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PubMed2004

Synthesis and antiviral activity of 3-formyl- and 3-cyano-2,5,6-trichloroindole nucleoside derivatives.

A series of trichlorinated indole nucleosides has been synthesized and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1) and for cytotoxicity. The previously reported 3-formyl-2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole (FTCRI) and its 3-cyano homologue (CTCRI) were chemically modified at the 3-position. The formation of hydrazones and oximes of FTCRI was accomplished by a dehydrative addition of the appropriate hydrazine or hydroxylamine derivatives, respectively. A carboxamide oxime and imidate were synthesized from CTCRI by the addition of hydroxylamine or methanol, respectively, to the 3-nitrile substituent. Analogues synthesized from FTCRI generally had less antiviral activity than either FTCRI or CTCRI. However, the derivatives of CTCRI were potent and selective inhibitors of HCMV in vitro. The analogue 2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole-3-carboxamide oxime was especially selective (HCMV IC50 = 0.30 microM, CC50 > 100 microM). None of the analogues had significant activity against HSV-1.

Antiviral Agents↗
PubMed2005

Muscarinic allosteric enhancers of ligand binding: pivotal pharmacophoric elements in hexamethonio-type agents.

Bisphthalimidopropyl-substituted hexamethonio compounds have been established as allosteric modulators of ligand binding to muscarinic acetylcholine receptors. Enhancers of ligand binding are of special interest. This study aimed to unravel the structural elements inducing positive cooperativity with the binding of an antagonist. [(3)H]-N-methylscopolamine binding to muscarinic M(2) receptors was measured in porcine heart homogenates. Dimethylation, but not monomethylation, of the lateral propyl chain in combination with an affinity increasing aromatic imide moiety, such as a 5-methylphthalimide and naphthalimide, on the same side of the molecule shifts the cooperativity toward positive values, resulting in enhancers of antagonist binding. Thus, lateral side chain dimethylation is a pivotal pharmacophoric element for positive cooperativity in hexamethonio-type muscarinic allosteric agents.

Allosteric Regulation↗
PubMed2006

Homology modeling of the serotonin 5-HT1A receptor using automated docking of bioactive compounds with defined geometry.

This paper describes a rhodopsin-based model of 5-HT(1A) serotonin receptor. The flexibility of the receptor was considered by using large number of models for ligand dockings. Rearrangements of the heptahelical bundle were introduced, which resulted in the improvement of correlation between computational results and experimental data. The model was validated by automated docking of conformationally restricted arylpiperazines. Specific interactions, responsible for the recognition of arylpiperazine derivatives, were identified. An ionic bond was formed between the protonated amine of ligands and Asp3.32. The aromatic moiety and its substituents specifically interacted with Phe6.52 and Ser5.42, respectively, while the carbonyl groups of imide part of ligands formed hydrogen bonds with Asn7.39 and Tyr7.43. The model reproduced the binding affinity of the test group of ligands (correlation r = 0.8 between pK(i) and docking score). It also gave the enrichment in virtual screening-like experiment (100 compounds), in which 34 high-affinity compounds were found among 50 top-scored ligands.

Binding Sites↗
PubMed1997

Synthesis and antimetastatic activity of L-iduronic acid-type 1-N-iminosugars.

L-Iduronic acid-type 1-N-iminosugars, (3R,4S,5R,6R)- and (3R,4S,5S,6R)-6-acetamido-4-amino-5-hydroxypiperidine-3-carboxylic acid (6 and 7, respectively), (3R,4S,5R,6R)-6-acetamido-4- guanidino-5-hydroxypiperidine-3-carboxylic acid (8), and (3R,4S,5R,6R)-4-amino- and -guanidino-5-hydroxy-6-(trifluoroacetamido) piperidine-3-carboxylic acid (9 and 10, respectively), were synthesized from siastatin B (1), isolated from Streptomyces culture, by the intramolecular Michael addition of O-imidate to its alpha,beta-unsaturated ester through cis oxiamination as a key step. Preincubation of B16 BL6 cells with these compounds inhibited invasion of the cells through reconstituted basement membranes. Pulmonary metastasis of B16 BL6 cells in mice was remarkably inhibited by pretreatment of the cells with these compounds in culture.

Animals↗
PubMed1999

Synthesis and structure-activity relationships of a new model of arylpiperazines. 4. 1-[omega-(4-Arylpiperazin-1-yl)alkyl]-3-(diphenylmethylene) - 2, 5-pyrrolidinediones and -3-(9H-fluoren-9-ylidene)-2, 5-pyrrolidinediones: study of the steric requirements of the terminal amide fragment on 5-HT1A affinity/selectivity.

In the present paper, we report the synthesis and the binding profile on 5-HT1A, alpha1 and D2 receptors of a new series of 1-[omega-(4-arylpiperazin-1-yl)alkyl]-3-(diphenylmethylene)- 2, 5-pyrrolidinediones (III) (1-4) and -3-(9H-fluoren-9-ylidene)-2, 5-pyrrolidinediones (IV) (1-4), in which the alkyl linker contains 1-4 methylenes and the aryl group is variously substituted. The results obtained are compared to those previously reported for bicyclohydantoin (I) and the related bicyclic amine (II) series. A considerable part of the tested compounds 1-4 demonstrated moderate to high affinity for 5-HT1A and alpha1 receptor binding sites but had no affinity for D2 receptors. The study of the length of the alkyl chain and the imide substructure has allowed us to suggest some differences between the 5-HT1A and the alpha1-adrenergic receptors: (i) for III and IV, affinity for the 5-HT1A receptor as a function of the length of the methylene linker decreases in the order 4 > 1 >> 3 approximately 2, while for the alpha1 receptor affinity decreases in the order 3 approximately 4 > 1 approximately 2; (ii) the no-pharmacophoric steric pocket (receptor zone which does not hold the pharmacophore of the ligand but holds a nonessential fragment of the molecule) in the 5-HT1A receptor has less restriction than the corresponding pocket in the alpha1 receptor. Compounds 3a,e, which are highly selective for alpha1-adrenergic receptors, displayed antagonist activity. On the other hand, the best compromise between affinity and selectivity for 5-HT1A receptors is reached in these new series with n = 1, which is in agreement with our previous results for the bicyclohydantoin derivatives I. Two selected compounds (1d and 4e) retain agonist properties at postsynaptic 5-HT1A receptors. The same 5-HT1A agonist profile found in these compounds suggests the existence of two different no-pharmacophoric steric pockets in this receptor and a different interaction of compounds with n = 1 and n = 4. The information obtained from the interpretation of the energy minimization and 2D-NOESY experiments of compounds 1-4 together with the synthesis and binding data of new conformationally restrained analogues 4k-m is in good agreement with this working hypothesis.

Adenylyl Cyclases↗
PubMed2000

Histaprodifens: synthesis, pharmacological in vitro evaluation, and molecular modeling of a new class of highly active and selective histamine H(1)-receptor agonists.

A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liquid ammonia, followed by standard reactions. The title compounds displayed partial agonism on contractile H(1) receptors of the guinea-pig ileum and endothelium-denuded aorta, respectively, except 10 (histaprodifen; 2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) which was a full agonist in the ileum assay. While 10 was equipotent with histamine (1), methylhistaprodifen (13) and dimethylhistaprodifen (14) exceeded the functional potency of 1 by a factor of 3-5 (13) and 2-3 (14). Compounds 10 and 13-17 relaxed precontracted rat aortic rings (intact endothelium) with relative potencies of 3.3- up to 28-fold (compared with 1), displaying partial agonism as well. Agonist effects were sensitive to blockade by the selective H(1)-receptor antagonist mepyramine (pA(2) approximately 9 (guinea-pig) and pA(2) approximately 8 (rat aorta)). The affinity of 10 and 13-17 for guinea-pig H(1) receptors increased 20- to 100-fold compared with 1. Two lower homologues of 10 were weak partial H(1)-receptor agonists while two higher homologues of 10 were silent antagonists endowed with micromolar affinity for rat and guinea-pig H(1) receptors. In functional selectivity experiments, 10, 13, and 14 did not stimulate H(2), H(3), and several other neurotransmitter receptors. They displayed only low to moderate affinity for these sites (pA(2) < 6). For a better understanding of structure-activity relationships, the interaction of 1 and 10, 13 and 14 within the transmembrane (TM) domains of the human histamine H(1) receptor were studied using molecular dynamics simulations. Remarkable differences were found between the binding modes of 10, 13, and 14 and that of 1. The imidazole ring of 10, 13, and 14 was placed 'upside down' compared with 1, making the interaction of the N(pi)-atom with Tyr431 possible. This new orientation was mainly caused by the space filling substitution at the 2-position of the imidazole ring and influenced the location of the protonated N(alpha)-atom which was positioned more between TM III and TM VI. This orientation can explain both the increased relative potency and the maximum effect of 10, 13, and 14 compared with 1. Compound 13 (methylhistaprodifen; N(alpha)-methyl-2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) is the most potent histamine H(1)-receptor agonist reported so far in the literature and may become a valuable tool for the study of physiological and pathophysiological H(1)-receptor-mediated effects.

Animals↗
PubMed2000

Synthesis of PDK, a novel porphyrin-linked dicarboxylate ligand.

A novel trinucleating ligand system H4(PDK), for porphyrin-based diamine bis(Kemp's triacid)imide, was constructed by using two molecules of Kemp's triacid and one molecule of porphyrin as building blocks. The dimeso-substituted octaalkylporphyrin unit, carrying bromomethyl groups at the ortho positions of two trans-positioned meso-phenyl groups, was synthesized from (3,3'-diethyl-4,4'-dimethyl-2,2'-dipyrrolyl)methane and (alpha-bromo-o-tolualdehyde. The structures of both of the two atropisomers (alpha,alpha- and alpha,beta-) of bromoporphyrin, H2(alpha,alpha-BP) and H2(alpha,beta-BP), were determined by X-ray crystallography, with the alpha,beta-isomer as the free base form and the alpha,alpha-isomer as the zinc complex. Both the alpha,alpha- and alpha,beta-isomers of the bromomethyl porphyrins were converted to their aminomethyl derivatives, H2(alpha,alpha-AP) and H2(alpha,beta-AP), through the corresponding imidoporphyrin intermediates, H2(alpha,alpha-IP) and H2(alpha,beta-IP), by the Gabriel synthesis. The alpha,alpha- and alpha,beta-aminoporphyrins were coupled with Kemp's triacid anhydride-chloride to form H4(alpha,alpha-PDK) and H4(alpha,beta-PDK), respectively. Unlike the alpha,beta-isomer, the structure of which was determined by X-ray crystallography for the zinc complex, H4(alpha,alpha-PDK) has a remarkable and complicated solvent-dependent 1H NMR spectrum that suggests the existence of hydrogen bonding interactions between two convergent, tethered Kemp's triacid units, as predicted in a modeling study. The convergent feature is essential for the target ligand H4(alpha,alpha-PDK) to form trinuclear metal complexes with a bis(carboxylato) dimetallic unit sitting above a metalloporphyrin ring.

Dicarboxylic Acids↗
PubMed2001

Steric and electronic ligand perturbations in catalysis: asymmetric allylic substitution reactions using C2-symmetrical phosphorus-chiral (bi)ferrocenyl donors.

Three series of P-chiral diphosphines based on ferrocene (1a-f, 2a-c) and biferrocenyl skeletons (3a-c), including novel ligands 1f and 3c, were employed in palladium-catalyzed allylic substitution reactions. Steric effects imposed by the phosphine residues were studied using C2-symmetrical donors 1 (1 = 1,1'-bis(arylphenylphosphino)ferrocene with aryl groups a = 1-naphthyl, b = 2-naphthyl, c = 2-anisyl, d = 2-biphenylyl, e = 9-phenanthryl, and f = ferrocenyl), whereas para-methoxy- and/or para-trifluoromethyl substitution of the phenyl moieties in 1a enabled investigation of ligand electronic effects applying ferrocenyl diphosphines 2a-c. Ligands 3 (3 = 2,2'-bis- (arylphenylphosphino)-1,1'-biferrocenyls with aryl substituents a,c = 1-naphthyl (diastereomers) and b = 2-biphenylyl) allowed for comparison of backbone structure effects (bite angle variation) in catalysis. Linear and cyclic allylic acetates served as substrates in typical test reactions; upon attack of soft carbon and nitrogen nucleophiles on (E)-1,3-diphenylprop-2-ene-1-yl acetate the respective malonate, amine, or imide products were obtained in enantioselectivities of up to 99% ee. A crystal structure analysis of a palladium 1,3-diphenyl-eta 3-allyl complex incorporating ligand (S,S)-1a revealed a marked distortion of the allyl fragment, herewith defining the regioselectivity of nucleophile addition.

Journal Article↗
PubMed2001

Cyclization strategies for the synthesis of macrocyclic bisindolylmaleimides.

Three new approaches to the synthesis of macrocyclic bisindolylmaleimides 1-4 have been identified. Two strategies afford 8, the penultimate intermediate for the synthesis of 1-4, in 73% and 32% yield by intramolecular cyclization of 31 and 40, respectively. The optimum synthesis of 1 was achieved in nine steps and 15% yield by intramolecular formation of the macrocycle and maleimide in one step by reaction of the sodium indolate of 12 with methyl indole-3-glyoxylate 47. The mechanism of this reaction has been elucidated, using the trityl-protected derivative, to involve initial formation of the tricarbonyl imide 48, followed by irreversible alkylation of the indole nitrogen to generate the 17-membered macrocycle 49. Cyclization of 49 to hydroxymaleimide 50 and subsequent dehydration afforded 8a. This approach eliminated the problem of dimerization observed in the intramolecular cyclization reactions.

Diabetic Retinopathy↗
PubMed2000

Conjugate addition reactions of alpha-aminoalkylcuprates with alpha, beta-alkenyl-, alpha,beta-alkynyl-, alpha,beta-beta,gamma-allenyl-, and alpha,beta-gamma,delta-dienyl carboxylic acid derivatives, nitriles, and sulfoxides.

alpha-Aminoalkylcuprates prepared from alpha-lithio carbamates and CuCN.2LiCl participate in 1,4-addition reactions with alpha, beta-unsaturated esters, thiol esters, imides, and nitriles in poor to excellent yields depending upon the electron-withdrawing substituent and the substitution pattern of the unsaturated substrate. These reagents also undergo conjugate addition reactions with alpha,beta-alkynyl esters, sulfoxides, and nitriles and with alpha,beta-beta,gamma-unsaturated allenyl esters. Excellent stereocontrol is achieved in the conjugate additions of alpha-aminoalkylcuprates to the allenyl esters, while poor stereoselectivity results in the conjugate additions to the alkynyl derivatives. Deprotection and cyclization of the alkynyl adducts affords pyrrolin-2-ones, while similar treatment of the allenyl adducts affords 4-alkylidine- pyrrolidin-2-ones and pyrrolizidinones.

Carboxylic Acids↗
PubMed2001

Total synthesis and absolute configuration of minalemine A, a guanidine peptide from the marine tunicate Didemnum rodriguesi.

The total synthesis of the 3S,2S and 3R,2S diastereomers (1a and 1b) of minalemine A and the identification of the natural compound as the 3R,2S isomer is described. The key step in the synthesis is the preparation of the two enantiomers of the beta-amino diacid 3-(N-carboxymethyl)-aminodecanoic acid (Ncma), which were obtained by stereoselective alkylation with allyl bromide of two nonanoic acid imides bearing chiral oxazolidinones as chiral auxiliaries. Natural minalemine A shows identical 1H NMR and very similar 13C NMR spectra compared to the two synthetic diastereomers. Sufficient differences in their chromatographic behavior to allow conclusive identification were not found. However, the corresponding N-2-naphthoyl amides presented quite distinct circular dichroism spectra (CD), and these confirmed the 3R,2S configuration for the natural minalemines and the R configuration for the constituent beta-amino diacid, Ncma.

Animals↗
PubMed2001

Synthesis of beta-galactose-conjugated chlorins derived by enyne metathesis as galectin-specific photosensitizers for photodynamic therapy.

A first report on the synthesis and biological evaluation of the beta-galactose-conjugated purpurinimides (a class of chlorins containing a six-membered fused imide ring system) as Gal-1 (galectin-1) recognized photosensitizers, prepared from purpurin-N-propargylimide via enyne metathesis, is discussed. On the basis of examination of the available crystal structure of the galectin-1 N-acetyllactose amine complex, it was considered that the chlorin-based photosensitizers could be introduced into a carbohydrate skeleton to expand the repertoire of the galectin-1-specific ligands. Preliminary molecular modeling analysis utilizing the modeled photosensitizers and the available crystal structures of galectin-carbohydrate complexes indicated that addition of the photosensitizer to the carbohydrate moiety at an appropriate position does not interfere with the galectin-carbohydrate recognition. Under similar drug and light doses, compared to the free purpurinimide analogue, the purpurinimides conjugated either with galactose or with lactose (Gal(beta1-4)-Glc) produced a considerable increase in photosensitizing efficacy in vitro. This indicates the possibility for development of a new class of specific photosensitizers for photodynamic therapy (PDT) based on recognition of a cellular receptor.

Carbohydrates↗
PubMed2002

Synthesis of diazadibenzoperylenes and characterization of their structural, optical, redox, and coordination properties.

Tetraphenoxy-substituted diazadibenzoperylenes 5a,b were synthesized from tetrachloroperylene tetracarboxylic acid bisanhydride 1 through imidization with benzylamine, nucleophilic displacement of the four chlorine atoms by phenolates, carbonyl group reduction by LiAlH(4)/AlCl(3), and subsequent Pd/C-promoted debenzylation-dehydrogenation. The structural properties of these extended diazaarenes are discussed on the basis of a X-ray crystal structure of the N,N'-dibutylated diazadibenzoperylenium dication 6, which revealed a 25 degrees twist of the central six-membered ring leading to an atropisomeric pi-conjugated backbone. The chromophoric systems of 5 and 6 were characterized by optical absorption and fluorescence spectroscopy, which revealed an intense fluorescence with a quantum yield of 75% for 5 and 50% for 6. Cyclic voltammetry showed reversible oxidation and reduction waves for 6, whereas the oxidation of 5 afforded the irreversible deposition of a conductive film on the electrode surface. Finally, the potential use of ligands 5 in supramolecular chemistry has been evaluated by complexation experiments with carboxylic acids and zinc tetraphenylporphyrin (ZnTPP).

Journal Article↗
PubMed2001

Pi-aromatic and sulfur nucleophilic partners in cationic pi-cyclizations: intramolecular amidoalkylation and thioamidoalkylation cyclization via omega-carbinol lactams(1, 2).

NaBH(4) reduction of imides 1 and 6a,b,c followed by a pi-cyclization of the resultant N-acyliminium ions, generated in trifluoroacetic acid conditions, afforded two positional isomers, isoindolobenzothiazolinones 4 and 8, respectively. These ring closures proceeded via an intramolecular alpha-amidoalkylation with the classical pi-aromatic or the atypical sulfur atom as an internal nucleophile. A ready access to the related six-membered N,S-heterocyclic compounds such as isoindolobenzothiazinones 20a and 21a is also described. During this reaction, we have shown that omega-carbinol lactam precursor 14a led to endocyclic and exocyclic N-acyliminium ions 18a and 19a in equilibrium via the cyclic aza-sulfonium ion A. The latter furnished the expected products 20a and 21a in good yields. Similarly, different omega-carbinol lactams 14b-e substituted at C-angular position afforded the corresponding isoindolobenzothiazinones 20b-e and 21b-e bearing an angular alkyl, aralkyl, or aryl group. In the case of methyl 14b and benzyl 14e groups, an additional amount of the dehydration products 16b and 31 was isolated. These results indicate that the isomerization-pi-cyclization takes place via the cleavage of the thioether linkage in acidic medium.

Journal Article↗
PubMed2002

Asymmetric Diels-Alder, Michael, and aldol reactions using a planar chiral 1,3-oxazol-2(3H)-one derived from (R)-(+)-4-hydroxy-[2.2]paracyclophane.

(+)-(R)-[2.2]Paracyclophane[4,5-d]-1,3-oxazol-2(3H)-one exhibiting planar chirality has been used as a chiral auxiliary in asymmetric Diels-Alder, Michael, and aldol reactions of alpha,beta-unsaturated carboxy and enolate imides, respectively. The endo-exo- and face-diastereoselectivity is good and is controlled by the spatial relationship between the prochiral center and the C9-C10 ethylene bridge of the [2.2]paracyclophane moiety. The chiral auxiliary is easily removed and quantitatively recovered.

Journal Article↗
PubMed2002

Preparation of alpha-phosphono lactams via electrophilic phosphorus reagents: an application in the synthesis of lactam-based farnesyl transferase Inhibitors.

Conversion of N-alkyl lactams to the corresponding alpha-phosphono lactams has been investigated through procedures that involve formation of the lactam enolate and reaction with a phosphorus electrophile. With N-octylpyrrolidinone, the enolate could be trapped efficiently on oxygen by reaction with diethyl phosphorochloridate, and the resulting vinyl phosphate rearranges smoothly to the desired phosphonate upon treatment with additional LDA. Attempts to apply the same protocol to N-farnesyl lactams met with limited success. Studies with an isolated alpha-phosphono N-farnesyl lactam have shown that the farnesyl group is not stable to the excess of strong base required for rearrangement of a vinyl phosphate. However, a series of N-farnesyl lactams and imides was converted to the desired phosphonates through formation of the lactam enolate, reaction with diethyl phosphorochloridite, and subsequent oxidation of the phosphorus intermediate to the P(V) state.

Alkyl and Aryl Transferases↗
PubMed2002

Lewis acid-promoted Kharasch-Curran additions: a competition kinetics study of bromine atom transfer addition of N-alpha-bromoacetyl-oxazolidinone to 1-hexene.

Lewis acids can efficiently promote free radical atom transfer reactions of an oxazolidinone imide substrate, 1, derived from alpha-bromo acetic acid. Thus, 1 undergoes a radical chain addition to 1-hexene giving the atom transfer addition compound, 6, in the presence of scandium or ytterbium triflate in 1,2-dichloroethane or a cosolvent mixture of 1/9 THF/dichloromethane. In 1,2-dichloroethane the solution is heterogeneous, while the cosolvent mixture gives a homogeneous solution, even at temperatures of -78 degrees C. Competition experiments were carried out in both solvent systems with added carbon tetrachloride to study how Lewis acid affected the product distribution. In the presence of carbon tetrachloride, chloride 7 is formed in addition to 6 and the ratio of these two products depends on the amount of Lewis acid present. In the presence of ytterbium triflate, in the cosolvent system, the reaction rate of bromine atom transfer was enhanced up to 400-fold compared to the reaction without added Lewis acid. Significant rate enhancements were also obtained in the solvent 1,2-dichloroethane, although the analysis of the system is complicated by the heterogeneous nature of the medium. Computation of C-Br bond dissociation energies (BDE) of the complexed and uncomplexed oxazolidinone bromide suggest that complexation lowers the BDE due to the effect of the strong electron-withdrawing group on the C-Br bond dipole.

Alkenes↗
PubMed2003

An asymmetric synthesis of aza analogues of the tricyclic skeleton of daphnane and the ABC ring system of phorbol.

An asymmetric synthesis of aza analogues of the ABC ring system of phorbol and related compounds containing the 5-7-6-fused framework of daphnane involved construction of the central seven-membered ring by a regioselective reduction of a chiral imide and cyclization with trifluoromethanesulfonic acid. Subsequent demethylation and oxidative dearomatization of ring C afforded an enantiopure dienone 20 with the same relative and absolute configuration at the 9- and 10-positions of the phorbol skeleton.

Aza Compounds↗