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1.
Bioorg Med Chem ; 9(7): 1815-25, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11425583

ABSTRACT

The behavior under physiological conditions of MEN 10755, a novel disaccharide analogue of doxorubicin, was investigated in detail by a variety of spectroscopic techniques including spectrophotometry, fluorescence, and (1)H NMR. The pH dependent properties of MEN 10755 were also analysed by spectrophotometry and potentiometry within the pH range 5--11. It is found that MEN 10755 behaves very similarly to doxorubicin and reproduces closely its pH dependent pattern. Like doxorubicin, MEN 10755 undergoes dimerization with a significantly smaller association constant. The interaction of MEN 10755 with calf thymus DNA was studied in detail. Spectrophotometric and fluorescence titrations of MEN 10755 with calf thymus DNA show spectral patterns almost identical to those obtained with doxorubicin implying that the binding mechanism and the stability of the resulting adducts are very similar. An apparent affinity constant of 1.2 x 10(6) was determined for the interaction of MEN 10755 with calf thymus DNA to be compared with the value of 3.3 x 10(6) measured for doxorubicin, under the same conditions. The effects of both anthracyclines on the thermal denaturation profiles of calf thymus DNA were also analyzed; both compounds turned out to stabilize to a similar extent the DNA double helix and to give rise to a characteristic two-step melting profile. The implications of the present results for the pharmacological activity and the mechanism of action of this novel and promising antitumor compound are discussed.


Subject(s)
Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , DNA/drug effects , Disaccharides/chemistry , Disaccharides/pharmacology , Doxorubicin/analogs & derivatives , Doxorubicin/chemistry , Doxorubicin/pharmacology , Animals , Cattle , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy , Spectrometry, Fluorescence
3.
Bioorg Med Chem Lett ; 8(10): 1249-54, 1998 May 19.
Article in English | MEDLINE | ID: mdl-9871744

ABSTRACT

A series of tripeptide arginine aldehydes was synthesized by replacement of proline with 1,2-disubstituted cyclohexane derivatives in the sequence of D-MePhe-Pro-Arg-H. Based on molecular modeling, further modification of the D-MePhe residue resulted in a potent and selective thrombin inhibitor.


Subject(s)
Antithrombins/chemical synthesis , Cyclohexanes/chemical synthesis , Oligopeptides/chemical synthesis , Aldehydes , Amino Acid Sequence , Antithrombins/chemistry , Antithrombins/pharmacology , Arginine , Binding Sites , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Indicators and Reagents , Kinetics , Models, Molecular , Molecular Structure , Oligopeptides/chemistry , Oligopeptides/pharmacology , Protein Conformation , Stereoisomerism , Structure-Activity Relationship , Thrombin/metabolism
4.
Eur J Pharmacol ; 290(2): 125-32, 1995 Jul 18.
Article in English | MEDLINE | ID: mdl-8575526

ABSTRACT

The chemical structure corresponding to 1-hydroxy[1,1'-bicyclohexyl]-2-carboxylic acid 2-(diethylamino)-1-methylethyl ester has the classical profile of ester-type antimuscarinic drugs. The presence of three chiral carbons leads to eight stereoisomers and the substitutions on the cyclohexyl ring generate cis-isomers (1, named rociverine) and trans-isomers (2). The aim of this study was to determine the binding pattern of the eight stereoisomers and two derived compounds, (1S,2S)-1-hydroxy[1,1'-bicyclohexyl]-2-carboxylic acid 2-(dimethylamino)-1-ethyl ester (3) (1S,2S)-1-hydroxy[1,1'-bicyclohexyl]-2-carboxylic acid (S)-2-(diethylamino)-1-methylethyl ester methyl iodide (4), at the five cloned muscarinic receptors stably expressed in chinese hamster ovary cells, in order to define how stereochemical modifications could affect the affinity. Our data showed that cis-stereoisomers exhibited higher variations in affinity than trans-stereoisomers. Among the cis-stereoisomers, those with the (1R,2R) configuration showed considerably higher affinities (up to 240-fold) than those with the (1S,2S) configuration. The (1S,2S) configuration was important for binding selectivity; this was confirmed also by the use of the two additional compounds.


Subject(s)
Cyclohexanecarboxylic Acids/pharmacology , Muscarinic Antagonists/pharmacology , Parasympatholytics/pharmacology , Animals , CHO Cells , Cricetinae , Female , N-Methylscopolamine , Pirenzepine/metabolism , Receptors, Muscarinic/classification , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/metabolism , Scopolamine Derivatives/metabolism , Structure-Activity Relationship , Transfection
5.
Chirality ; 6(5): 382-8, 1994.
Article in English | MEDLINE | ID: mdl-8068497

ABSTRACT

The enantiomers of 1-methyl-3-(10H-phenothiazine-10-ylmethyl)-1-azoniabicyclo[2 ,2,2]octane iodide (1) were prepared by chiral chromatographic resolution of the precursor mequitazine (2). The (+)-(S)-enantiomer 1b is 10-fold more potent than (-)-(R)-enantiomer 1a as a histamine antagonist, while the two enantiomers show the same antimuscarinic activity in vitro. The absolute configuration of the more active dextrorotatory isomer has been determined by X-ray analysis. Conformational analysis and molecular modeling suggest that the (+)-(S)-enantiomer can adopt a conformation similar to that attributed to the receptor binding conformers of classical antihistamines.


Subject(s)
Bronchodilator Agents/chemistry , Bronchodilator Agents/pharmacology , Phenothiazines/chemistry , Phenothiazines/pharmacology , Acetylcholine/pharmacology , Animals , Bronchodilator Agents/chemical synthesis , Crystallography, X-Ray , Drug Interactions , Guinea Pigs , Histamine/pharmacology , In Vitro Techniques , Molecular Structure , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Optical Rotation , Phenothiazines/chemical synthesis , Stereoisomerism , Trachea/drug effects , Trachea/physiology
6.
J Med Chem ; 36(6): 699-707, 1993 Mar 19.
Article in English | MEDLINE | ID: mdl-8459398

ABSTRACT

A series of monoamidic derivatives of cis- and trans-1,2-cyclohexanedicarboxylic and 1,2-cyclopentanedicarboxylic acids bearing either a carboxylic, sulfhydrylic, or hydroxamic group in the side chain were synthesized and evaluated in vitro for their inhibitory activity against angiotensin converting enzyme. The compounds were designed as potential ACE inhibitors of novel structure, assuming that a monoamidic residue of an 1,2-cyclomethylenedicarboxylic acid could be an alternative structure to the acylproline moiety, the carboxyl-terminal portion common to various ACE inhibitors. The most active compounds were found in the hydroxamic derivatives of cyclohexane series; within this series of derivatives a marked increase of potency was caused by alkylation of the amidic nitrogen with a methyl or ethyl group. Therefore enantiomers of the selected hydroxamic derivatives of cis- and trans-1,2-cyclohexanedicarboxylic acid were prepared by two different chiral synthetic routes and evaluated in vitro for their ACE inhibitor potencies. The active enantiomers both of the cis series (21a, 21c) and trans series (16b, 16d) were found to have all R configuration at the C-2 and R or S configuration at the C-1, while in the classical ACE inhibitors S configuration at the terminal carboxylate (corresponding to the C-1 of our compounds) is strictly required for activity. The most potent compound of the series was (1S,2R)-cis-2[[[2-(hydroxyamino)-2-oxoethyl]methylamino]carbonyl] cyclohexanecarboxylic acid (21a) with an IC50 value of 7.0 nM compared with the value of 3.0 nM for captopril. Further 21a was shown to be highly selective and competitive ACE inhibitor. These results indicate that this non-amino acid structure of inhibitors meets the ACE active site requirements for the binding. The binding compatibility of the most active compounds with a model of ACE active site was evaluated by molecular modeling techniques.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Carboxylic Acids/chemical synthesis , Cyclohexanecarboxylic Acids/chemical synthesis , Hydroxamic Acids/chemical synthesis , Hydroxylamines/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Binding Sites , Carboxylic Acids/pharmacology , Cyclohexanecarboxylic Acids/pharmacology , Hydroxamic Acids/pharmacology , Hydroxylamines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship
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