New renin inhibitors with pseudodipeptidic units in P(1)-P(1') and P(2')-P(3') positions

A series of four new potential renin inhibitors has been synthesized. The structure of the compounds was designed in such a way as to produce agents resistant to enzymatic degradation, metabolically stable, possibly potent and with improved oral absorption. All positions of the 8-13 fragment of the human angiotensinogen were occupied by unnatural units (two unnatural amino acids in positions P(3) and P(2) and two pseudodipeptides in positions P(1)-P(1') and P(2')-P(3')). Both N- and C-terminal functions of the inhibitors were blocked with tert-Boc and ethyl ester groups. Their hydrophobicity evaluated as a log P value, calculated by a computer method, was 6.57 and 6.08 respectively. All peptides were obtained by the carbodiimide method in solution and purified by chromatography on the SiO(2) column. Their resistance to enzymatic degradation was assayed by determination of stability against chymotrypsin activity. The potency was measured in vitro by a spectrofluorimetric method (assay of Leu-Val-Tyr-Ser released from the N-acetyltetradecapeptide substrate by renin in the presence of the inhibitor). All inhibitors were stable to chymotrypsin. Their IC(50) (M/l) values were: 9.6 x 10(-4) (12), 1.6 x 10(-5) (17), 1.0 x 10(-5) (22) and 1.0 x 10(-5) (23) respectively.     

2-Benzopyrylium salts containing thiophene substituents in positions 1 and 3

2-Benzopyrylium salts containing heterocyclic substituents have not previously been known. In order to obtain 2-benzopyrylium salts containing thiophene substituents in position 3, we have studied the acylation of 3,4-dimethoxybenzyl 2-thienyl ketone (I), which was obtained with a yield of 36% by the acylation of thiophene (at 75° C) with homoveratric acid in the presence of polyphosphoric acid (PPA). Compound I forms yellow crystals with mp 74–75° C (from benzene), bp 220° C (6mm). Found %: C 63.40; H 5.38; S 13.55. C₁₁H₁₃O₃S. Calculated %: C 64.12; H 5.34; S13.21.Translated from Khimiya Geterotsiklicheskikh Soedinenii.Vol. 6, No. 7, pp. 1003–1004, July, 1970.     

Polymer-supported approach for solution-phase synthesis of cysteine trap protease inhibitors: procedure for straightforward optimization of the P1-P1' pocket

Peptide-based reversible and irreversible cysteine proteases inhibitors are well reported in the literature. Many of these compounds have an electrophilic carbonyl group as a cysteine trap in the place of a scissile amide moiety of the natural substrate. As a common mechanism strategy, we have designed a probe library of a cysteine trap for rapid optimization of P1-P1' pockets of different cysteine proteases. The synthesis of this library using a straightforward methodology based on polymer-supported reagents and scavengers to avoid tedious purification steps has been achieved. For the selective monobromination of diazo ketones, preparation of a new supported reagent, piperidinoaminomethylpolystyrene hydrobromide, is also described.     

Design,synthesis, and evaluation of matrix metalloprotease inhibitors bearing cyclopropane-derived peptidomimetics as P1' and P2' replacements

We have previously used trisubstituted cyclopropanes as peptide replacements to induce conformational constraints in known pseudopeptide inhibitors of a number of important enzymes. Cyclopropane-derived peptide mimics are novel in that they are among the few replacements that locally orient the peptide backbone and the amino acid side chain in a predefined manner. Although these dipeptide isosteres have been employed to orient amino acid side chains mimicking the gauche(-) conformation of chi(1)-space, their ability to project the side chains into an anti orientation has not been evaluated. As a first step toward this goal, the conformationally constrained pseudopeptides 8 and 10 and their corresponding flexible analogues 9 and 11 were prepared and tested as inhibitors of matrix metalloproteinases (MMPs). These compounds are analogues of 4 and 5, which were known to be potent MMP inhibitors. The anti orientations of the isopropyl side chain in 8 and the aromatic ring in 10 relative to the peptide backbone substituents on the cyclopropane were predicted to correspond to the known orientations of the P1' and P2' side chains of 5 when bound to MMPs. Hence, 8 and 10 were designed explicitly to probe topological features of the S1' or the S2' binding pockets of the MMPs. They were also designed to explore the importance of the P1'-P2' amide group, which is known to form highly conserved hydrogen bonds in several MMP-inhibitor complexes, and the viability of introducing a retro amide linkage between P2' and P3'. Pseudopeptides 8 and 9 were found to be weak competitive inhibitors of a series of MMPs. Any entropically favorable conformational constraints that were induced by the cyclopropane in 8 were thus overwhelmed by the loss of the hydrogen bonding capability associated with the P1'-P2' amide group. On the other hand, compounds 10 and 11, which contain a P2'-P3' retro amide group, were modest competitive inhibitors of a series of MMPs. The results obtained for 10 and 11 suggest that there may be a loss of hydrogen bonding capability associated with introducing the P2'-P3' retro amide group. However, because the conformationally constrained pseudopeptide 10 was significantly more potent than its flexible analogue 11, trisubstituted cyclopropanes related to 3 may serve as useful rigid dipeptide replacements in some biologically active pseudopeptides.     

Syntheses and biological activities of renin inhibitors containing statine analogues

Syntheses and biological activities of dipeptide renin inhibitors that contain statine analogues are described. The key steps of the synthetic approach to dipeptide renin inhibitors are the asymmetric synthesis of 2(R)-substituted-3-aminocarbonylpropionic acids and the diastereoselective syntheses of (3S,4S)-statine analogues. These inhibitors (2,14-40) inhibited human renin in the 3-140 nM range. Inhibitor ES 6864 (2) was found to be a highly potent inhibitor of human renin (IC50: 4.6 x 10(-9) M) and showed high enzyme specificity. Oral administration of ES 6864 at 3 mg/kg to conscious, sodium-depleted marmosets inhibited plasma renin activity (PRA) more than 80% after 1 h.     

New synthesis of 2',3'-didehydro-2',3'-dideoxynucleosides.

The 3'-iodonucleoside 4 and the 3'-O-methylsulfonylthymidine 9 have been synthesized by condensation of silylated uracils 2 with methyl 5-O-tert-butyldiphensilyl-2,3-dideoxy-3-iodo-D-threo-pentofuran oside (3) and methyl 5-O-tert-butyldiphenylsilyl-2-deoxy-3-methylsulfonyl-D-erythro- pentofuranoside (8), respectively. The nucleoside 4 and 9 produced the corresponding 2',3'-didehydro-2',3'-dideoxynucleosides 5 in an elimination reaction on treatment with sodium methoxide. The compounds 5b showed no antiviral activity against HIV-1.     

Synthesis and characterization of liquid crystals containing a non-activated 1' ,3' ,3'-trimethylspiro\[2H-1-benzopyran-2,2-indoline] group

Two series of mesogens derived from the non-activated spiropyran dyes 6-hydroxy-1 ,3 ,3- trimethylspiro\[2H -1-benzopyran-2,2-indoline] (series trimethylspiro\[2 H -1-benzopyran-2,2-indoline] (series 2 ) have been synthesized. Analysis by differential scanning calorimetry, polarizing microscopy and X-ray diffraction showed compounds in series 1 form monotropic nematic and SmA phases, while compounds in series 2 form only a monotropic nematic phase.     

Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis C NS3/4A protease

Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.     

Cephalosporins containing carbonate functions at positions 3 and 7

Sulfones of 7-alkoxycarbonyloxy-substituted cephalosporanic acid tert-butyl esters were synthesized by reduction of 7-oxocephalosporanic acid tert-butyl ester, acylation of the intermediate 7-hydroxycephalosporanate with 2,2,2-trichloroethyl chloroformate or di-tert-butyl pyrocarbonate, and oxidation of the sulfur atom. Sulfones of 7-chloro- and 7-alkylidene-substituted 3-alkoxycarbonyloxymethylcephalosporanic acid tert-butyl esters were obtained by replacement of the bromine atom in tert-butyl 3-bromomethylcephalosporanates with hydroxy group and acylation of the latter with chlorocarbonic esters. The cytotoxic activity of the synthesized substances was studied in vitro and also their ability to inhibit elastase.Latvian Institute of Organic Synthesis, Riga LV-1006Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 847–853, June, 2000.     

Phases containing tungsten in Cu(1) positions

A tetragonal (123) phase of composition CdBa₂Cu₂WO₈ with the complete and selective substitution of tungsten atoms for copper in the Cu(1) positions is synthesized from CdWO₄ and BaCuO₂ at 800°C in flowing oxygen. The percentage of the (123) phase in the sample is at least 90%; the unit cell parameters are a = b = 0.4151(3) nm, c = 1.2537(8) nm. The X-ray diffraction pattern shows a superstructure with all three of the unit cell parameters being doubled.     

Unusual Recyclization of 2(1-Bromostyryl)-4-oxo-1'3-benzoxazinium Perchlorate into 2'3'4'5-Tetrahydro-1'4-benzoxazepine-4'5-dione

Russian Journal of Organic Chemistry -     

New telluride-mediated elimination for novel synthesis of 2',3'-didehydro-2',3'-dideoxynucleosides

Several 2',3'-dideoxynucleosides (ddNs) and 2',3'-didehydro-2',3'-dideoxynucleosides (d4Ns) are FDA-approved anti-HIV drugs. Via conveniently synthesized 2,2'-anhydronucleosides, we have developed a novel synthesis of d4Ns by discovering and applying a new telluride-mediated elimination reaction. Our experiment results show that after substitution of 2,2'-anhydronucleosides with a telluride monoanion, a telluride intermediate is formed, and its elimination leads to formation of the olefin products (d4Ns). Our mechanistic study indicates that this telluride-assisted reaction consists of two steps: substitution (or addition) and elimination. By using dimethyl ditelluride (0.1 equiv) as the reagent, d4Ns can be synthesized with yields up to 90% via this telluride-mediated elimination. Our novel strategy has great potential to simplify synthesis of these drugs and to further reduce cost of AIDS treatment and will also facilitate development of novel d4N and ddN analogues.     

Endo- and Exocyclic Substitutions in α-P4S3I2

Two isomers each of α-P₄S₂SeX₂ and α-P₄SSe₂X₂ (X=Cl, Br) have been identified by ³¹P-NMR spectroscopy in mixtures obtained from thermal reaction of PX₃ and P₄S_1.4Se_1.6. Systematic changes in chemical shifts and coupling constants with electronegativity of the ligand by exocyclic substitution and with alteration of the molecular geometry by the replacement of sulfur by selenium are reported.     

X-ray Structure of 1- (3' -Phenyl-4' -morpholinyl-2' 5' - dithiole-1' - ylidene)-3, 4-biscarboethoxy-2-thionaphthalene

1INTR0DUCTIONa-Thiocarbonylthioformamideshavebeensynthesizedsince1980[l-23,however,thereisn0reP0rtofthesecomP0undsrelatedtheirpropertiesandreactivities(3).Ac-cordingtothepublishedpapers('-",adithioketone,adithioesterandadithioth-ioesteraresnitablefort4 2JcycloadditionwithalkenicandacetylenicdienophileS.Wewanttoknowwhethera-thiocarbonylthioformamideshavethesamecharacters,thereforethereactionofathiobenzoylthioformmorpholine(1)withdiethylacetylenedicarboxylate(2)wasexplored.Theredultsshowth…     

New dioxadiaza-, trioxadiaza- and hexaaza-macrocycles containing dibenzofuran units

New dioxadiaza-, trioxadiaza-, and hexaaza-macrocycles containing rigid dibenzofuran groups (DBF) were prepared by a convenient synthetic route in high yields. The structures of the macrocycles were unequivocally established by electrospray mass spectrometry (ESIMS) studies together with NMR spectroscopy, with the exception of [14](DBF)N₃. The structures of the copper complex of [14](DBF)N₃ and of the diprotonated form of [22](DBF)N₂O₃ were determined by single crystal X-ray diffraction. Conformational analyses on the free macrocycles [14](DBF)N₃ and [22](DBF)N₂O₃ as well as on their larger counterparts containing two DBF units were undertaken in order to understand the synthetic findings.     

Variations of the P2 group in HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimicking scaffold

A short synthetic protocol leading to HIV-1 protease inhibitors with a tertiary alcohol based transition-state mimicking unit and different P2 side chains has been developed.     

Highly predictive CoMFA and CoMSIA models for two series of stromelysin-1 (MMP-3) inhibitors elucidate S1' and S1-S2' binding modes

Three-dimensional quantitative structure-activity relationship models have been derived using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for two training sets of arylsulfonyl isoquinoline-based and thazine/thiazepine-based matrix metalloproteinase inhibitors (MMPIs). The crystal structure of stromelysin-1 (MMP-3) was used to pinpoint areas on the ligands and receptors where steric and electrostatic effects (for CoMFA) and steric, electrostatic, hydrogen-bond donor, hydrogen-bond acceptor, and hydrophobic effects (for CoMSIA) correlate with an increase or decrease in experimental biological activity. The most predictive CoMFA and CoMSIA models were obtained using training-series subsets that sampled a wide range of activities, together with docking and scoring, inertial alignment, investigation of various partial charge formalisms, and manual adjustment of each compound within the active site. The models developed in this study are in agreement with experimentally observed MMP-3 structure-activity relationship data and offer new insights into binding modes involving the partly solvent-exposed S1-S2' subpocket and certain zinc-chelating groups.