P J Claes

KU Leuven, Leuven, VLG, Belgium

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Publications (36)143.74 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cycloaddition of different acetylenic compounds on the azido function of 3′-azido-2′,3′-dideoxythymidine and 3′-azido-2′,3′-dideoxyuridine afforded products with a 1,2,3-triazol-1-yl substituent in the 3′-position. In contrast with the parent compounds, these triazolyl derivatives had no appreciable activity against human immunodeficiency virus (HIV-1).
    Journal of Heterocyclic Chemistry 11/2009; 26(6):1635-1642. DOI:10.1002/jhet.5570260624 · 0.87 Impact Factor
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    ABSTRACT: The synthesis of the four building blocks used for the preparation of hexitol nucleic acids were optimized. The nucleoside analogues with a purine base moiety are best prepared by a nucleophilic substitution reaction, whereas the pyrimidine nucleosides can best be obtained using Mitsunobu-type conditions.
    European Journal of Organic Chemistry 07/1997; 1997(7):1453 - 1461. DOI:10.1002/jlac.199719970724 · 3.15 Impact Factor
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    ABSTRACT: Based on the structure-activity relationship for antiviral activity, a series of 3′-deoxy-3′-N-functionalized thymidine analogues derived from 3′-amino-3′-deoxythymidine was synthesized. These compounds were evaluated for their antiviral activity. Three of the prepared molecules namely 3′-(1,2,4-triazol-1-yl)carbimidoylamino-3′-deoxythymidine 6, 3′-(3-amino-1-methyl-1,2,4-triazol-5-yl)amino-3′-deoxythymidine 8b and 3′-N-cyano-O-phenylisourea-3′-deoxythymidine 7 show moderate but selective in vitro activity against HIV-1 and HIV-2. These data demonstrate that some steric bulk in the 3′-position is compatible with anti-HIV activity
    Tetrahedron 05/1995; 51(18):5369-5380. DOI:10.1016/0040-4020(95)00198-H · 2.82 Impact Factor
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    ABSTRACT: In view of the selective anti-HSV activity of 1,5-anhydro-2,3-dideoxy-2- (5-iodouracil-1-yl)-D-arabino-hexitol, a series of novel 1,5-anhydrohexitol nucleosides were synthesized and evaluated for their inhibitory activity against several viruses. The 5-iodouracil 3 and the 5-ethyluracil 4 derivatives are highly selective TK-dependent inhibitors of HSV-1 and HSV-2. Broad anti-herpes virus activity was noticed for 5-fluorocytosine 6 and 2,6-diaminopurine 10 analogues. From a transport study of 3, using the thymidine influx competition method, one can conclude that intracellular uptake of this compound most probably occurs by passive diffusion. X-ray analysis of compounds 3 and 9 showed that the heterocyclic base of 1,5-anhydrohexitol pyrimidine and purine is placed in the axial position and that the sugar ring adopts a slightly distorted chair conformation.
    Journal of Medicinal Chemistry 04/1995; 38(5):826-35. DOI:10.1021/jm00005a010 · 5.48 Impact Factor
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    ABSTRACT: A number of 5-heteroaromatic-substituted 2'-deoxyuridines were synthesized from 5-iodo-2'-deoxyuridine using tetraorganotin reagents and palladium complexes as catalyst. The palladium-catalyzed cross-coupling reaction between 5-iodo-2'-deoxyuridine and stannylated heteroaromatics was optimized for the synthesis of the 5-thien-3-yl-2'-deoxyuridine and 5-furan-3-yl-2'-deoxyuridine. 5-(5-Iodothien-2-yl)-2'-deoxyuridine was used as starting material for the synthesis of 5-(5-methylthien-2-yl)-2'-deoxyuridine, 5-(5-vinylthien-2-yl)-2'-deoxyuridine, and 5-(5-ethynylthien-2-yl)-2'-deoxyuridine. 5-(5-Nitrothien-2-yl)-2'-deoxyuridine was synthesized using cericammonium nitrate as reagent. 5-(Isoxazol-5-yl)-2'-deoxyuridine was synthesized from 5-(3-oxopropyn-1-yl)-2-'-deoxyuridine. Finally,5-(5-chlorothien-2-yl)-beta-D-arabinofuranosyluracil and 5-(5-bromothien-2-yl)-beta-D-arabinofuranosyluracil were obtained by halogenation of 5-thien-2-yl-beta-D-arabinofuranosyluracil. Introduction of an alkyl substituent in the 5-position of the thienyl group of 5-thien-2-yl-2'-deoxyuridine or substitution of the 2-deoxyribofuranose ring by an arabinofuranose moiety gave decreased activity against HSV-1 and VZV replication when compared with the 5''-halogenated-5-thien-2-yl-2'-deoxyuridines. 5-(5-Bromothien-2-yl)-2'-deoxyuridine caused prompt healing of HSV-1 keratitis when administered as eye drops (0.2%) to rabbits.
    Journal of Medicinal Chemistry 03/1993; 36(5). DOI:10.1021/jm00057a003 · 5.48 Impact Factor
  • Contributions to nephrology 02/1993; 101:213-9. · 1.53 Impact Factor
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    ABSTRACT: In a companion paper (previous paper in this issue), we report on the synthesis and microbiological evaluation of new derivatives of the aminoglycoside antibiotic kanamycin B carrying substitutions in 6" (halogeno, or amino, amido, thioalkyl, and alkoxy groups, each series with increasingly bulkier chains). These modifications were intended to potentially modulate the interactions of kanamycin B with phospholipids since these are related to inhibition of lysosomal phospholipase activities and lysosomal phospholipidosis, an early and predictive index of the nephrotoxic potential of aminoglycosides. The new derivatives were therefore examined for inhibitory potency in vitro toward lysosomal phospholipase A1 acting on phosphatidylcholine included in negatively charged liposomes. No simple correlation was observed between the nature or the size of the 6''-substituent and the inhibitory potencies of the corresponding derivatives, although certain groups (diethylamino, isopropylthio) caused a significant increase in inhibitory potency, whereas an N-acetyl-N-methylamino substituent had the opposite effect. 6''-Deoxy-6''-chlorokanamycin B, however, was the only derivative showing both a decrease (albeit limited) of inhibitory potency toward phospholipase A1 associated with the maintenance of a satisfactory microbiological activity (actually equal or slightly better than that of kanamycin B). Computer-aided conformational analysis showed that this chloro substituent did not allow the molecule to insert itself very differently compared to kanamycin B or 6''-deoxykanamycin B in a monolayer of phosphatidylinositol, all three drugs adopting an orientation largely parallel to the hydrophobic-hydrophilic interface and being largely "embedded" in the bilayer at that level. In contrast, the N-acetyl-N-methylamino and isopropylthio substituents caused the corresponding derivatives to adopt an orientation largely perpendicular to the interface, because of the attraction of this substituent, and therefore of the 3''-amino sugar moiety of kanamycin B into the hydrophobic domain of the monolayer, whereas the opposite part of the drug (2',6'-diamino sugar) protruded into the aqueous phase. No simple correlation, however, could be drawn between these changes of conformation and the relative inhibitory potencies of the derivatives.
    Journal of Medicinal Chemistry 05/1991; 34(4):1476-82. DOI:10.1021/jm00108a036 · 5.48 Impact Factor
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    ABSTRACT: The clinical use of the potent, wide-spectrum aminoglycoside antibiotics is limited by oto- and nephrotoxicities. The latter is related to the binding of these polycationic drugs to negatively charged phospholipids and to the subsequent inhibition of lysosomal phospholipases. In order to explore the influence of a modification of the hydrophobic/hydrophilic balance at a specific site of an aminoglycoside, kanamycin B has been chemically modified in position 6" by substitution of the hydroxyl group with a halogen atom (or a pseudohalogen group), or an amino, an amido, a thioalkyl, or an alkoxy group, each series containing increasingly bulkier chains. Examination of the antibacterial activity of the synthesized compounds revealed a negative correlation between the size of the 6"-substituent and the antibacterial activity against kanamycin B sensitive Gram-positive and -negative organisms. Only derivatives with small substituents in position 6", namely chloro, bromo, azido, amino, methylcarbamido, acetamido, methylthio, methylsulfinyl, O-methyl, O-ethyl, and O-isopropyl, showed acceptable activity (geometric mean of minimum inhibitory concentrations for Gram-negative strains less than or equal to 2.5 mg/L; value for kanamycin B, 0.5 mg/L). In vitro toxicological evaluation of all derivatives and computer-aided conformational analysis of selected compounds inserted in a phosphatidylinositol monolayer are presented in the following paper in this issue.
    Journal of Medicinal Chemistry 05/1991; 34(4):1468-75. DOI:10.1021/jm00108a035 · 5.48 Impact Factor
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    ABSTRACT: Substitution of the C-1 atom in the 2-deoxystreptamine moiety of gentamicin C2, a broad-spectrum aminoglycoside antibiotic, by an axial hydroxymethyl group has been reported to confer protection against most clinically important bacterial enzymes inactivating aminoglycosides, while simultaneously reducing the nephrotoxic potential of this drug. We report here on a similar modification of kanamycin B. Microbiological evaluation, however, revealed no useful protection, as established by the almost complete lack of activity of 1-C-(hydroxymethyl)kanamycin B against an array of organisms producing defined types of aminoglycoside-inactivating enzymes and against which 1-C-(hydroxymethyl)gentamicin C2 and amikacin (1-N-[(S)-2-hydroxy-4-aminobutyryl]kanamycin A) are active. Moreover, toxicological evaluation, based on the in vitro measurement of the drug inhibitory potential toward lysosomal phospholipases, a predictive test of the intrinsic nephrotoxic potential of aminoglycosides, showed not decreased but rather increased toxicity. Comparative conformational analysis of the interactions of the drug with a phosphatidylinositol monolayer explained the lack of protective effect, since no significant change of the mode of insertion of the derivative in this monolayer was detected compared to that of kanamycin B. Combination of a 1-C-(hydroxymethyl) substituent with a 6"-chloro, 6"-acetamido substituent resulted in a partial improvement of the toxicological behavior with no loss of activity for the 6"-chloro and the 6"-azido derivatives, but not to the extent of obtaining better derivatives than kanamycin B itself. We, therefore, suggest that the advantages of an axial hydroxymethyl substituent at C-1 are probably restricted to the gentamicin family and do not extend to kanamycins. It might be concluded that the structural differences between gentamicins and kanamycins play an important, still undescribed role both in their effective recognition by aminoglycoside-inactivating enzymes, which are responsible for most of the clinically important cases of resistance to aminoglycosides, and also in the interactions with phospholipids, which in turn cause nephrotoxicity.
    Journal of Medicinal Chemistry 05/1991; 34(4):1483-92. DOI:10.1021/jm00108a037 · 5.48 Impact Factor
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    ABSTRACT: Various 3'-deoxythymidine analogues with an heterocyclic five-membered ring in the 3'-erythro position have been synthesized. The pyrrol-1-yl (3) and the 1,2,4-triazol-4-yl (5) compounds were synthesized from 1-(3-amino-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine. The pyrazol-1-yl (16a), imidazol-1-yl (16b), and 1,2,4-triazol-1-yl (16c) derivatives were obtained by epoxide opening of the corresponding 1-(2,3-anhydro-beta-D-lyxofuranosyl)thymines followed by 2'-deoxygenation. Only the 3'-pyrrol-1-yl derivative showed marginal antiviral activity against human immunodeficiency virus.
    Journal of Medicinal Chemistry 02/1990; 33(2). DOI:10.1021/jm00164a063 · 5.48 Impact Factor
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    ABSTRACT: beta-Lactam antibiotics do not accumulate in phagocytes, probably because of their acidic character. We therefore synthesized a basic derivative of penicillin G, namely, 14C-labeled N-(3-dimethylamino-propyl)benzylpenicillinamide (ABP), and studied its uptake and subcellular localization in J774 macrophages compared with that of 14C-labeled penicillin G. Whereas the intracellular concentration (Ci) of penicillin G remained lower than its extracellular concentration (Ce), ABP reached a Ci/Ce ratio of 4 to 5. Moreover, approximately 50% of intracellular ABP was found associated with lysosomes after isopycnic centrifugation of cell homogenates in isoosmotic Percoll or hyperosmotic sucrose gradients. The behavior of ABP was thus partly consistent with the model of de Duve et al. (C. de Duve, T. de Barsy, B. Poole, A. Trovet, P. Tulkens, and A. Van Hoof, Biochem. Pharmacol. 23:2495-2531, 1974), in which they described the intralysosomal accumulation of weak organic bases in lysosomes. Although ABP is microbiologically inactive, our results show that beta-lactam antibiotics can be driven into cells by appropriate modification. Further efforts therefore may be warranted in the design of active compounds or prodrugs that may prove useful in the chemotherapy of intracellular infections.
    Antimicrobial Agents and Chemotherapy 04/1987; 31(3):410-6. DOI:10.1128/AAC.31.3.410 · 4.45 Impact Factor
  • R Busson · P J Claes · H Vanderhaeghe
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    ABSTRACT: The British Pharmacopoeia test controlling the composition of gentamicin sulfate is based on CW 60 MHz magnetic resonance spectroscopy. Application of this method to FT 90 MHz spectra was evaluated. Results clearly show the limitations of this technique and point out the need for more reliable assay methods. Thus a 13C nuclear magnetic resonance (NMR) procedure for quantitative analysis of gentamicin sulfate was developed. Ratios of 4 gentamicin components (C1, C2, C1a, and C2a) were obtained from peak height measurements of selected resonance signals in spectra recorded under steady-state conditions. Relative response factors were determined from spectra of a reference mixture or, alternatively, from spectra of the individual pure components. Results obtained by the 13C NMR method were in agreement with those obtained by liquid chromatography using pre-column derivatization.
    Journal - Association of Official Analytical Chemists 07/1986; 69(4):601-8.
  • P Herdewijn · P J Claes · H Vanderhaeghe
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    ABSTRACT: The total synthesis of (+/-)-1-methylene-2,2- dimethyl-7-amino-1-carbacephem-4-carboxylic acid (1) is described. The reaction scheme was essentially that described by Christensen et al. for the synthesis of (+/-)-1-carbacephems. In vitro antibacterial activities of the 7-phenoxyacetyl and 7-D-alpha-phenylglycyl derivatives of 1 were compared with those of 7-(phenoxyacetamido)desacetoxycephalosporanic acid and cefalexin. Derivatives of 1 were 2-4 times less active against most of the sensitive organisms than the corresponding 7-aminodesacetoxycephalosporanic acid analogues. The activity of the 7-D-alpha-phenylglycyl derivative of 1 however was about 20 times lower than that of cefalexin when measured against Staphylococcus aureus ATCC 6538P.
    Journal of Medicinal Chemistry 06/1986; 29(5):661-4. · 5.48 Impact Factor
  • Piet Herdewijn · Paul J. Claes · Hubert Vanderhaeghe
    Journal of Medicinal Chemistry 05/1986; 29(5):661-664. DOI:10.1021/jm00155a013 · 5.48 Impact Factor
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    ABSTRACT: Aminoglycoside antibiotics induce a lysosomal phospholipidosis in kidney proximal tubules after conventional therapy in animals and man. We have previously demonstrated that these drugs bind to negatively charged phospholipid bilayers at acid pH and inhibit the activity of lysosomal acid phospholipases in vitro and in vivo. A combined biochemical and conformational study [Brasseur et al., Biochem. Pharmac. 33, 629 (1984)] showed major and consistent differences between 6 aminoglycosides in current clinical use with respect to the stability of the complexes they form with phosphatidylinositol, their inhibitory potency towards the activity of lysosomal phospholipases and their current toxicity ranking (e.g. gentamicin greater than amikacin greater than streptomycin). In the present study we have extended this approach to experimental derivatives of streptomycin. The derivatives examined were: dihydrostreptomycin, dideguanyldihydrostreptomycin, streptomycylamine, dideguanylstreptomycylamine, N-butyl- and N-benzyl-dideguanylstreptomycylamine. These compounds were examined for (i) their binding to negatively charged liposomes, measured by gel permeation on Sepharose 4B; (ii) their interactions with phosphatidylinositol assessed by semi-empirical conformational analysis and (iii) their inhibitory effect on the activities of lysosomal phospholipases towards phosphatidylcholine present in negatively charged liposomes. Streptomycin and gentamicin were also used as reference compounds with low and high affinity (and inhibitory potency), respectively. Our observations can be summarized as follows: (i) the replacement of the aldehyde in the streptose ring by a methylamino group strikingly changes the conformation of the molecule, allowing a better interaction with phosphatidylinositol. Thus, streptomycylamine binds much more tightly to phospholipid bilayers and shows a higher inhibitory potency towards phospholipase activity, as compared to streptomycin. The conformational analysis shows, however, that this effect is only partially due to the additional cationic charge carried by streptomycylamine. Other modifications of the streptomycin molecule, such as the replacement of the guanidinium groups by aminogroups or the addition of hydrophobic moieties (butyl or benzyl groups) to the streptose do not markedly further strengthen the interactions of the molecule with phosphatidylinositol. (ii) Even though some derivatives (e.g. dideguanylstreptomycylamine) bind as tightly to phospholipids as gentamicin, they remain much less inhibitory towards lysosomal phospholipases.(ABSTRACT TRUNCATED AT 400 WORDS)
    Biochemical Pharmacology 05/1985; 34(7):1035-47. DOI:10.1016/0006-2952(85)90607-0 · 4.65 Impact Factor
  • L Verbist · P J Claes · R Busson · H Vanderhaeghe
    Journal of Antimicrobial Chemotherapy 03/1985; 15(2):250-1. · 5.44 Impact Factor
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    ABSTRACT: The synthesis of 6 beta-bromopenicillanic acid labeled with deuterium and tritium in the beta-methyl group is described. The S-sulfoxide of benzyl- or p-methoxybenzyl 6 alpha-bromopenicillanate is refluxed in benzene containing an excess of tert-BuOD, D2O or HTO. After deoxygenation and deprotection of the ester, the labeled 6 alpha-bromopenicillanic acid is epimerized (N,O-bis(trimethylsilyl)acetamide/1,5-diazabicyclo[4.3.0]non-5-ene in CH2Cl2). The two epimers are separated by column chromatography.
    The Journal of Antibiotics 02/1985; 38(1):75-82. DOI:10.7164/antibiotics.38.75 · 2.04 Impact Factor
  • L. VERBIST · P. J. CLAES · R. BUSSON · H. VANDERHAEGHE
    Journal of Antimicrobial Chemotherapy 01/1985; 15(2):250-251. DOI:10.1093/jac/15.2.250 · 5.44 Impact Factor
  • P J Claes · R Busson · H Vanderhaeghe
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    ABSTRACT: Commercial samples of gentamicin from different origins were analyzed by paired-ion high-performance liquid chromatography (HPLC) on a C18 bonded phase. The procedure uses pre-column derivatization with a omicron-phthalaldehyde-mercaptoacetic acid reagent and UV detection (350 nm). The ratios of the four gentamicin components (C1, C1a, C2a and C2) were determined and compared with the compositions obtained by an independent method based on 13C NMR spectrometry. Quantitation by HPLC, based on peak heights and peak areas, was performed with the aid of an external standard, which was an artificial mixture of the four components. The latter were prepared by separation of the gentamicins C1, C2 + C2a and C1a by chromatography on silica gel, followed by chromatography of the C2 + C2a fraction on a cellulose phosphate column.
    Journal of Chromatography A 09/1984; 298(3):445-57. DOI:10.1016/S0021-9673(01)92742-6 · 4.26 Impact Factor
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    ABSTRACT: Aminoglycoside antibiotics induce an early and characteristic lysosomal phospholipidosis in cultured fibroblasts and in kidney tubular cells. The authors have recently demonstrated an inhibition of lysosomal phospholipase A 1 and A 2 by gentamicin and amikacin in vitro. In vivo, gentamicin decreases the activity of phospholipase A 1. In the present study, they examined 14 aminoglycosides for in vitro inhibition of phospholipases. To mimic the situation prevailing in lysosomes, the enzymatic activities were assayed with phospholipid vesicles (liposomes) with a composition similar to that of lysosomal phospholipids (phosphatidylcholine, sphingomyelin, phosphatidylinositol, cholesterol; 4:4:3:5.5, molar ratio). The authors measured the hydrolysis of 1-palmitoyl-2-[1- 14C] oleoyl phosphatidylcholine contained in the liposomes by a soluble fraction of highly purified lysosomes isolated from rat liver. Similar IC 50s (concentration causing 50% inhibition of enzymatic activity) were observed for dibekacin, gentamicin (with no major difference between C 1, C 1(a), or C 2), netilmicin, tobramycin, and kanamycin B. Sisomicin was slightly more inhibitory. Kanamycin A, N 1-(L-4-amino-2-hydroxy-1-oxobutyl) dibekacin, and amikacin showed increasing IC 50s. Streptomycin caused the least inhibition. Octa- and tetramethylkanamycin A are much less inhibitory than the parent drug. These results point to the number, the nature, and the respective positions of the cationic groups as essential determinants in causing inhibition of phospholipid breakdown. The binding of three aminoglycosides (gentamicin, amikacin, streptomycin to the liposomes at pH 5.4 was also measured by gel permeating and was found to be related to the respective inhibitory potency of each drug. Insofar as lysosoma phospholipidosis is an early sign of intoxication by aminoglycosides, these results may serve as a basis for the development or screening of less toxic compounds in this class of antimicrobial agents.
    Antimicrobial Agents and Chemotherapy 04/1983; 23(3):440-9. DOI:10.1128/AAC.23.3.440 · 4.45 Impact Factor

Publication Stats

482 Citations
143.74 Total Impact Points

Institutions

  • 1972–1995
    • KU Leuven
      • • Laboratory for Medicinal Chemistry
      • • Faculty of Science
      Leuven, VLG, Belgium
  • 1985–1986
    • Catholic University of Louvain
      • Institute of Condensed Matter and Nanosciences (IMCN)
      Лувен-ла-Нев, Walloon, Belgium
  • 1982
    • University of Liège
      Luik, Wallonia, Belgium
    • Instytut Farmaceutyczny
      Warszawa, Masovian Voivodeship, Poland