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ABSTRACT: The cryptolepines originate from the roots of the climbing shrub Cryptolepis sanguinolenta (Lindi) Schitr(Periplocaeae) which is used in Central and West Africa in traditional medicine for the treatment of malaria.
Evaluation for the first time of a series of chloro- and aminoalkylamino derivatives of neo- and norneocryptolepines for potential schistosomicidal and molluscicidal activities.
A series of chloro- and aminoalkylamino substituted neo- and norneocryptolepine derivatives were synthesized. They were tested in vitro against viable Schistosoma mansoni Sambon mature worms in culturemedium with fetal serum and antibiotics and in dechlorinated water against the snail vector Biomphalaria alexandrina Ehrenberg. Active compounds were further subjected to determination of their IC50 values.
Results showed that six neocryptolepine and two norneocryptolepine derivatives had in vitro schistosomicidal activity on Egyptian and Puerto Rican strains of S. mansoni. The most effective derivative (2-chloro-5-methyl-N-(2-morpholin-4-ethyl)-5H-indolo[2,3b]quinoline-11-amine) has IC50 and IC90 1.26 and 4.05 μM and 3.54 and 6.83 μM with the Egyptian and Puerto Rican strains of Schistosoma, respectively. All eight derivatives showed molluscicidal activity against the vector snail B. alexandrina. The most active compound (2-chloro-11-(4-methylpiperazin-1-yl)-6H-indolo[2,3-b] quinoline) has LC50 0.6 and LC90 3.9 ppm after 24 h.
The findings demonstrate that introducing chloro- and aminoalkylamino side chain initiated both schistosomicidal and molluscicidal activities in these derivatives. The structure–activity relationship of this series of compounds is discussed.
Pharmaceutical Biology 02/2012; 50(2):134-40. · 0.88 Impact Factor
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Ibrahim El Sayed,
Pieter Van der Veken,
Koen Steert,
Liene Dhooghe,
Steven Hostyn,
Gitte Van Baelen,
Guy Lemière,
Bert U W Maes,
Paul Cos,
Louis Maes,
Jurgen Joossens,
Achiel Haemers,
Luc Pieters,
Koen Augustyns
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ABSTRACT: A series of chloro- and aminoalkylamino-substituted neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline) derivatives were synthesized and evaluated as antiplasmodial agents. The evaluation also included cytotoxicity (MRC5 cells), inhibition of beta-hematin formation, and DNA interactions (DNA-methyl green assay). Introduction of aminoalkylamino chains increased the antiplasmodial activity of the neocryptolepine core substantially. The most efficient compounds showed antiplasmodial activities in the nanomolar range. N(1),N(1)-Diethyl-N(4)-(5-methyl-5H-indolo[2,3-b]quinolin-8-yl)pentane-1,4-diamine 11c showed an IC(50) of 0.01 microM and a selectivity index of 1800.
Journal of Medicinal Chemistry 05/2009; 52(9):2979-88. · 4.80 Impact Factor
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ABSTRACT: Acute myocardial infarction (MI) is death or necrosis of myocardial cells due to lack of blood supply. One of the causes may be thrombosis resulting from inherited resistance to activated protein C caused by the factor V Leiden (FVL) mutation.
To check for the presence of FVL mutation among Egyptian cases with MI compared to normal population controls.
This study is a form of a prospective controlled study including 44 MI cases with an age ranging from 25 to 80 years and sex of 36 males (81.8%) and 8 females (18.2%). These cases were taken randomly from those admitted in the Intensive Care Units of Mansoura University Hospitals, Egypt. Of these cases, 10 cases (55.6%) were smokers, 7 cases (75.0%) had a positive family history of MI, 8 cases (18.18%) were diabetic and 20 cases (45.45%) were hyperlipidemic. For association and risk analysis, cases were compared to 211 healthy unrelated control subjects of matched age and sex. Factor V Leiden (G1691A) gene mutation was detected using a multiplex allele-specific PCR amplification.
Mutant A allele frequency of factor V Leiden was significantly higher in cases (30.68%) than in controls (10.19%) (p<0.0001, OR=3.9). Total cases showed significant higher frequency heterozygous mutant genotype GA (43.0%) compared to controls (16.6%), (p<0.0001, OR=4.45). Also total cases showed significant higher frequency of the homozygous mutant genotype AA (9.0%) compared to controls (1.9%), (p=0.0094, OR=8.19). On the other hand, no significant difference was found between cases subgroups related to age, sex, smoking, diabetes and hyperlipedemia.
Frequency of factor V Leiden mutation among Egyptian cases with myocardial infarction is relatively high. So, families of affected subjects should be genotyped and counseled for proper prophylaxis.
Hematology (Amsterdam, Netherlands) 07/2008; 13(3):170-4. · 1.33 Impact Factor
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ABSTRACT: A monomeric variant of triosephosphate isomerase (TIM) with a new engineered binding groove has been characterized further. In this variant (ml8bTIM), the phosphate binding loop had been shortened, causing the binding site to be much more extended. Here, it is reported that in the V233A variant of ml8bTIM (A-TIM), three important properties of the wild-type TIM active site have been restored: (i) the structural properties of loop-7, (ii) the binding site of a conserved water molecule between loop-7 and loop-8 and (iii) the binding site of the phosphate moiety. It is shown that the active site of A-TIM can bind TIM transition state analogs and suicide inhibitors competently. It is found that the active site geometry of the A-TIM complexes is less compact and more solvent exposed, as in wild-type TIM. This correlates with the observation that the catalytic efficiency of A-TIM for interconverting the TIM substrates is too low to be detected. It is also shown that the A-TIM active site can bind compounds which do not bind to wild-type TIM and which are completely different from the normal TIM substrate, like a citrate molecule. The binding of this citrate molecule is stabilized by hydrogen bonding interactions with the new binding groove.
Protein Engineering Design and Selection 05/2008; 21(4):257-66. · 2.94 Impact Factor
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Jurgen Joossens,
Omar M Ali, Ibrahim El-Sayed,
Georgiana Surpateanu,
Pieter Van der Veken,
Anne-Marie Lambeir,
Buddy Setyono-Han,
John A Foekens,
Anneliese Schneider,
Wolfgang Schmalix,
Achiel Haemers,
Koen Augustyns
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ABSTRACT: A set of small nonpeptidic diaryl phosphonate inhibitors was prepared. Some of these inhibitors show potent and highly selective irreversible uPA inhibition. The biochemical and modeling data prove that the combination of a benzylguanidine moiety with a diaryl phosphonate ester results in optimized molecules for derivatizing the serine alcohol in the uPA active site. Selected compounds show significant antimetastatic effects in the BN-472 rat mammary carcinoma model. We report in this paper a preclinical proof of concept that selective, irreversible uPA inhibitors could be valuable in antimetastatic therapy.
Journal of Medicinal Chemistry 01/2008; 50(26):6638-46. · 5.25 Impact Factor
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ABSTRACT: The synthesis of novel dipeptidyl alpha-fluorovinyl sulfones using a Horner-Wadsworth-Emmons approach on N-Boc-l-phenylalaninal is described. Inhibitory assays against a Leishmania mexicana cysteine protease (CPB2.8DeltaCTE) revealed low biological activity. Relative rates of Michael additions of 2'-(phenethyl)thiol with vinyl sulfone and alpha-fluorovinyl sulfone were determined, and ab initio calculations on several Michael acceptor model structures were performed; both were in agreement with the biological testing results.
Bioorganic & medicinal chemistry letters 01/2008; 17(23):6563-6. · 2.65 Impact Factor
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ABSTRACT: The unexpected 1,3-benzodithiine derivatives 5b,c were obtained from the reactions of trimethylsilyldiazomethane 2 with C-sulfonyldithioformates, bearing pentachlorophenylthio group, 1b,c via unprecedented cyclization of the transient thiocarbonyl ylides 4b,c. While the corresponding reaction with C-sulfonyldithioformates, bearing phenylthio group, afforded 5a via [2 + 3]-cycloadditive dimerization of a transient thiocarbonyl ylides 4a. Under the same reaction condition, C-sulfonyldithioformates 1d–f react with diazomethane and/or phenyldiazomethane to afford the unsymmetrical 1,3-dithiolane 7d,e and thiirane 8e,f derivatives, respectively. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:28–33, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20246
Heteroatom Chemistry 01/2007; 18(1):28 - 33. · 1.24 Impact Factor
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ABSTRACT: The importance of the fully conserved active site proline, Pro168, for the reaction mechanism of triosephosphate isomerase (TIM) has been investigated by studying the enzymatic and crystallographic properties of the P168A variant of trypanosomal TIM. In TIM, Pro168 follows the key catalytic residue Glu167, situated at the beginning of the flexible active site loop (loop 6). Turnover numbers of the P168A variant for its substrates are reduced approximately 50-fold, whereas the Km values are approximately 2 times lower. The affinity of the P168A variant for the transition state analogue 2-phosphoglycolate (2PG) is reduced 5-fold. The crystal structures of unliganded and liganded (2PG) P168A show that the phosphate moiety of 2PG is bound similarly as in wild-type TIM, whereas the interactions of the carboxylic acid moiety with the side chain of the catalytic Glu167 differ. The unique properties of the proline side chain at position 168 are required to transmit ligand binding to the conformational change of Glu167: the side chain of Glu167 flips from the inactive swung-out to the active swung-in conformation on ligand binding in wild-type TIM, whereas in the mutant this conformational change does not occur. Further structural comparisons show that in the wild-type enzyme the concerted movement of loop 6 and loop 7 from unliganded-open to liganded-closed appears to be facilitated by the interactions of the phosphate moiety with loop 7. Apparently, the rotation of 90 degrees of the Gly211-Gly212 peptide plane of loop 7 plays a key role in this concerted movement.
Biochemistry 01/2007; 45(51):15483-94. · 3.42 Impact Factor
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ABSTRACT: This paper describes the structure-activity relationship in a series of tripeptidyl diphenyl phosphonate irreversible urokinase plasminogen activator (uPA) inhibitors, originally derived from an arginyltripeptide. uPA is considered an interesting target in anticancer drug design. The selectivity of these inhibitors for uPA is enhanced by the optimization of the P4 position. The most interesting compound shows an IC(50) of 5 nM, with a selectivity index of more than 3000 toward other Arg/Lys-specific proteases such as tissue-type plasminogen activator, plasmin, factor Xa, and thrombin. A synthetic strategy for the preparation of small libraries of diphenyl phosphonate analogues of capped tripeptides is described. It is shown that uPA is irreversibly inhibited, and interactions with the active site were modeled. Finally, a diparacetamol phosphonate analogue was developed to circumvent the release of cytotoxic phenol.
Journal of Medicinal Chemistry 10/2006; 49(19):5785-93. · 5.25 Impact Factor
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Angewandte Chemie International Edition 05/2003; 42(14):1640-2. · 13.45 Impact Factor
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ABSTRACT: C-Sulfonyldithioformates (2) (R1 = ArSO2, R2 = ArS) readily add to anthracene and 9-methylanthracene (1) in a Diels–Alder fashion with formation of 9,10-dihydro-10,9-(epithiomethano)anthracenes (3) which in turn may suffer thermally induced elimination of arenesulfinic acid to yield the 9-anthracenedithiocarboxylic esters (4). The reactions with the unsymmetrical diene 9-methylanthracene take place in a highly stereoselective fashion. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:170–174, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10119
Heteroatom Chemistry 03/2003; 14(2):170 - 174. · 1.24 Impact Factor
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ABSTRACT: [reaction: see text] Transient silenes that are strongly influenced by reversed Si[double bond]C bond polarization are formed upon heating of tris(trimethylsilyl)silylamides. The silenes are trapped with 2,3-dimethyl-1,3-butadiene to quantitatively yield only one of the possible diastereomers of the functionalized cyclic allylsilanes.
Organic Letters 06/2002; 4(11):1915-8. · 5.86 Impact Factor
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Sulfur Reports 04/1995; 16(2):235-291.
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