Additional Substituents Research Articles

Multipolar interactions in the D pocket of thrombin: large differences between tricyclic imide and lactam inhibitors

Two series of tricyclic inhibitors of the serine protease thrombin, imides (+/-)-1-(+/-)-8 and lactams (+/-)-9-(+/-)-13, were analysed to evaluate contributions of orthogonal multipolar interactions with the backbone C=O moiety of Asn98 to the free enthalpy of protein-ligand complexation. The lactam derivatives are much more potent and more selective inhibitors (K(i) values between 0.065 and 0.005 microM, selectivity for thrombin over trypsin between 361- and 1609-fold) than the imide compounds (Ki values between 0.057 and 23.7 microM, selectivity for thrombin over trypsin between 3- and 67-fold). The increase in potency and selectivity is explained by the favorable occupancy of the P-pocket of thrombin by the additional isopropyl substituent in the lactam derivatives. The nature of the substituent on the benzyl ring filling the D pocket strongly influences binding potency in the imide series, with Ki values increasing in the sequence: F < OCH2O < Cl < H < OMe < OH < N(pyr)<< Br. This sequence can be explained by both steric fit and the occurrence of orthogonal multipolar interactions with the backbone C[double bond, length as m-dash]O moiety of Asn98. In contrast, the substituent on the benzyl ring hardly affects the ligand potency in the lactam series. This discrepancy was clarified by the comparison of X-ray structures solved for co-crystals of thrombin with imide and lactam ligands. Whereas the benzyl substituents in the imide inhibitors are sufficiently close (< or =3.5 Angstroms) to the C=O group of Asn98 to allow for attractive orthogonal multipolar interactions, the distances in the lactam series are too large (> or =4 Angstroms) for attractive dipolar contacts to be effective.

Predictive theory for the combination kinetics of two alkyl radicals

An ab initio transition state theory based procedure for accurately predicting the combination kinetics of two alkyl radicals is described. This procedure employs direct evaluations of the orientation dependent interaction energies at the CASPT2/cc-pvdz level within variable reaction coordinate transition state theory (VRC-TST). One-dimensional corrections to these energies are obtained from CAS+1+2/aug-cc-pvtz calculations for CH3 + CH3 along its combination reaction path. Direct CAS+1+2/aug-cc-pvtz calculations demonstrate that, at least for the purpose of predicting the kinetics, the corrected CASPT2/cc-pvdz potential energy surface is an accurate approximation to the CAS+1+2/aug-cc-pvtz surface. Furthermore, direct trajectory simulations, performed at the B3LYP/6-31G* level, indicate that there is little local recrossing of the optimal VRC transition state dividing surface. The corrected CASPT2/cc-pvdz potential is employed in obtaining direct VRC-TST kinetic predictions for the self and cross combinations of methyl, ethyl, iso-propyl, and tert-butyl radicals. Comparisons with experiment suggest that the present dynamically corrected VRC-TST approach provides quantitatively accurate predictions for the capture rate. Each additional methyl substituent adjacent to a radical site is found to reduce the rate coefficient by about a factor of two. In each instance, the rate coefficients are predicted to decrease quite substantially with increasing temperature, with the more sterically hindered reactants having a more rapid decrease. The simple geometric mean rule, relating the capture rate for the cross reaction to those for the self-reactions, is in remarkably good agreement with the more detailed predictions. With suitable generalizations the present approach should be applicable to a wide array of radical-radical combination reactions.

Diastereoselective reduction of enantiopure N- p-toluenesulfinyl ketimines derived from pyridyl ketones

DIBAL reduction of enantiopure N- p-toluenesulfinyl ketimines derived from 2-pyridyl ketones bearing an additional substituent on the 6-position of the pyridine ring afforded the related N- p-toluenesulfinyl amines with high yields and diastereoselectivities. The results of a number experiments exploring the conversion of a optically active 1-substituted N-toluenesulfinyl 1-(6-bromopyridin-2-yl)methylamine in a number of more complex pyridine derivatives with maintenance of the toluenesulfinyl group N-protecting group is also reported.

Fluorine-18-Labelled Fluoropyridines: Advances in Radiopharmaceutical Design

Positron Emission Tomography is a high-resolution, sensitive, functional imaging technique, which can efficiently give access to the distribution, pharmacokinetics and -dynamics of a drug in vivo and which can therefore advantageously play a key-role in both drug discovery and development. This molecular imaging technique requires the preparation of a positron-emitting radiolabelled probe or radiotracer and for this purpose, fluorine-18 is becoming, more and more often, the radionuclide of choice (adequate physical and nuclear characteristics and potential wide use and -distribution of fluorine-18-labelled radiopharmaceuticals). Considering chemical structures showing a fluoropyridinyl moiety, nucleophilic heteroaromatic substitution at the ortho-position with no-carrier-added [18F]fluoride appears today as the most efficient method for the radiosynthesis of radiotracers and radiopharmaceuticals of high specific radioactivity when compared to homoaromatic-, but also aliphatic, nucleophilic radiofluorination. Like for the aliphatic nucleophilic radiofluorinations, only a good leaving group is required (a halogen, or better a nitro- or a trimethylammonium group). There is no need for an additional strong electron-withdrawing substituent for activation of the aromatic ring such as in the homoaromatic nucleophilic radiofluorinations, except if one considers meta-fluorination. Nucleophilic heteroaromatic substitution and consequent fluorine-18 incorporation are generally performed in DMSO with the no-carrier-added, activated K[18F]F-K222 complex using conventional heating at a moderately high temperature (120-150 degrees C) or microwave irradiation (100 Watt) for a short period of time (1-2 minutes) and often lead to high radiochemical yields. This review summarizes some of the recent applications of these nucleophilic heteroaromatic substitutions in the pyridine series and highlights its potential in the design (not seldom by hydrogen, hydroxyl or halogen replacement by fluorine) and preparation, of often drug-based, fluorine-18-labelled radiotracers and radiopharmaceuticals of high specific radioactivity for PET imaging.

Synthesis and anthelmintic properties of arylquinolines with activity against drug-resistant nematodes

2,4-Disubstituted quinolines with additional substituents in positions 5–8 have been found to have anthelmintic properties. A number of 2,4-dimethoxy-6- or 8-arylquinolines have potent activity against the sheep nematode Haemonchus contortus, with LD 99 values of the same order of magnitude as levamisole. These arylquinolines maintain their activity against levamisole-, ivermectin- and thiabendazole-resistant strains of H. contortus.

Isocoumarins as estrogen receptor beta selective ligands: Isomers of isoflavone phytoestrogens and their metabolites

In a search for new ligands selective for the estrogen receptor beta (ERβ), we prepared a series of non-steroidal compounds having an isocoumarin core structure. An interesting feature of these derivatives is that they bear the same functionalities as the well-known ERβ -selective, isoflavone phytoestrogens daidzein and genistein, but in an isomeric arrangement. These compounds could be prepared efficiently by electrophilic cyclization of acetylenic ester precursors, followed by simple manipulations to introduce additional substituents. Through a reduction of some of the isocoumarins, we also obtained isomeric analogs of the isoflavone metabolites equol and dehydroequol. The compounds we prepared were evaluated in ER binding assays, and selected compounds were studied further in cell-based gene transcription assays. Several of the isocoumarins and their analogs are high-affinity ligands that show considerable selectivity for ERβ in terms of binding affinity, and strikingly high ERβ selectivity in terms of potency in gene transcription assays. Two of the best compounds, which combine high transcriptional potency with an ERβ selectivity greater than 1000, should prove to be excellent probes of ERβ function in vivo.

Structure-selectivity relationship in the chemoselective hydrogenation of unsaturated nitriles

Several unsaturated nitriles of various structures (cinnamonitrile, cyclohex-1-enyl-acetonitrile, acrylonitrile, 3,3-dimethyl-acrylonitrile, geranylnitrile, and 2- and 3-pentenenitrile) with different substituents at the double bond were hydrogenated over Cr-doped Raney cobalt and nickel and over their undoped equivalents. The substitution and the position of the double bond relative to the nitrile group are crucial in determining the chemoselectivity for the unsaturated amine. The double bond is not hydrogenated when it is sterically hindered or if it is too far from the nitrile group (cyclohex-1-enyl-acetonitrile, double bond at C-6 in geranylnitrile). In conjugated systems, such as acrylonitrile or 2-pentenylnitrile, the activated double bond is hydrogenated before the nitrile. An additional methyl substituent at the double bond enhances the selectivity for unsaturated amines and, thus, 3,3-dimethyl-acrylonitrile and geranylnitrile were hydrogenated with selectivity up to 40%. The highest selectivities for unsaturated amines (up to 90%) were reached during the hydrogenation of nonconjugated systems, such as cyclohex-1-enyl-acetonitrile and 3-pentenylnitrile.

Opinion of the Scientific Panel on food additives, flavourings, processing aids and materials in contact with food (AFC) related to Flavouring Group Evaluation 13 (FGE.13); Furfuryl and furan derivatives with and without additional side-chain substituents

Opinion of the Scientific Panel on food additives, flavourings, processing aids and materials in contact with food (AFC) related to Flavouring Group Evaluation 13 (FGE.13); Furfuryl and furan derivatives with and without additional side-chain substituents

Derivatives of 16α-hydroxy-dehydroepiandrosterone with an additional 7-oxo or 7-hydroxy substituent: Synthesis and gas chromatography/mass spectrometry analysis

Derivatives of 16α-hydroxy-dehydroepiandrosterone, which have an additional oxygen substituent at position 7 (oxo or hydroxy group), were synthesized. Firstly, 17,17-dimethoxyandrost-5-ene-3β,16α-diyl diacetate was prepared and then oxidized with a complex of chromium(VI) oxide and 2,5-dimethylpyrazole to the respective 7-oxo derivative. This key intermediate was both deprotected or reduced by l-Selectride ® or sodium borohydride in the presence of cerium(III) chloride and then deprotected to give 7-oxo, 7α-hydroxy and 7β-hydroxy derivatives of 16α-hydroxy-dehydroepiandrosterone. The target compounds were characterized by 1H and 13C NMR spectra and in the form of O-methyloxime-trimethylsilyl derivatives, by gas chromatography/mass spectrometry methods.

Functionalized Homoleptic cis- and trans-C,N-ortho-Chelated Aminoaryl Platinum(II) Complexes

For the synthesis of corner building blocks with a 90° angle, to be used for the construction of larger structures, several homoleptic platinum(II) complexes [Pt(η2-C,N)2] (10−14), as both cis- and trans-isomers, have been prepared starting from newly synthesized ortho-lithiated (dimethylamino)methyl arene ligands. The aryl groups of these arylplatinum(II) complexes contain additional substituents such as halides or methyl, naphthyl, or (dimethylamino)methyl groups. With these functionalities on the aryl rings the cis/trans ratio could be tuned. The presence of steric groups ortho to the metal center (methyl or naphthyl) favors the formation of planar-chiral cis-isomers. The trans-isomers isomerize irreversibly to the thermodynamically favored cis-isomers upon heating. The arylplatinum(II) complexes were used in various substitution reactions. Addition of a stronger coordinating ligand changes the denticity of the C,N-attached ligands. The halide functionalities were exploited for chemoselective lithiatio...

Controlled Synthesis of Cis or Trans Isomers of 1,3-Disubstituted Tetrahydroisoquinolines and 2,5-Disubstituted Pyrrolidines

[reactions: see text] The stereoselective outcome of Pd(II)- or Ag(I)-catalyzed intramolecular N-alkylation to afford 1,3-disubstituted 1,2,3,4-tetrahydroisoquinolines was examined. In the absence of additional substituents, Pd(II) allows a facile access to the cis isomers, while Ag(I) favors formation of the trans isomers. The same observation was made for the synthesis of 2,5-disubstituted pyrrolidines. Possible reasons for the observed stereoselectivities are discussed.

Ultrafast transient lens spectroscopy of various C40 carotenoids: lycopene, β-carotene, (3R,3′R)-zeaxanthin, (3R,3′R,6′R)-lutein, echinenone, canthaxanthin, and astaxanthin

The ultrafast internal conversion (IC) dynamics of seven C(40) carotenoids have been investigated at room temperature in a variety of solvents using two-color transient lens (TL) pump-probe spectroscopy. We provide comprehensive data sets for the carbonyl carotenoids canthaxanthin, astaxanthin, and-for the first time-echinenone, as well as new data for lycopene, beta-carotene, (3R,3'R)-zeaxanthin and (3R,3'R,6'R)-lutein in solvents which have not yet been investigated in the literature. Measurements were carried out to determine, how the IC processes are influenced by the conjugation length of the carotenoids, additional substituents and the polarity of the solvent. TL signals were recorded at 800 nm following excitation into the high energy edge of the carotenoid S2 band at 400 nm. For the S2 lifetime solvent-independent upper limits on the order of 100-200 fs are estimated for all carotenoids studied. The S1 lifetimes are in the picosecond range and increase systematically with decreasing conjugation length. For instance, in the sequence canthaxanthin/echinenone/beta-carotene (13/12/11 double bonds) one finds tau1 approximately 5, 7.7 and 9 ps for the S1-->S0 IC process, respectively. Hydroxyl groups not attached to the conjugated system have no apparent influence on tau1, as observed for canthaxanthin/astaxanthin (tau1 approximately 5 ps in both cases). For all carotenoids studied, tau1 is found to be insensitive to the solvent polarity. This is particularly interesting in the case of echinenone, canthaxanthin and astaxanthin, because earlier measurements for other carbonyl carotenoids like, e.g., peridinin partly showed dramatic differences. The likely presence of an intramolecular charge transfer state in the excited state manifold of C40 carbonyl carotenoids, which is stabilized in polar solvents, has obviously no influence on the measured tau1.

Convenient Formation of Six- to Nine-Membered Carbocyclic Rings by 2-Pyridyl Radical Cyclization: A Generalized Synthesis of Pyridine-Fused Linear Tricyclic Systems

Intramolecular cyclization of 2-pyridyl radicals derived from 2-bromopyridin-3-yl substituted methylenecycloalkanes 19-22, vinylcycloalkanols 23 and 24, allylcycloalkanols 26-28, and butenylcycloalkanols 32-34 proceed via 6-, 7-, 8-, and 9-endo-trig pathways, giving six-, seven-, eight-, and nine-membered ring annulated pyridines respectively. However, the vinyl cyclopentanol 25 produced only the 6-exo-cyclized product 46, while the substituted allylcyclohexanol 29 and the butenylcyclohexanol 31 failed to cyclize, producing only the double bond isomerized debrominated olefins. Thus the method provides a useful entry to diverse classes of fused pyridines, with the ring size of the cycloalkane and the presence of additional substituents in the ring playing an important role in determining the outcome of the reactions.

Role of Mg2+ and pH in the modification of Salmonella lipid A after endocytosis by macrophage tumour cells

Lipid A of Salmonella typhimurium is covalently modified with additional acyl and/or polar substituents in response to activation of the PhoP/PhoQ and/or PmrA/PmrB signalling systems, which are induced by growth at low Mg2+ concentrations and mild acid pH respectively. Although these conditions are thought to exist within macrophage phagolysosomes, no direct evidence for lipid A modification after endocytosis has been presented. To address this issue, we grew S. typhimurium inside RAW264.7 cells in the presence of 32Pi, and then isolated the labelled lipid A fraction, which was found to be extensively derivatized with phosphoethanolamine, aminoarabinose, 2-hydroxymyristate and/or palmitate moieties. S. typhimurium grown in tissue culture medium synthesized lipid A molecules lacking all these substituents with the exception of the 2-hydroxymyristate chain, which was still present. Using defined minimal media to simulate the intracellular pH and Mg2+ concentrations of endosomes, we found that lipid A of S. typhimurium grown in an acidic, low-Mg2+ medium closely resembled lipid A isolated from bacteria internalized by RAW264.7 cells. A subset of S. typhimurium lipid A modifications were induced by low Mg2+ alone. Escherichia coli K-12 W3110 modified its lipid A molecules in response to growth under acidic but not low-Mg2+ conditions. Growth in a high-Mg2+, mildly alkaline medium resulted in suppression of most lipid A modifications with the exception of the 2-hydroxymyristate in S. typhimurium. Although lpxO transcription was stimulated by growth on low Mg2+, the biosynthesis of lipid A species containing 2-hydroxymyristate was independent of PhoP/PhoQ and PmrA/PmrB in S. typhimurium. Our labelling methods should be applicable to studies of lipid A modifications induced by endocytosis of diverse bacteria.

Synthesis and in vitro evaluation of new benzovesamicol analogues as potential imaging probes for the vesicular acetylcholine transporter

Our goal was to synthesize new stereospecific benzovesamicol analogues, which could potentially be used as SPECT or PET radioligands for the vesicular acetylcholine transporter (VAChT). This paper describes the chemical synthesis, resolution and determination of binding affinity for four enantiomeric pairs of derivatives. Their intrinsic affinities were determined by competition against binding of [ 3H]vesamicol to human VAChT. Of the eight enantiomers, ( E)-( R, R)-5-AOIBV [( R, R)- 3], and ( R, R)-5-FPOBV [( R, R)- 4] displayed the highest binding affinities for VAChT ( K d = 0.45 and 0.77 nM, respectively), which indicated that an elongation of the chain from 5-idodo as in the case of 5-iodobenzovesamicol (5-IBVM), to a 5-( E)-3-iodoallyloxy or 5-fluoropropoxy substituent, as in 5-AOIBV and 5-FPOBV, respectively, was very well tolerated at the vesamicol binding site. The enantiomer ( R, R)-4-MAIBV [( R, R)- 16], which retains the basic structure of (−)-5-IBVM but possess an additional aminomethyl substituent in the 4-position of the piperidine ring, displayed lower binding affinity ( K d = 8.8 nM). Nevertheless, the result suggests that substitution at this position may be an interesting alternative to investigate for development of new benzovesamicol analogues. As expected, the corresponding ( S, S) enantiomers displayed lower K d values, they were approximately 10-fold lower in the case of ( S, S)-5-FPOBV ( K d = 8.4 nM) and ( E)-( S, S)-5-AOIBV ( K d = 4.3 nM). ( R, R)- 3, and ( R, R)- 4 showed the same high affinity for VAChT as (−)-5-IBVM and may be suitable as imaging agents of cholinergic nerve terminals.

Ylidyl‐substituted Phosphonio‐benzophospholides as Chelating Ligands

AbstractPhosphonio‐benzo[c]phospholides with an additional phosphonium ylide substituent in 3‐position were synthesized by deprotonation of appropriately substituted 1, 3‐bis‐phosphonio benzophospholide cations and characterized by spectroscopic and analytical data. The ability of these molecules to act as bidentate P, C‐chelating ligands to transition metal atoms was demonstrated in the reactions with [W(CO)4(norbornadiene)] and [MCl2(cyclooctadiene)] (M = Pd, Pt). The PdII and PtII complexes are distinguished by a strong inclination towards addition of H2O to the 10π‐electron system of the ligand. The molecular structures of a W0 complex with a P, C‐chelating ylidyl‐phosphonio‐benzophospholide ligand and of the product resulting from H2O‐addition to a corresponding PtII complex were determined. The structural parameters of the W0 complex provide evidence for the presence of substantial steric strain around the metal atom.

Evaluation of human thymidine kinase 1 substrates as new candidates for boron neutron capture therapy.

Thymidine analogs containing o-carboranylalkyl groups at the 3-position were screened as potential substrates for human thymidine kinase 1 (TK1), an enzyme that is selectively expressed in a variety of rapidly proliferating cells, including tumor cells. On the basis of previous studies, 12 of these were identified as potential delivery agents for boron neutron capture therapy, a therapeutic method used for the treatment of high-grade brain tumors. Compound 4 with a pentylene spacer between the o-carborane cage and the thymidine scaffold and compound 10, which has an additional dihydroxypropyl substituent at the o-carborane cage, were the best substrates for TK1 with kcat/Km values of 27% and 36% relative to that of thymidine, respectively. These compounds showed partial competitive inhibition for thymidine phosphorylation by TK1. Neither compound was a substrate of recombinant human thymidine phosphorylase nor were their respective 5'-monophosphates substrates of 5'-deoxynucleotidase 1, thereby indicating potential in vivo stability. The octanol/water partition coefficient for compound 10 was 2.09, suggesting that it has excellent physiochemical properties for crossing the blood brain barrier and penetrating brain tissue. The in vitro cytotoxic effect of the 12 analogs was moderate to low in mammalian cell cultures with IC50 values between 10 and 160 micromol/L. Compounds 4 and 10 were taken up selectively and retained by the murine fibroblast L929 cell line, in contrast to its TK1-deficient variant. These findings suggest that compound 10 is a promising candidate for selective delivery of boron-10 to malignant cells, and additional in vivo studies are planned to evaluate it for boron neutron capture therapy of brain tumors.

Guaianolides from two subspecies of Amphoricarpos neumayeri from Montenegro

Quantitative 1H NMR measurements revealed Δ 11(13) sesquiterpene γ-lactones as the main constituents (⩾1% per weight of dried plant material) in the crude extracts of the aerial parts of Amphoricarpos neumayeri ssp. neumayeri and ssp. murbeckii from mountains Orjen and Visitor (Montenegro), respectively. Preparative silica gel chromatography afforded thirteen guai-11(13)-en-12,6α-olides, named amphoricarpolides ( 1– 13), with the same relative (1αH,4βH,5αH,7βH) configuration of the basic skeleton. The common structural feature of lactones 2– 13 was 3β,15-dioxygenation pattern. The only exception was 1 (3-deoxyamphoricarpolide), containing a single oxygen substituent (15-OH). Eight of them exhibited an additional oxygen substituent, 9β-OH ( 5 and 6), 2α-OH ( 8– 12), or 2α-OAc ( 13). Compound 7 was epoxydated at 10α(14)-position, whereas the remaining lactones contained a 10(14) double bond.

Chlorophyll Breakdown in Tobacco: On the Structure of Two Nonfluorescent Chlorophyll Catabolites

In extracts of senescent leaves of the tobacco plant Nicotiana rustica, two colorless compounds with UV/VIS characteristics of nonfluorescent chlorophyll catabolites (NCCs) were detected and tentatively identified as Nr-NCCs. These two polar NCCs were found in similar amounts in the fresh extracts, and their constitutions could be determined by spectroscopic analysis. The data showed both of the two Nr-NCCs to have the same tetrapyrrolic core structure, as reported previously for all other NCCs from senescent higher plants. In the less polar catabolite, named Nr-NCC-2, this core structure was conjugated with a glucopyranose unit, as similarly discovered earlier in Bn-NCC-2, an NCC from oilseed rape (Brassica napus). The more polar NCC from tobacco leaves, Nr-NCC-1, carried an additional malonyl substituent at the 6'-OH group of the glucopyranosyl moiety. Partial (enzyme-catalyzed) hydrolysis of Nr-NCC-1 gave Nr-NCC-2, while enzyme-catalyzed malonylation of Nr-NCC-2 gave Nr-NCC-1, establishing the identity of their basic tetrapyrrole structure. In earlier work (on the polar NCCs from oilseed rape), only separate glucopyranosyl and malonyl functionalities were detected. Nr-NCC-1, thus, represents a further variant of the structures of NCCs from senescent higher plants and exhibits an unprecedented peripheral refunctionalization in chlorophyll catabolites.

Lead‐Catalyzed Synthesis of Azo Compounds by Ammonium Acetate Reduction of Aromatic Nitro Compounds.

AbstractFor Abstract see ChemInform Abstract in Full Text.