Quinocarmycin analog DX-52-1 inhibits cell migration and targets radixin, disrupting interactions of radixin with actin and CD44

In the course of screening for new small-molecule modulators of cell motility, we discovered that quinocarmycin (also known as quinocarcin) analog DX-52-1 is an inhibitor of epithelial cell migration. While it has been assumed that the main target of DX-52-1 is DNA, we identified and confirmed radixin as the relevant molecular target of DX-52-1 in the cell. Radixin is a member of the ezrin/radixin/moesin family of membrane-actin cytoskeleton linker proteins that also participate in signal transduction pathways. DX-52-1 binds specifically and covalently to the C-terminal region of radixin, which contains the domain that interacts with actin filaments. Overexpression of radixin in cells abrogates their sensitivity to DX-52-1's antimigratory activity. Small interfering RNA-mediated silencing of radixin expression reduces the rate of cell migration. Finally, we found that DX-52-1 disrupts radixin's ability to interact with both actin and the cell adhesion molecule CD44.     

Synthesis of quinone derivatives of quinocarcin

O-Demethyl-DX-52-1 (3a) was prepared from quinocarcin (1) in two steps (cyanation and O-demethylation). Upon treatment with Fremy's salt, 3a and its esters 3b, 3c afforded the desired quinone 4-6 in good yields. Various substituted quinones 12-37, 47-50 were prepared from 4-6 by Thiele acetylation followed by hydrolysis of acetates and halogenation, by direct addition of amine, alcohol and mercaptan, and by epoxidation and subsequent opening of the epoxide ring with aniline. The quinonemonoketals 39b and 40 were obtained from the corresponding methoxyphenols 7b and 38b. Addition of hydroxylamine gave the quinoneoxime 44 regiospecifically. The antitumor activity of the bis-methylthioquinone (37) among the various derivatives was the most promising.     

Computer simulation of the binding of quinocarcin to DNA. Prediction of mode of action and absolute configuration

Summary Computer-based models were derived for the covalent and noncovalent binding of the antitumor antibiotic quinocarcin to a representative DNA segment, d(ATGCAT)₂. They showed that a mode of action, involving opening of the oxazolidine ring to give an iminium ion, followed by initial noncovalent binding in the minor groove and subsequent alkylation of the 2-amino group of guanine, was rational and attended by favorable interaction energies in each step. The best model had the aryl ring of quinocarcin lying in the 3 direction from the covalent binding site and anR configuration at the carbon involved in covalent bond formation. It also showed that the preferred absolute configuration for quinocarcin was the reverse of that arbitrarily assigned in the literature.     

Indoline derivatives I: synthesis and factor Xa (FXa) inhibitory activities

A series of bisamidine derivatives each having a ring structure in the center of the molecule was synthesized and their Factor Xa (FXa) inhibitory activities were evaluated. Among them, some indoline derivatives showed potent inhibitory activities in vitro. In particular, (R)-18a having an (R)-configuration at the 2-position of the indoline ring exhibited the most potent FXa inhibitory activity in vitro, more potent than DX-9065a. Furthermore, (R)-18a exhibited more potent anticoagulant activity than DX-9065a. We also succeeded in obtaining an X-ray crystal structure of FXa bound with (R)-18a.     

Stereoselective lithiation and alkylation and aldol reactions of chiral 5-methyl-3-(o-aryl)-oxazolidinones

Alkylation and aldol reactions carried out on axially chiral, diastereoenriched oxazolidinedione derivatives were found to be highly stereoselective with respect to substitution at the 5-position of the oxazolidindione ring. Thus, diastereoenriched 5-methyl-3-(o-iodophenyl)-2-thioxo-4-oxazolidinone and 5-methyl-3-(o-aryl)-2,4-oxazolidinediones were prepared and lithiated at C-5 of the oxazolidine ring and the subsequent electrophilic quench with alkyl halides or benzaldehyde yielded products with the same diastereomer ratios as the starting materials.     

Nitroxydes-88 : Etude de la conformation par R.P.E. d'un biradical

Dispiro(2,2,6,6-tetramethyl piperidine piperidine 1-oxy)-4,4'(oxazolidine 3'-oxyl)-2',1'-cydobexane] has been studied by ESR and NMR. Detailed analysis of the ESR spectrum of the frozen solution shows that the C-N bond of oxazolidine ring is equatorial relative to the chair piperidiae ring. Landé (g), dipolar (D) and hyperfine (A) tensors have been determined. Proton hyperfine splittings of cyclohexane ring have been measured by NMR at room temperature, with the results consistent with the C-N bond of oxazolidine ring being in equatorial position relative to the chair cyclobexane ring.     

Synthesis and thermal crosslinking of oxazolidine‐functionalized polyurethanes

A new oxazolidine derivative was obtained from phenol, 2‐amino‐2‐methylpropane‐1,3‐diol and paraformaldehyde. The reaction of this novel oxazolidine diol with phenylisocyanate lead to a urethane model compound which can be polymerized thermally by oxazolidine ring opening to give a Mannich bridge structure. Linear segmented polyurethanes were prepared by reaction of different ratios of oxazolidine diol and commercial polyethylenglycol (M_w ～ 400) with 4,4′‐methylenbis (cyclohexylisocyanate) (HMDI, 90% isomers mixture). The polyurethanes were thermally characterized and crosslinked by oxazolidine ring opening to obtain materials which showed improved thermal stability. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 4965–4973, 2007     

Structure-activity relationships of 2-aminothiazole derivatives as inducible nitric oxide synthase inhibitor

Nitric oxide synthase (NOS) has been divided into two major sub-enzymes, i.e. inducible NOS (iNOS) and constitutive NOS (cNOS). Although nitric oxide (NO) plays an important role as host defense mediator, excessive production of NO by iNOS has been involved in the pathology of many inflammatory diseases. Recently, we reported that the 2-imino-1,3-oxazolidine (1a) weakly inhibits iNOS and that introduction of an alkyl moiety on the oxazolidine ring of 1a enhances the inhibitory activity and selectivity for iNOS. In our search for better iNOS inhibitors, we focused our efforts on the 2-aminothiazole scaffold 3 as it possesses a ring similar to that of 1a. In this study, we evaluated the inhibitory activity of a series of 2-aminothiazole derivatives against both iNOS and neuronal NOS (nNOS). Our results show that introduction of appropriately-sized substituents at the 4- and 5-position of the 2-aminothiazole ring improves the inhibitory activity and selectivity for iNOS. We also found that the selectivity of 5a [5-(1-methyl)ethyl-4-methylthiazol-2-ylamine] and 5b [5-(1,1-dimethyl)ethyl-4-methylthiazol-2-ylamine] for iNOS was similar to that of oxazolidine derivative 1b (4-methyl-5-propyl-2-imino-1,3-oxazolidine) and much higher than that of L-NAME. However, we could not enhance the inhibitory activity against iNOS by introducing an alkyl substituent into the 2-aminothiazole ring as we could in the case of oxazolidine one. On the other hand, introduction of bulky or hydrophilic substituent at any position of the 2-aminothiazole ring remarkably decreased or even abolished the inhibitory activity against NOS.     

Sodium cyanoborohydride: a reagent for selective reduction of the oxazolidine ring of C20-diterpenoid alkaloids

A very selective reduction of the oxazolidine ring of C₂₀-diterpenoid alkaloid derivatives in the presence of other functional groups, e.g., an α,β unsaturated ketone or a simple ketone, has been achieved in almost quantitative yield using sodium cyanoborohydride.     

Triazole antifungals. II. Synthesis and antifungal activities of 3-acyl-4-methyloxazolidine derivatives

Triazole compounds with an oxazolidine ring were designed and synthesized as a potential inhibitor of the fungal cytochrome P450 14 alpha-demethylase. In testing for antifungal activity against a mouse systemic Candida albicans infection, (4R,5R)-3-acyl-4-methyloxazolidine derivatives 4 exhibited remarkably high efficacy after oral or parenteral dosing. The potent activity of 4 is hypothesized to be a consequence of a structural similarity between 4 and lanosterol, a target molecule of the cytochrome P450 14 alpha-demethylase. Highly stereoselective synthesis of these oxazolidines is also described.     

Catalytic Hydrogenation of Chiral 2-(2-Furyl)-3,4-dimethyl-5-phenyloxazolidine

Reduction of chiral 2-(2-furyl)-3,4-dimethyl-5-phenyloxazo-lidines-1,3 by H₂/Raney nickel proceeds simultaneously as hydrogenation of the furan ring and opening of the oxazolidine ring on C2-O bond. Diastere-oselectivity in the first reaction was established as ca 40% and 80% depending on the configuration of the oxazolidine 1 and 2.     

Synthesis of mixed secondary amino alcohols from oxazolidine derivatives

The reaction of oxides (epichlorohydrin, glycidol methyl ether, and ethylene oxide) with oxazolid-2-one and 2-imino-5-methyloxazolidine has been studied. It has been established that the oxides add in position 3 of the oxazolidine ring with the formation of the corresponding S-(-hydroxyalkyl) derivatives, the alkaline cleavage of which leads to mixed secondary amino alcohols.     

Studies on the benzo[1,2]cyclohepta[3,4,5-d,e]isoquinoline ring system

The syntheses of various oxidation states of the novel benzo[1, 2]cyclohepta[3, 4, 5-d, e]-isoquinoline ring system is described. The ring system was obtained by the Schmidt rearrangement, with exclusive alkyl migration, of 1, 6, 7, 11b-tetrahydro - 2H - dibenz-[cd,h]azulen-2-one and by a Bischler-Napieralski reaction of suitable derivatives of 10, 11-dihydro-5H-dibenzo[a, d]cycloheptene - 5 - methylamine. 4, 5, 10, 11 - Tetramethoxy derivatives of the new ring system were best prepared by a Pictet-Spengler reaction of the appropriate amine.     

Structure-activity relationship of cyclic nitroxides as SOD mimics and scavengers of nitrogen dioxide and carbonate radicals

Synthetic nitroxide antioxidants attenuate oxidative damage in various experimental models. Their protective effect reportedly depends on ring size and ring substituents and is greater for nitroxides having lower oxidation potential. The present study focuses on the kinetics and mechanisms of the reactions of piperidine, pyrrolidine and oxazolidine nitroxides with HO2*/O2*-, *NO2 and CO3*- radicals, which are key intermediates in many inflammatory and degenerative diseases. It is demonstrated that nitroxides are the most efficient scavengers of *NO2 at physiological pH (k = (3-9) x 10(8) M(-1) s(-1)) and among the most effective metal-independent scavengers of CO3*- radicals (k = (2 - 6) x 10(8) M(-1) s(-1)). Their reactivity toward HO2*, though not toward *NO2 and CO3*-, depends on the nature of the ring side-chain and particularly on the ring-size. All nitroxide derivatives react slowly with O2*- and are relatively inefficient SOD mimics at physiological pH. Even piperidine nitroxides, having the highest SOD-like activity, demonstrate a catalytic activity of about 1000-fold lower than that of native SOD at pH 7.4. The present results do not indicate any correlation between the kinetics of HO2*/O2*-, *NO2 and CO3*- removal by nitroxides and their protective activity against biological oxidative stress and emphasize the importance of target-oriented nitroxides, i.e., interaction between the biological target and specific nitroxides.     

Cross-metathesis of C-allyl iminosugars with alkenyl oxazolidines as a key step in the synthesis of C-iminoglycosyl alpha-amino acids. A route to iminosugar containing C-glycopeptides

[structures: see text] A general access to a novel class of sugar alpha-amino acids composed of iminofuranose and iminopyranose residues anomerically linked to the glycinyl group through an alkyl chain is described. A set of eight compounds was prepared by the same reaction sequence involving as an initial step the Grubbs Ru-carbene-catalyzed cross-metathesis (CM) of various N-Cbz-protected allyl C-iminoglycosides with N-Boc-vinyl- and N-Boc-allyloxazolidine. The isolated yields of the CM products (mixtures of E- and Z-alkenes) varied in the range 40-70%. Each mixture was elaborated by first reducing the carbon-carbon double bond using in situ generated diimide and then unveiling the N-Boc glycinyl group [CH(BocNH)CO2H] by oxidative cleavage of the oxazolidine ring by the Jones reagent. All amino acids were characterized as their methyl esters. The insertion of a model C-iminoglycosyl-2-aminopentanoic acid into a tripeptide via sequential carboxylic and amino group coupling with L-phenylalanine derivatives was carried out as a demonstration of the potential of these sugar amino acids in designed glycopeptide synthesis.     

Synthesis of (-)-quinocarcin by directed condensation of alpha-amino aldehydes

An enantioselective synthesis of the natural antiproliferative agent quinocarcin was achieved by the directed condensation of optically active alpha-amino aldehyde intermediates. Condensation of the N-protected alpha-amino aldehyde 1, prepared in eight steps (19% yield) from (R,R)-pseudoephedrine glycinamide, with the C-protected alpha-amino aldehyde derivative 2, prepared in seven steps (34% yield) from (R,R)-pseudoephedrine glycinamide, afforded the corresponding imine in quantitative yield. Without isolation, direct treatment of this imine intermediate with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and hydrogen cyanide led to cleavage of the fluorenylmethoxycarbonyl (Fmoc) protective group followed by addition of cyanide (Strecker reaction) to form the bis-amino nitriles 3 as a mixture of diastereomers, in 91% yield. Treatment of the diastereomers 3 with trimethylsilyl cyanide and zinc chloride in 2,2,2-trifluoroethanol at 60 degrees C led to stepwise cyclization to form the tetracyclic product 4 (42% yield from 1 and 2). The latter intermediate was transformed into (-)-quinocarcin (1) in five steps (45% yield). The yield of quinocarcin was 19% from 1 and 2 (7 steps), and 4% from pseudoephedrine glycinamide (15 steps).     

Syntheses d'oxazolidines substituees par l'adamantane et de nitroxydes oxazolidines stables derives de l'adamantane

Adamantane oxazolidine derivatives have been prepared. The corresponding mono and biradicals have molecular shapes well suited to the study of the motion anisotropy in solution.     

High-performance liquid chromatographic separation of racemic and diastereomeric mixtures of 2,4-pentadienoate-iron tricarbonyl derivatives

beta-Cyclodextrin chiral stationary phase facilitates the chiral separation of the (+/-)-methyl-5-formyl-2,4-pentadienoate-iron tricarbonyl (1) racemic mixture. The separation of oxazolidine derivatives 2 and 3 diastereomers were achieved with a C18 column but the compounds underwent in-column hydrolysis to give (-)- and (+)-1, respectively. This hydrolysis was exploited for the determination of 2 and 3 by the beta-cyclodextrin column, namely 2 and 3 were initially and completely hydrolyzed in the column to give (-)- and (+)-1 and this racemic mixture was then separated by this chiral column.     

Reaction between hydrazines and chiral α-acetylenic ketones: synthesis of novel enantiomerically pure pyrazolyl-β-amino alcohols

A simple and efficient methodology toward the stereoselective synthesis of novel, enantiomerically pure, pyrazolyl-β-amino alcohols is presented. Thus, when hydrazines 4a,b were allowed to react at 0°C with chiral α-acetylenic ketones of type 3, pyrazolyl oxazolidine derivatives 5a–d were formed with total regioselectivity in 92–97% yield. Subsequent oxazolidine ring opening by means of TFA, and re-protection of the amino group as the N-Boc derivatives, afforded enantiopure amino alcohols 7a–d.     

On triazoles XLIV [1]. synthesis of new ring systems containing imidazo[2′,1′:3,4] [1,2,4] triazolo [1,5‐a]pyrimidine and imidazo[1′,2′:2,3][1,2,4]triazolo[1,5‐a]pyrimidine skeleton

Dedicated to Dr. János Császár on the occasion of his 70^th birthday Ring transformation of 2‐cyanoimido‐3‐methyl‐1,3‐oxazolidine ( 10 ) yielded 5‐amino‐3‐[N‐(2‐hydrox‐yethyl)‐N‐methyl]amino‐1H‐1,2,4‐triazole ( 6 ) that was ring closed with different β‐keto esters to 2‐[N‐(2‐hydroxyethyl)‐N‐methyl]amino‐1,2,4‐triazolo[1,5‐a]pyrimidinones ( 4 ). Cyclisation of derivatives 4 led to imidazo[2′,1′:3,4][1,2,4]triazolo[1,5‐a]pyrimidines ( 2 ) and imidazo[1′,2′:2,3][1,2,4]triazolo[1,5‐a]pyrim‐idines ( 3 ) representing 10 novel ring systems. Besides spectroscopical evidence of structure of derivatives 2 and 3 X‐ray diffraction analysis of derivative 2b was also performed.