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Biomedical subjects

G J Koomen

Publications and source records attributed to G J Koomen.

13 recordsLinked to original sources
PubMed2004

New (1-deaza)purine derivatives via efficient C-2 nitration of the (1-deaza)purine ring.

Nitration of substituted (1-deaza)purines using a mixture of tetrabutylammonium nitrate (TBAN) and trifluoracetic acid anhydride (TFAA) was applied to prepare nitrosubstituted (1-deaza)purines at low temperature. The nitro group influences the system twofold: 1) it activates other substituents towards nucleophilic aromatic substitution and 2) it can be substituted itself leading to a variety of di-substituted (1-deaza)purines, also via solid phase syntheses. Several of the molecules obtained were studied for their antiprotozoal activity and for interactions with the different human adenosine receptors.

Acetic Anhydrides↗
PubMed2001

Inhibition of BCRP-mediated drug efflux by fumitremorgin-type indolyl diketopiperazines.

A library of 42 diastereoisomeric mixtures of fumitremorgin-type indolyl diketopiperazines, prepared by parallel solid-phase synthesis, was screened for Breast Cancer Resistance Protein inhibitory activity and compared with GF120918. Demethoxy-fumitremorgin C was synthesized by solid-phase techniques and tested as well. Structure-activity relationship studies have identified several potent analogues, both in assays using the T6400 mouse and the T8 human cell line, whereas low cytotoxicity was seen at effective concentrations.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2000

2-Nitro analogues of adenosine and 1-deazaadenosine: synthesis and binding studies at the adenosine A1, A2A and A3 receptor subtypes.

The influence of nitro substituents on the properties of adenosine and 1-deazaadenosine was studied. Combination of a nitro group at the 2-position with several N6 substituents such as cyclopentyl and m-iodobenzyl gave a series of analogues with good adenosine receptor affinity, showing directable selectivity for the A1, A2A and A3 adenosine receptor subtypes.

Adenosine↗
PubMed1998

Generation of specific deoxynojirimycin-type inhibitors of the non-lysosomal glucosylceramidase.

The existence of a non-lysosomal glucosylceramidase in human cells has been documented (van Weely, S., Brandsma, M., Strijland, A., Tager, J. M., and Aerts, J. M. F. G. (1993) Biochim. Biophys. Acta 1181, 55-62). Hypothetically, the activity of this enzyme, which is localized near the cell surface, may influence ceramide-mediated signaling processes. To obtain insight in the physiological importance of the non-lysosomal glucosylceramidase, the availability of specific inhibitors would be helpful. Here we report on the generation of hydrophobic deoxynojirimycin (DNM) derivatives that potently inhibit the enzyme. The inhibitors were designed on the basis of the known features of the non-lysosomal glucosylceramidase and consist of a DNM moiety, an N-alkyl spacer, and a large hydrophobic group that promotes insertion in membranes. In particular, N-(5-adamantane-1-yl-methoxy)pentyl)-DNM is a very powerful inhibitor of the non-lysosomal glucosylceramidase at nanomolar concentrations. At such concentrations, the lysosomal glucocerebrosidase and alpha-glucosidase, the glucosylceramide synthase, and the N-linked glycan-trimming alpha-glucosidases of the endoplasmic reticulum are not affected.

1-Deoxynojirimycin↗
PubMed1998

Trans/cis (Z/E) photoisomerization of the chromophore of photoactive yellow protein is not a prerequisite for the initiation of the photocycle of this photoreceptor protein.

The chromophore of photoactive yellow protein (PYP) (i.e., 4-hydroxycinnamic acid) has been replaced by an analogue with a triple bond, rather than a double bond (by using 4-hydroxyphenylpropiolic acid in the reconstitution, yielding hybrid I) and by a "locked" chromophore (through reconstitution with 7-hydroxycoumarin-3-carboxylic acid, in which a covalent bridge is present across the vinyl bond, resulting in hybrid II). These hybrids absorb maximally at 464 and 443 nm, respectively, which indicates that in both hybrids the deprotonated chromophore does fit into the chromophore-binding pocket. Because the triple bond cannot undergo cis/trans (or E/Z) photoisomerization and because of the presence of the lock across the vinyl double bond in hybrid II, it was predicted that these two hybrids would not be able to photocycle. Surprisingly, both are able. We have demonstrated this ability by making use of transient absorption, low-temperature absorption, and Fourier-transform infrared (FTIR) spectroscopy. Both hybrids, upon photoexcitation, display authentic photocycle signals in terms of a red-shifted intermediate; hybrid I, in addition, goes through a blue-shifted-like intermediate state, with very slow kinetics. We interpret these results as further evidence that rotation of the carbonyl group of the thioester-linked chromophore of PYP, proposed in a previous FTIR study and visualized in recent time-resolved x-ray diffraction experiments, is of critical importance for photoactivation of PYP.

Bacterial Proteins↗
PubMed1996

Spectral tuning, fluorescence, and photoactivity in hybrids of photoactive yellow protein, reconstituted with native or modified chromophores.

Photoactive yellow proteins (PYPs) constitute a new class of eubacterial photoreceptors, containing a deprotonated thiol ester-linked 4-hydroxycinnamic acid chromophore. Interactions with the protein dramatically change the (photo)chemical properties of this cofactor. Here we describe the reconstitution of apoPYP with anhydrides of various chromophore analogues. The resulting hybrid PYPs, their acid-denatured states, and corresponding model compounds were characterized with respect to their absorption spectrum, pK for chromophore deprotonation, fluorescence quantum yield, and Stokes shift. Three factors contributing to the tuning of the absorption of the hybrid PYPs were quantified: (i) thiol ester bond formation, (ii) chromophore deprotonation, and (iii) specific chromophore-protein interactions. Analogues lacking the 4-hydroxy substituent lack both contributions (chromophore deprotonation and specific chromophore-protein interactions), confirming the importance of this substituent in optical tuning of PYP. Hydroxy and methoxy substituents in the 3- and/or 5-position do not disrupt strong interactions with the protein but increase their pK for protonation and the fluorescence quantum yield. Both deprotonation and binding to apoPYP strongly decrease the Stokes shift of chromophore fluorescence. Therefore, coupling of the chromophore to the apoprotein not only reduces the energy gap between its ground and excited state but also the extent of reorganization between these two states. Two of the PYP hybrids show photoactivity comparable with native PYP, although with retarded recovery of the initial state.

Bacterial Proteins↗
PubMed1995

Inhibition of pig kidney diamine oxidase by nazlinin and nazlinin derivatives.

Nazlinin (1-(4-butylamino)-1,2,3,4-tetrahydro-beta-carboline) (1), an alkaloid recently isolated from Nitraria schoberi, and its two derivatives, 1-(4-butylamino)-3,4-dihydro-beta-carboline (2) and 1-(4-butylamino)-beta-carboline (3), were synthesized and their interaction with pig kidney diamine oxidase (PKDO) was studied. Nazlinin appeared to be a very poor substrate while 3 was a good substrate with an apparent Km of 9.3-10(-5) M. The enzyme was inhibited by 1 and 2. With both compounds the mode of inhibition found was non-competitive and inhibition constants calculated from the slopes and intercepts of double-reciprocal plots show that 2 is a much more potent inhibitor than the natural product. The relationship between the structure of these compounds and the results found is discussed.

Amine Oxidase (Copper-Containing)↗
PubMed1987

Pyrido[2,1-i]-purines: a new class of fluorescent stains.

7-oxo-pyrido[2,1-i]-purine nucleosides 1a and 1b are highly fluorescent molecules with absorptions and emissions in the visible region. They show little or no cytotoxicity; interactions with isolated enzyme systems could not be detected, and these molecules appear to enter the cell via a purine nucleoside-specific carrier. We demonstrate for one case a specific interaction with cell components. The fluorescence of pyrido[2,1-i]-purine 2 is solvent-dependent and stains the lipophilic parts of a cell.

Animals↗
PubMed1980

Potential carcinostatics. 4. Synthesis and biological properties of erythro- and threo-beta-fluoroaspartic acid and erythro-beta-fluoroasparagine.

(E)- and (Z)-Di-tert-butyl 2-amino-3-fluoro-2-butene-1,4-dioate [(E)- and (Z)-2] were synthesized in two ways: (a) by elimination of hydrogen fluoride from di-tert-butyl beta,beta-difluoroaspartate under the influence of 1,5-diazabicyclo[4.3.0]non-5-ene and (b) by amination with the ammonium acetate of di-tert-butyl monofluorooxaloacetate (3), obtained via condensation of tert-butyl monofluoroacetate with di-tert-butyl oxalate. Reduction of 2 with sodium cyanoborohydride yielded a mixture of di-tert-butyl monofluoroaspartates in which the erythro isomer constituted the major product. The structure of this isomer (4a) was established by X-ray crystallographic analysis of the corresponding acid 5a. Esterification of 5a to the beta-methyl ester 6, followed by aminolysis, yielded erythro-beta-fluoroasparagine (7). Tests with 5a and 7 in the L-5178Y test system showed that the compounds exhibited toxicity at levels at which no antitumor activity was observed.

Animals↗
PubMed1977

Potential carcinostatics. Synthesis and biological properties of d- and 1-beta,beta-difluoroaspartic acid and beta,beta-difluoroasparagine.

Di-tert-butyl beta,beta-difluorooxaloacetate, prepared by fluorination of di-tert-butyl oxaloacetate with perchloryl fluoride, was converted to di-tert-butyl beta,beta-difluoroaspartate via its O-methyl oxime, followed by reduction. The tert-butyl ester was hydrolyzed to give a mixture of dl-beta,beta-difluoroaspartic acid, which was resolved via its brucine salts. dl-Difluoroaspartic acid was converted into beta,beta-difluoroasparagine by monoesterification and subsequent ammonolysis. Racemic beta,beta-difluoroaspartic acid inhibits aspartate aminotransferase. Cell growth of 3T3-F cells was slightly inhibited by l-beta,beta-difluoraspartic acid while the d enantiomer was without effect in this test system.

Animals↗