Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation

Signal Transducer and Activator of Transcription 5 (STAT5) protein, a component of the STAT family of signaling proteins, is considered to be an attractive therapeutic target because of its involvement in the progression of acute myeloid leukemia. In an effort to discover potent molecules able to inhibit the phosphorylation-activation of STAT5, twenty-two compounds were synthesized and evaluated on the basis of our knowledge of the activity of 2-(3′,4′,5′-trimethoxybenzoyl)-3-iodoacetamido-6-methoxy benzo[b]furan derivative 1 as a potent STAT5 inhibitor. Most of these molecules, structurally related to compound 1, were characterized by the presence of a common 3′,4′,5′-trimethoxybenzoyl moiety at the 2-position of different benzoheterocycles such as benzo[b]furan, benzo[b]thiophene, indole and N-methylindole. Effects on biological activity of the iodoacetamido group and of different moieties (methyl and methoxy) at the C-3 to C-7 positions were examined. In the series of benzo[b]furan derivatives, moving the iodoacetylamino group from the C-4 to the C-5 or C-6 positions did not significantly affect antiproliferative activity. Compounds 4, 15, 20 and 23 blocked STAT5 signals and induced apoptosis of K562 BCR-ABL positive cells. For compound 23, the trimethoxybenzoyl moiety at the 2-position of the benzo[b]furan core was not essential for potent inhibition of STAT5 activation

Aryl and Heterocyclic Derivatives of Combretastatin A-4 Endowed with Anticancer Properties

Combretastatins are natural antimitotic agents isolated from the bark of the South African tree Combretum caffrum. Among these compounds, combretastatin A-4 (CA-4) possesses the most potent and interesting antitumor activity. Its mechanism of action is thought to be related to tubulin-binding properties that result in rapid tumour endothelial cell damage, neovascular shutdown and subsequent haemorrhagic necrosis. A large number of combretastatin A-4 analogues has been obtained and studied for cell-growth inhibition activity. These structural derivatives may be classified taking into account A-ring, B-ring or bridge modifications. Following our previous experience in arotinoid field, we envisaged novel bridge modified combretastatins taking into consideration six-membered aromatic rings as bioisosteric conformationally locked double bond analogs. Terphenyl backbone is the simplest scaffold emerged from our project, and despite already known and used in other synthetic and medicinal chemistry fields, nothing was reported in the antineoplastic research. We then adopted a versatile double Suzuki coupling strategy to easily reach a series of terphenyl or diphenyl pyridine combretastatin analogs. Besides six-membered rings, the synthesis of novel isoxazole and isoxazoline derivatives at the bridge position was envisaged to give precious information on conformationally locked combretastatins. Several possible isomers were obtained with different substitutions. The antiproliferative activity of bridge modified combretastatins, tested on HL60 cells showed that terphenyl compounds were scarcely active, having IC50 and AC50 over 10 and 20 μM, but pyridine derivatives demonstrated much more interesting, in special way having the nitrogen placed near to ring A junction. The isoxazole and isoxazoline derivatives had also a very variable behaviour, being the 3,5 disubstituted not much active, but having the 4,5 isoxazolines the most interesting antiproliferative activity in the series of our new analogues. It is worth noting that high potency was found for compounds bearing both cis and trans substitutions at the isoxazoline ring. Both intrinsic (as evidenced through investigation on mitochondrial membrane potential and confirmed in experiments with a caspase-9 inhibitor) and extrinsic (interaction with Fas receptor and reduced activity towards Fas-ligand resistant cell lines) proapoptotic pathways appeared to be influenced, finally resulting in a block into G2 cell-cycle phase. We studied different derivatives bearing the terphenyl structure, varying the substitution pattern of rings substitution. A peculiar behaviour was observed for compounds bearing a 4-carboxy group at ring B. Indeed, when tested in HL60 culture for antiproliferative activity, we observed an unexpected increase of cell population with respect to control. Following further studies, these compounds appeared to support cell viability and decrease apoptotic occurrence even in serum-free media, behaving in similar way as natural 14-hydroxy-retro-retinol (14-HRR). Moreover, these terphenyls were able to protect cultured neuronal cells treated with staurosporin (apoptotic inducer), but no protection was observed towards necrotic stimulations with glutamate. Taking into account that many neurodegenerative pathologies involve the apoptosis of neuronal populations, we think that terphenyl structures could be considered as leads for a novel protective therapeutic strategy

Pro‑apoptotic activity of novel synthetic isoxazole derivatives exhibiting inhibitory activity against tumor cell growth in vitro

In order to develop potential anticancer agents stimulating apoptosis, novel 3,4‑isoxazolediamide and 4,5,6,7‑tetrahydro‑isoxazolo‑[4,5‑c]‑pyridine derivatives have been synthetized. The original structures of geldanamycin and radicicol, which are known natural heat shock protein (HSP) inhibitors, were deeply modified because both of them exhibit several drawbacks, such as poor solubility, hepatotoxicity, intrinsic chemical instability or deprivation of the in vivo activity. This novel class of synthetic compounds containing the isoxazole nucleus exhibited potent and selective inhibition of HSP90 in previous studies. Biological assays (focusing on in vitro antiproliferative effects and pro‑apoptotic activity) in human erythroleukemic K562 cells (as a model system referring to tumor cells grown in suspension), glioblastoma U251‑MG and glioblastoma temozolomide (TMZ)‑resistant T98G cell lines (two model systems referring to tumor cells grown attached to the flask), were performed. Almost all isoxazole derivatives demonstrated significant antiprolif‑ erative and pro‑apoptotic activities, showing induction of both early and late apoptosis of K562 cells. Different effects were observed on the glioma U251‑MG and T98G cells, depending on the structure of the analogues. Antiproliferative and pro‑apoptotic activities in K562 cells were associated with the activation of the erythroid differentiation program. The present study demonstrated that 3,4‑isoxazolediamide and 4,5,6,7‑tetrahydro‑isoxazolo‑[4,5‑c]‑pyridine derivatives should be considered for in vivo studies focusing on the development of anticancer drugs acting, at least partially, via activation of apoptosis

Stereoselective synthesis of N,N’-Diaryl-2,5-dioxopiperazines from Homochiral or Racemic 2-Bromopropananilides.

N,N¢-Diaryl-2,5-dioxopiperazines 8 and 9, related to the amino acid alanine, are easily obtained by self-cyclocoupling of 2-bromopropananilides 7. The cis-(R,R) or cis-(S,S)/trans-(R,S) distribution is controlled, to varying extents, by starting either from a single enantiomer or racemate and by the promoter, aryl substituent, and solvent. 1H NMR spectra of the members of six diastereomeric couples and X-ray structures of representative products are reported

1,5,7-Triazabicyclo[4.4.0]dec-1- ene (TBD), 7-Methyl-TBD (MTBD) and the polymer-supported TBD (P-TBD):Three efficient catalysts for the nitroaldol (Henry) reaction and for the addition of dialkyl phosphites to unsaturated systems.

The 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and its 7-methyl derivative (MTBD) have been proven to be of great synthetic utility as catalysts in the nitroaldol (Henry) reaction and for the addition of dialkyl phosphites to a variety of carbonyl compounds. The catalysts were in many cases superior to the parent tetramethylguanidine (TMG). In general the reaction proceeds in a few minutes at 0°C. The polymer-supported-TBD (P-TBD) was also proven to be an efficient promoter of the above cited nucleophilic additions

STEREOSELECTIVE FORMATION OF GLYCOCONJUGATED LACTAMIDES FROM CHIRAL 2-BROMOPROPANAMIDES

The silver oxide promoted reaction of chiral 2-bromopropanamides with 1,2:3,4-di-O-isopropylidene-D-galactopyranose or with 1,2:5,6-di-O-isopropylidene-D-glucofuranose takes place with complete stereoselectivity and moderate chemical yield, giving diastereochemically pure glycoconjugate lactamides characterised through NMR spectroscopy

Facile synthesis of pyrazoles and pyrroles via thermolysis of tetrazolo[1,5-b]pyridazines, tetrazolo[1,5-a]pyrimidines and tetrazolo[1,5-a]pyridines

A simple and high yielding preparation of pyrazoles and pyrroles is described. Thermolysis of tetrazolo[1,5-b]pyridazines, tetrazolo[1,5-a]pyrimidines and tetrazolo[1,5-a]pyridines allowed easy ring contraction thus providing a facile preparation of cyanopyrazole and cyanopyrrole heterocycles. Since the cyano group is a versatile precursor of other functionalities, the reaction appears of particular interest for the construction of a variety of pyrazoles and pyrroles. The simple preparation of the starting tetrazole derivatives, the relatively mild conditions employed, and the very short reaction times make this versatile procedure of great synthetic utility and applicable both to small and large scale preparation

Synthetic Approach to non-Isosteric Peptidomimetics Related to Human Endothelin

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Concise enantioselective synthesis and attribution of the absolute configuration of two-carbon bridge methoxylated cocaines and pseudococaines

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Versatile Synthesis of New Cytotoxic Agents Structurally Related to Emiasterlins

A representative series of structural analogues of the antimitotic tripeptides hemiasterlins have been synthesized. The key-step of this synthetic strategy consists of an Ag2O-promoted nucleophilic substitution on a common precursor, a chiral non-racemic 2-bromoacyl derivative. Simple variation of nucleophile substituents allows a rapid and stereocontrolled development of new series of derivatives. Some reported compounds showed potent biological activity as growth inhibitors of cancer cell lines and tubulin polymerization inhibitors