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Increased angiogenesis and vascular endothelial growth factor (VEGF) levels contribute to higher metastasis and mortality in uveal melanoma (UM), an aggressive malignancy of the eye in adults. (±)-MRJF22 , a prodrug of the sigma (σ) ligand haloperidol metabolite II conjugated with the histone deacetylase (HDAC) inhibitor valproic acid, has previously demonstrated a promising antiangiogenic activity. Herein, the asymmetric synthesis of (R)-(+)-MRJF22 and (S)-(-)-MRJF22 was performed to investigate their contribution to (±)-MRJF22 antiangiogenic effects in human retinal endothelial cells (HREC) and to assess their therapeutic potential in primary human uveal melanoma (UM) 92-1 cell line. While both enantiomers displayed almost identical capabilities to reduce cell viability than the racemic mixture, (S)-(-)-MRJF22 exhibited the highest antimigratory effects in endothelial and tumor cells. Given the fundamental contribution of cell motility to cancer progression, (S)-(-)-MRJF22 may represent a promising candidate for novel antimetastatic therapy in patients with UM.

Several recently identified antifungal compounds share the backbone structure of acetophenones. The aim of the present study was to develop new isobutyrophenone analogs as new antifungal agents. A series of new 2,4-dihydroxy-5-methyl isobutyrophenone derivatives were prepared and characterized by 1 H, 13 C NMR and MS spectroscopic data. These products were evaluated for in vitro antifungal activities against seven plant fungal pathogens by the mycelial growth inhibitory rate assay. Compounds 3, 4a, 5a, 5b, 5e, 5f and 5g showed a broad-spectrum high antifungal activity. On the other hand, for the first time, these compounds were also assayed as potential inhibitors against Class II fructose-1,6-bisphosphate aldolase (Fba) from the rice blast fungus, Magnaporthe grisea. Compounds 5e and 5g were found to exhibit the inhibition constants (Ki) for 15.12 and 14.27 μM, respectively, as the strongest competitive inhibitors against Fba activity. The possible binding-modes of compounds 5e and 5g were further analyzed by molecular docking algorithms. The results strongly suggested that compound 5g could be a promising lead for the discovery of new fungicides via targeting Class II Fba., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The hydrochloride salts of buphedrone and pentedrone, two new designer drugs, have recently been identified in shipments destined for Canada. To confirm their identities, we have synthesized reference materials for these methcathinone analogues and herein provide complete characterization by FTIR, FT-Raman, ¹H NMR, ¹³C NMR, GC/MS and ESI-HRMS., (Copyright © 2011 John Wiley & Sons, Ltd.)

Radical cyclization reactions were performed by 5-exo-dig mode to yield cis-fused bicyclic systems, leading to the synthesis of bis-butyrolactone class of natural products. The study was aimed at understanding the impact of alkyl side chains of furanoside ring systems in L-ara configuration on the radical cyclization. It was amply demonstrated by experimental studies that the increase in the length of the alkyl side chain has an effect on the cyclization: while efficient cyclization reactions could be realized with methyl and ethyl side chains, the yields were significantly reduced in the case of n-pentyl side chain. Theoretical studies using DFT and (RO)MP2 methods were carried out to analyze the influence of the substitution pattern on the cyclization barriers.

Arylcycloalkylamines, such as phenyl piperidines and piperazines and their arylalkyl substituents, constitute pharmacophoric groups exemplified in several antipsychotic agents. A review of previous reports indicates that arylalkyl substituents can improve the potency and selectivity of the binding affinity at D(2)-like receptors. In this paper, we explored the contributions of two key pharmacophoric groups, that is, 4'-fluorobutyrophenones and 3-methyl-7-azaindoles, to the potency and selectivity of synthesized agents at D(2)-like receptors. Preliminary observation of binding affinities indicates that there is little predictability of specific effects of the arylalkyl moieties but the composite structure is responsible for selectivity and potency at these receptors.

New polymethylene derivatives of nucleic bases containing a keto function in the omega-position were synthesized by alkylation of nucleic bases with 2-(3-chloropropyl)-2-phenyl-1,3-dioxolane and the subsequent deblocking of the keto group; their physicochemical properties were studied. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 6; see also http://www.maik.ru.

The diastereomers of ketones 2 and 3 are shown to exhibit distinct photochemical reactivities due to conformational preferences; while the anti isomers of 2 and 3 undergo efficient Yang cyclization in 75-90% yields with a remarkable diastereoselectivity (> 90%), the syn isomers predominantly undergo Norrish Type II elimination. The differences in the product profiles of the diastereomers are consistent with a mechanistic picture involving the formation of precursor diastereomeric triplet 1,4-biradicals in which the substituents at alpha and beta-positions stabilize the cisoid (cyclization) or transoid (elimination) geometry. The fact that such a diastereomeric relationship does indeed ensue at the triplet-excited-state itself is demonstrated via the nanosecond laser-flash photolysis of model ketones 1. The diastereomeric discrimination in the product profiles observed for ketones 2 and 3 as well as in the triplet lifetimes observed for ketones 1 can both be mechanistically traced back to different conformational preferences of the ground-state diastereomeric ketones and the intermediary 1,4-biradicals. Additionally, it emerges from the present study that the syn and anti diastereomers of ketones 2 and 3 represent two extremes of a broad range of widely examined butyrophenones, which lead to varying degrees of Yang photocyclization depending on the alkyl substitution pattern.

This study presents new pharmacological and molecular modelling studies on a recently described series of conformationally constrained butyrophenones. Alignment-free three-dimensional quantitative structure-activity relationship models developed on the basis of GRid Independent descriptors and partial least squares regression analysis, allow feasible predictions of activity of new compounds and reveal structural requirements for optimal affinity, particularly in the case of the 5-HT(2A) receptor. The requirements for the 5-HT(2A) affinity consist in a precise distance between hydrogen bond donor (protonated amino group) and hydrogen bond acceptor groups, as well as an optimal distance between the protonated amino group and the farthest extreme of the compounds. Another significant result has been the characterisation of two structurally similar compounds as interesting pharmacological tools (1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-5-yl)ethyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine and 1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine). In spite of their structural similarity, the first compound shows clearly higher affinity for the 5-HT(2C) receptor (about 100 fold) and higher Meltzer ratio (1.17 vs. 0.99) than the second. Moreover, the first compound inhibits arachidonic acid release in a biphasic concentration-dependent way in functional experiments at the 5-HT(2A) receptor and it acts as inverse agonist at the 5-HT(2C) receptor, behaviours that are not shown by the second compound.

A series of 52 conformationally constrained butyrophenones have been synthesized and pharmacologically tested as antagonists at 5-HT(2A), 5-HT(2B), and 5-HT(2C) serotonin receptors, useful for dissecting the role of each 5-HT(2) subtype in pathophysiology. These compounds were also a consistent set for the identification of structural features relevant to receptor recognition and subtype discrimination. Six compounds were found highly active (pK(i) > 8.76) and selective at the 5-HT(2A) receptor vs 5-HT(2B) and/or 5-HT(2C) receptors. Piperidine fragments confer high affinity at the 5-HT(2A) receptor subtype, with benzofuranone- and thiotetralonepiperidine as the most selective derivatives over 5-HT(2C) and 5-HT(2B) receptors, respectively; K(i) (2A/2C) and/or K(B) (2A/2B) ratios greater than 100 were obtained. Compounds showing a more pronounced selectivity at 5-HT(2A)/5-HT(2C) than at 5-HT(2A)/5-HT(2B) bear 6-fluorobenzisoxazolyl- and p-fluorobenzoylpiperidine moieties containing one methylene bridging the basic piperidine to the alkanone moiety. An ethylene bridge between the alkanone and the amino moieties led to ligands with higher affinities for the 5-HT(2B) receptor. Significant selectivity at the 5-HT(2B) receptor vs 5-HT(2C) was observed with 1-1[(1-oxo-1,2,3,4-tetrahydro-3-naphthyl)methyl]-4-[3-(p-fluorobenzoyl)propyl]piperazine (more than 100-fold higher). Although piperidine fragments also confer higher affinity at 5-HT(2C) receptors, only piperazine-containing ligands were selective over 5-HT(2A). Moderate selectivity was observed at 5-HT(2C) vs 5-HT(2B) (10-fold) with some compounds bearing a 4-[3-(6-fluorobenzisoxazolyl)]piperidine moiety in its structure. Molecular determinants for antagonists acting at 5-HT(2A) receptors were identified by 3D-QSAR (GRID-GOLPE) studies. Docking simulations at 5-HT(2A) and 5-HT(2C) receptors suggest a binding site for the studied type of antagonists (between transmembrane helices 2, 3, and 7) different to that of the natural agonist serotonin (between 3, 5, and 6).

A series of novel conformationally restricted butyrophenones (6-aminomethyl-4,5,6,7-tetrahydrobenzo[b]furan-4-ones bearing 4-(6-fluorobenzisoxazolyl)piperidine, 4-(p-fluorobenzoyl)piperidine, 4-(o-methoxyphenyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, or linear butyro(or valero)phenone fragments) were prepared and evaluated as antipsychotic agents by in vitro assays for affinity for dopamine receptors (D(1), D(2), D(4)) and serotonin receptors (5-HT(2A), 5-HT(2B), 5-HT(2C)), by neurochemical studies, and by in vivo assays for antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cyclohexanone structure. Compounds 20b, with a benzoylpiperidine moiety, and 20c, with a benzisoxazolyl fragment, were selective for 5-HT(2A) receptors. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(p-fluorobenzoyl)piperidine (20b, QF1003B) and N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)p iperidine (20c, QF1004B) suggest that they may be effective as antipsychotic (neuroleptic) drugs.

We describe a practical and efficient route for synthesis of 2-aminomethyl-1,2,3,9-tetrahydro-4H-carbazol-4-ones using an effective Fisher indole methodology. The most active compounds, 4b (QF 2003B) and 4c (QF 2004B), with pKi (5-HT2A/D2) ratio of 1.28 show an antipsychotic profile according to Meltzer's classification.

Four new 2-(2-piperidinoethyl)benzocycloalkanone derivatives, 20-23, were prepared and evaluated as potential antipsychotic agents in receptor binding assays for dopamine (DA) and 5-HT2A receptors and in functional and behavioral screens. Their affinities for D2 receptors (Ki's in the nanomolar range: 46.7-70.7) and D1 receptors (Ki's in the micromolar range: 1.09-2.81) were slightly lower than that showed by haloperidol (Ki's in the nanomolar range: 5.01 and 97.72 for D2 and for D1 receptors, respectively). The ratio of pKi's values D1/D2 showed that the new molecules are more D2-selective than haloperidol. In contrast, in the [3H]-ketanserin binding assays the new compounds had greater affinity for 5-HT2A receptors (pKi's 7.89-8.60) than haloperidol (pKi 7.70) and in functional studies, endothelium-stripped aorta rings, the pA2 values (6.75-8.12) were slightly lower than that of ketanserin (8.87) in suppressing serotonin-induced contractions. The pKi's for D2 binding (and to a lesser extent pKi's for D1 binding) tend to be greater among typical (classical) than among atypical antipsychotics, while these two classes of antipsychotics exhibit no difference with regard to pKi's for 5-HT2A receptors. The ratios of pKi's for 5-HT2A/D2 receptors may be useful for rapid screening of new compounds, and its potential induction of extrapyramidal symptoms (ratio values > 1.12 were predictive of an atypical antipsychotic profile). The new molecules had a ratio value in the range 1.08-1.20, while haloperidol showed a ratio of 0.93. In the behavioral screening tests, the new molecules showed antagonist activity of amphetamine-inducing hyperactivity and apomorphine-induced climbing (predictive tests for antipsychotic activity). In the catalepsy test (predictive test for induction of extrapyramidal symptoms), the values obtained were in accordance with an atypical antipsychotic drugs profile.

A series of optically active analogues of the H1-antihistamine ebastine, with chiral center(s) at the benzhydryl and/or phenylbutyl part of the molecule, have been synthesized. Their in vitro antihistaminic and antimuscarinic activities were investigated, along with a molecular modelling study. It was found that introduction of the benzhydryl chiral center yielded significant stereoselectivity for both antihistaminic and antimuscarinic activities. The steric preferences of the benzhydryl chiral center for antihistaminic and antimuscarinic actions were mirror images of each other. The (-)-isomer of 4-methylebastine (6d) showed more than 10-fold higher in vitro antihistaminic potency than ebastine. Meanwhile the selectivity of 6d for histamine H1-receptors was also increased by more than 20 times in comparison with ebastine. The chirality at the phenylbutyl part of the molecule does not significantly alter the antihistaminic or antimuscarinic activity of the compounds although the (S)-isomers showed slightly but unanimously higher antihistaminic activity than the (R)-isomers. These results have been discussed with existing stereoselectivity data of antihistamines and an asymmetric pharmacophore model for H1-antagonists has been described.

The antiserotoninergic activity at the serotonin receptor subtype 2 (5-HT2) of seven new 2-aminoethylbenzocyclanones was determined with respect to serotonin-induced contractions in rat aorta and compared with that of ketanserine (pA2 = 8.87). Competitive antagonism was observed in six compounds (6.72 < or = pA2 < or = 8.12). Three-dimensional structures and molecular electrostatic potential distributions of ketanserine and 2-aminoethylbenzocyclanones were analyzed. Several molecular features correlated with the rank of antiserotoninergic activity. In the case of the cyclanone fragment, the rank of activity was associated with the degree of planarity of the bicyclic system. The steric and electrostatic effects due to the loss of planarity were analyzed. In the case of the amino moiety, activity was associated with a particular spatial pattern defined by the amino nitrogen, the aromatic system, and molecular electrostatic potential minima generated by the oxygen atom.

The synthesis of some 4'-[4-(N2-methyl-2-phenyl)-N1-ethyldiamine]-buthyrophenones as intermediates for variety of buthyrophenones is described.

Starting from beta-benzoylpropionic acid we synthesized 3-(aminomethyl)tetralones in which the amino substituent was 4-(N-piperazinyl)-p-fluorobutyrophenone, 4-benzoylpiperidine, 4-hydroxy-4-phenylpiperidine or 4-(o-methoxyphenyl)piperazine. The possible dopamine antagonist activity of these compounds was investigated in both "in vitro" and "in vivo" experiments. These compounds potently inhibited [3H]spiperone binding to D2 striatal receptors and moderately inhibited [3H]SCH-23390 binding to D1 striatal receptors (Kis in the nanomolar and micromolar ranges, respectively). Apomorphine-induced stereotypies and amphetamine group toxicity were antagonized, to different extents, by the compounds under study, with a potency similar to that of haloperidol. Interestingly, no catalepsy was observed after administration of the new compounds (2-8 mg/kg). The most active compounds "in vivo" 14 and 15 possessed two butyrophenone pharmacophores. However, the tetralone moiety appeared not critical for their antidopaminergic activity, since all target compounds were less active than haloperidol. These studies provide a pharmacological basis for future research on these new compounds devoid of cataleptogenic activity.

The synthesis of two nitrogen mustard derivatives (VIII and IX) related to the well-known local anesthetic ketocaine (III) is reported. These compounds were tested in mice implanted with Ehrlich ascites tumor cells, and the antitumor activity was compared with that of two previously synthesized analogues (I and II) lacking the nitro group and with that of doxorubicin. The monofunctional compound IX was inactive, but the bifunctional compound VIII showed potent antitumor activity (%T/C greater than 254 at 20 mg/kg).

6,7-Dichloro-2,3-dihydro-2-benzo[b]furancarboxylic acid derivatives having a 3,3-N,S-disubstituted-2-propenoyl group at the 5-position were prepared by alkylation of 5-(thiocarbamoyl)acetyl derivatives of the 2,3-dihydro-2-benzo[b]furancarboxylic acid ester or by acetal exchange reaction of 5-[3,3-bis(alkylthio)-2-propenoyl] derivatives. Synthesis of 5-[4 and/or 5-(di)substituted-4-thiazolin-2-ylidene]acetyl-2,3- dihydro-2-benzo[b]furancarboxylic acids was also achieved by the reaction of 2-halo-1-methoxyethyl isothiocyanate with the 5-acetyl derivative in the presence of base or through sulfide contraction of 2-[[6,7-dichloro-2-methoxycarbonyl-2,3-dihydrobenzo[b]furan-5-yl) carbonyl)-methylthio]thiazolium bromide. Some of the compounds which were synthesized showed potent natriuretic activities in rats and mice. The structure-activity relationship is also discussed.

No-carrier-added fluorine-18- (18F) labeled N-methylspiroperidol (4) was synthesized from four different substrates: p-nitrobenzonitrile (1), cyclopropyl p-nitrophenyl ketone (2A), p-cyclopropanoyl-N,N,N-trimethylanilinium iodide (2B) and p-cyclopropanoyl-N,N,N-trimethylanilinium perchlorate (2C) using the nucleophilic aromatic substitution reaction. Radiochemical yield, synthesis time, experimental simplicity, and specific activity were compared. In addition, factors which influence the yield of the nucleophilic aromatic substitution were studied. Based on these studies, the synthesis of 4 from 2A maximizes product specific activity and experimental simplicity and provides 4 in 10-15% radiochemical yield [based on [18F-] with a mass of less than 2 nmol and a specific activity of greater than 10 Ci/mumol (EOB)]. The synthesis of 4 from 8-[4-(4-nitrophenyl)-4-oxobutyl]-3-methyl-1-phenyl-1,3,8-triazaspiro+ ++ [4.5]decan-4-one (5) and Cs[18F] using the nucleophilic aromatic substitution reaction gave unacceptably low and erratic yields. The biodistribution of 4 in mice showed a maximum brain uptake of 1.1% of the administered dose at 5 min and declined to approximately 0.6% at 120 min.

The reaction between o-hydroxybutyrophenone and tris(2-chloroethyl)amine gave two analogues (II, V) of the well-known local anesthetic ketocaine (I). Compounds II and V showed interesting antitumor activity in mice implanted with Ehrlich ascites tumor cells (% T/C = 149 at 5 mg/kg and 171 at 50 mg/kg, respectively). Further studies on the pharmacological behavior of these new compounds are in progress.

Itanoxone synthesis by Friedel-Crafts reaction between itaconic anhydride and 2-chlorobiphenyl was studied. Five isomers corresponding to possible impurities were prepared and studied to perfect a reliable and practical method to detect these impurities in itanoxone.

The preparation of 5-phenylbicyclo [3.3.1]nonan-2-one is described starting from the ketal of 4-phenyl-4-(2-carbethoxyethyl)cyclohexan-1-one. The ketone was then taken on to the butyrophenone derivatives of endo-and exo-5phenylbicyclo[3.3.1]nonyl-2-amine. CNS screening results of these compounds are described.

The preparation of butyrophenone derivatives of 4-aryl-4-(hydroxymethyl)cyclohex-1-ylamines starting from the corresponding 4-cyano-4-phenylcyclohexan-1-ones is described. Substitution was varied with both rings; both isomers of 4-phenyl-4-(hydroxymethyl)cyclohex-1-ylamine were characterized. Those derivatives which carried p-fluoro substitution on the butyrophenone exhibited hypotensive activity in the rat with diminished CNS activity compared to compounds lacking the hydroxymethyl group. The effect of substitution on the 4-aryl ring is discussed.

p-Bromospiperone was prepared from the reaction of spiperone with bromine. It was tested for dopamine receptor binding affinity in vitro and its ability to stimulate prolactin secretion in vivo. The results indicate no significant change of biological activities due to the bromination of spiperone.

A series of new butyrophenones was synthesized, the aim being to reduce neuroleptic activity and enhance the hypotensive effects of this class of drugs. The compounds were screened for toxicity according to the Irwin scheme and tested in anaesthetized cats for their effects on systemic arterial pressure. The most interesting compound, i.e. 1-(4'-fluorobenzoyl)-3-pyrrolidinyl-propane, was tested also in anaesthetized rabbits, cats, and dogs and in concious dogs. Moreover its central nervous system effects were tested in rats and mice. The compound proved practically devoid of neurological effects and showed interesting hypotensive activity.

The synthesis and in vitro dopamine D2 receptor binding of a conformationally restricted analog of 4-piperidinobutyrophenone is described. 2-(2-Piperidinoethyl)-1-tetralone displaces [3H]spiperone from the rat striatal dopamine receptor with an IC50 of 1.2 X 10(-4)mol/l.