds have been prepared and investigated as carbonic anhydrase inhibitors, showing that some of them are very potent and selective CAIs. This article will review the latest developments in the synthesis and biological activity of these Cglycosides.

Paramagnetic nanoemulsions with unified signals for sensitive 19F MRI cell tracking.

As a promising cell tracking technology, 19F MRI suffers from low sensitivity. Here, fluorinated nanoemulsions with a unified 19F signal and paramagnetic relaxation enhancement were developed as 19F MRI cellular tracers with high stability, size controllability, biocompatibility, cellular uptake, and dual-modality for sensitive in vivo RAW264.7 cell tracking.

Novel nonsecosteroidal VDR agonists with phenyl-pyrrolyl pentane skeleton.

In order to find the vitamin D receptor (VDR) ligand whose VDR agonistic activity is separated from the calcemic activity sufficiently, novel nonsecosteroidal analogs with phenyl-pyrrolyl pentane skeleton were synthesized and evaluated for the VDR binding affinity, antiproliferative activity in vitro and serum calcium raising ability in vivo (tacalcitol used as control). Among them, several compounds showed varying degrees of VDR agonistic and growth inhibition activities of the tested cell lines. The most effective compound 2g (EC50: 1.06 nM) exhibited stronger VDR agonistic activity than tacalcitol (EC50: 7.05 nM), inhibited the proliferations of HaCaT and MCF-7 cells with IC50 of 2.06 µM and 0.307 µM (tacalcitol: 2.07 µM and 0.057 µM) and showed no significant effect on serum calcium.

Synthesis of Z-(pinacolato)allylboron and Z-(pinacolato)alkenylboron compounds through stereoselective catalytic cross-metathesis.

The first examples of catalytic cross-metathesis (CM) reactions that furnish Z-(pinacolato)allylboron and Z-(pinacolato)alkenylboron compounds are disclosed. Products are generated with high Z selectivity by the use of a W-based monoaryloxide pyrrolide (MAP) complex (up to 91% yield and >98:2 Z:E). The more sterically demanding Z-alkenylboron species are obtained in the presence of Mo-based MAP complexes in up to 93% yield and 97% Z selectivity. Z-selective CM with 1,3-dienes and aryl olefins are reported for the first time. The utility of the approach, in combination with catalytic cross coupling, is demonstrated by a concise and stereoselective synthesis of anticancer agent combretastatin A-4.

Synthesis and anti-inflammatory activity of novel (substituted)benzylidene acetone oxime ether derivatives: molecular modeling study.

Herein, we report the design, synthesis, and pharmacological properties of a series of substituted benzylidene acetone oxime ether derivatives from the corresponding oxime derivatives. All the newly synthesized compounds were investigated in vivo for their anti-inflammatory activities using carrageenin-induced rat paw oedema model. Among the compounds examined, compounds 5b and 7a showed the highest activity, nearly equivalent to that of the standard drug diclofenac sodium. Hence, they were screened for their analgesic activities using acetic acid-induced writhing model in mice and also, their ulcerogenic effects were studied. Compound 7a was found to possess significant anti-inflammatory and analgesic activities with negligible ulcerogenic effect. Docking study of the synthesized compound 7a into the active site of COX-1 and COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

DNA-targeting pyrroloquinoline-linked butenone and chalcones: synthesis and biological evaluation.

A series of conjugates of alpha,beta-unsaturated ketone systems, phenyl-butenone and diaryl-propenones (chalcones), with the tricyclic planar pyrroloquinoline nucleus were synthesised and evaluated for their anticancer properties. The aim was to target DNA by butenone and chalcones, and determine the occurrence of interactions with the macromolecule or related functional enzymes. The ability to inhibit cell growth was assayed on three human tumor cell lines, and the capacity to form molecular complexes with DNA was studied by linear flow dichroism (LD). The effect on the activity of the nuclear enzyme DNA topoisomerase II was also investigated. A noticeable cytotoxic effect was observed for all pyrroloquinoline-conjugated compounds 5 and 7a-c, particularly against human melanoma cell line JR8 (IC(50) 1.2-3.3 microM); the unconjugated chalcones (8a-c) and butenone had a lower or no effect at the tested concentrations. LD experiments confirmed the pyrroloquinoline nucleus as an efficacious carrier for intercalative complexation with DNA. The ability of pyrroloquinoline derivatives to intercalate between base pairs appears to inhibit the relaxation of supercoiled DNA by topoisomerase II, while they induce no significant DNA cleavage. Since the concentrations inhibiting the enzyme appear relatively high with respect to cytotoxicity, the effective intercalation could affect the activity of more DNA processing enzymes and these overall nuclear effects may induce cell death.

Design, synthesis, and preliminary pharmacological evaluation of 4-aminopiperidine derivatives as N-type calcium channel blockers active on pain and neuropathic pain.

Several compounds with a 4-aminopiperidine scaffold decorated on both nitrogen atoms by alkyl or acyl moieties containing the structural motifs of verapamil and of flunarizine, as well as those that are more frequent in known N-type calcium channel antagonists, have been synthesized. Antinociceptive activity on the mouse hot-plate test was used to select molecules to be submitted to further studies. Active compounds were tested in vitro on a PC12 rat pheochromocytoma clonal cell line, to evaluate their action on N-type calcium channels, and on a rat model of neuropathic pain. Two compounds that show N-type calcium channel antagonism and are endowed with potent action on pain and neuropathic pain (3 and 18) have been selected for further studies.

A novel, one-pot ring expansion of cyclobutanones. Syntheses of carbovir and aristeromycin.

A novel, one-pot ring-expansion procedure was developed using Me3S(O)I, NaH, and Sc(OTf)3. The scope and limitations were briefly examined, and a tentative mechanism was proposed. Application of the methodology to known cyclobutanone 1 provided the corresponding cyclopentanone, which was successfully advanced to (+)-carbovir and (+)-aristeromycin.

Solid-phase synthesis of a combinatorial array of 1,3-bis(acylamino)-2-butanones, inhibitors of the cysteine proteases cathepsins K and L.

To more rapidly prepare members of the 1,3-bis(acylamino)-2-butanone class of cysteine protease inhibitors, a solid-phase synthesis was developed. 1-Azido-3-amino-2,2-dimethoxybutane (4), which has the two amino groups differentiated and the ketone protected as a a ketal, served as a surrogate for the 1,3-diamino-2-butanone core. Amine (4) was coupled to the BAL-resin-linked carboxylic acids derived from alpha-amino acid esters. Evaluation of a small combinatorial array by measuring inhibition constants (Ki,appS) against cathepsins K, L, and B provided some structure-activity relationship trends with respect to selectivity and potency. Novel, potent inhibitors of cathepsins K and L were identified.

Synthesis and anticancer activity of new phenyl-ring substituted 4-morpholino-1-phenylthio-2-butanones [Mannich bases].

The preparation of phenyl-ring substituted 4-morpholino-1-phenylthio-2-butanones 4a-e is described. These compounds were evaluated against P-388 leukemia and human cancer rhinopharynx KB cells in vitro; some compounds were found to exhibit activity against these cell lines.