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ChemMedChem Jan 2011A series of 52 cis-configured 1-alkyl-3-phenylaziridine-2-carboxylates were synthesized as new pseudo-irreversible inhibitors of Candida albicans secreted aspartic acid...
A series of 52 cis-configured 1-alkyl-3-phenylaziridine-2-carboxylates were synthesized as new pseudo-irreversible inhibitors of Candida albicans secreted aspartic acid protease 1 (SAP1), SAP2, SAP3, and SAP8. Some of the compounds, which were obtained as diastereomers with S,S- and R,R-configured aziridine rings by Cromwell synthesis of racemic (2R,3S+2S,3R)-dibromophenylpropionic acid ester with amines, followed by ester hydrolysis and coupling to hydrophobic amino acid esters, were separated by preparative HPLC. The absolute configuration of the aziridine ring was assigned by a combination of experimental circular dichroism (CD) investigations and quantum chemical CD calculations. In agreement with previous docking studies, the diastereomers all exhibit similar activity. The compounds were found to be more active against the related mammalian enzyme cathepsin D, presumably due to productive interactions of the N-alkyl substituent with the highly lipophilic S2 pocket. The most active inhibitors (5, 9, 10, 21, and 28), characterized by benzyl, cyclohexylmethyl, tert-butyl, or 1,4-dimethylpentyl moieties at the aziridine nitrogen atom, exhibit k(2nd) values between 500 and 900×10³ M⁻¹ min⁻¹ and K(i) values near or below 1 μM for cathepsin D.
Topics: Aspartic Acid Proteases; Aziridines; Candida albicans; Cathepsin D; Circular Dichroism; Enzyme Inhibitors; High-Throughput Screening Assays; Isoenzymes; Kinetics; Stereoisomerism
PubMed: 21082722
DOI: 10.1002/cmdc.201000370 -
Organic Letters Feb 2016A general and direct strategy for the synthesis of chiral spiro-aziridine oxindoles has been developed via an aza-Corey-Chaykovsky reaction of isatin-derived...
A general and direct strategy for the synthesis of chiral spiro-aziridine oxindoles has been developed via an aza-Corey-Chaykovsky reaction of isatin-derived N-tert-butanesulfinyl ketimines with excellent selectivity (dr = 98:2 to >99:1). The method is explored for the synthesis of chiral 3-substituted spiro-aziridine oxindoles with high (2S,3S)-selectivity over (2S,3R).
Topics: Aziridines; Catalysis; Imines; Indoles; Isatin; Molecular Structure; Nitriles; Oxindoles; Stereoisomerism
PubMed: 26781920
DOI: 10.1021/acs.orglett.5b03564 -
Organic & Biomolecular Chemistry Oct 2015Phosphonated derivatives of trifluoromethyl aziridine were obtained with good yield from aziridine-2-carbaldehyde by two distinct methods, which resulted in different...
Phosphonated derivatives of trifluoromethyl aziridine were obtained with good yield from aziridine-2-carbaldehyde by two distinct methods, which resulted in different diastereoselectivities. Using thiols as nucleophiles ring opening reactions of trifluoromethylated derivatives of aziridine-2-phosphonates proceeded regio- and diastereoselectively, giving rise to γ-amino-γ-trifluoromethyl phosphonates.
Topics: Amination; Aziridines; Halogenation; Hydrocarbons, Fluorinated; Methylation; Models, Molecular; Organophosphonates; Stereoisomerism; Sulfhydryl Compounds
PubMed: 26299334
DOI: 10.1039/c5ob01411e -
Nuclear Medicine and Biology Jul 2012The small molecule 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(fluoromethyl)butanoic acid (NST732) is a member of the ApoSense family of compounds, capable of...
Synthesis of ApoSense compound [18F]2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(fluoromethyl)butanoic acid ([18F]NST732) by nucleophilic ring opening of an aziridine precursor.
INTRODUCTION
The small molecule 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(fluoromethyl)butanoic acid (NST732) is a member of the ApoSense family of compounds, capable of selective targeting, binding and accumulation within cells undergoing apoptotic cell death. It has application in molecular imaging and blood clotting particularly for monitoring antiapoptotic drug treatments. We are investigating a fluorine-18-radiolabeled analog of this compound for positron emission tomography studies.
METHODS
We prepared the tosylate precursor methyl 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(tosyloxymethyl)butanoate (4) to synthesize fluorine-18-labeled NST732. Fluorination reaction of the tosylate precursor in 1:1 acetonitrile:dimethylsulfoxide with tetrabutyl ammonium fluoride proceeds through an aziridine intermediate (4A) to afford two regioisomers: 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-fluorobutanoate (5) and methyl 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(fluoromethyl)butanoate (6). Acid hydrolysis of the fluoromethylbutanoate (6) isomer produced NST732. As the fluorination reaction of the tosylate precursor proceeds through an aziridine intermediate (4A) and the fluorination conceivably could be done directly on the aziridine, we have separately prepared an aziridine precursor (4A). Fluorine-18 labeling of the aziridine precursor (4A) was performed with [(18)F]tetrabutyl ammonium fluoride to afford the same two regioisomers (5 and 6). The [18F]2-((5-dimethylamino)naphthalene-1-sulfonamido)methyl)-2-fluorobutanoic acid (NST732) was then obtained by the hydrolysis of corresponding [18F]-labeled ester (6) with 6 N hydrochloric acid.
RESULTS
Two regioisomers obtained from the fluorination reaction of aziridine were easily separated by high-performance liquid chromatography. The total radiochemical yield was 15%±3% (uncorrected, n=18) from the aziridine precursor in a 70-min synthesis time with a radiochemical purity>99%.
CONCLUSION
Fluorine-18-labeled ApoSense compound [18F]NST732 is prepared in moderate yield by direct fluorination of an aziridine precursor.
Topics: Aminobutyrates; Aziridines; Butyric Acid; Chemistry Techniques, Synthetic; Radiochemistry; Reference Standards; Sulfonamides
PubMed: 22336374
DOI: 10.1016/j.nucmedbio.2011.12.008 -
The Journal of Organic Chemistry Nov 2014A general study is undertaken to examine the scope of the reductive ring opening of aziridine-2-carboxylates with samarium diiodide. The competition between C-C and C-N...
A general study is undertaken to examine the scope of the reductive ring opening of aziridine-2-carboxylates with samarium diiodide. The competition between C-C and C-N bond cleavage is examined as a function of the nature of the N-substituent of the aziridine, the nature of the substituent in the 3-position of the aziridine, and whether the substituent in the 3-position is in a cis or trans relationship with the carboxylate in the 2-position. The desired C-N bond cleavage leads to β-amino esters that are the predominant products for most aziridines with an N-activating group. However, C-C cleavage products are observed with an aryl group in the 3-position; this can be particularly pronounced with cis-aziridines where a nearly equal mixture of the two is observed. Exclusive formation of the C-N cleavage product is observed for all aziridines with the strongly N-activating p-toluene sulfonate group. Similarly high selectivity is observed for the 2-trimethylsilylethyl sulfonate group (SES), which is easier to remove. The utility of these methods is illustrated in the synthesis of protected forms of (R)-β(3)-DOPA and L-DOPA from the same aziridine, the former by SmI2-mediated reductive opening at C-2 and the latter by palladium-mediated reductive opening at C-3.
Topics: Aziridines; Benzenesulfonates; Esters; Palladium; Stereoisomerism; Trimethylsilyl Compounds
PubMed: 25329528
DOI: 10.1021/jo501694h -
Chemical Communications (Cambridge,... Oct 2009A chiral zirconium catalyst prepared from Zr(O(t)Bu)4 and a chiral tridentate BINOL was found to be effective for asymmetric meso-aziridine ring-opening reactions with...
A chiral zirconium catalyst prepared from Zr(O(t)Bu)4 and a chiral tridentate BINOL was found to be effective for asymmetric meso-aziridine ring-opening reactions with aniline derivatives. The N-benzhydryl group on the product obtained was easily cleaved to give the corresponding amine in high yield under reductive conditions.
Topics: Aniline Compounds; Aziridines; Catalysis; Stereoisomerism; Zirconium
PubMed: 19774248
DOI: 10.1039/b914271c -
Nature May 1976
Topics: Animals; Aziridines; Azirines; Culicidae; Hydrogen-Ion Concentration; Insect Control; Thiotepa
PubMed: 5682
DOI: 10.1038/261135a0 -
Mutation Research Jan 1990
Review
Topics: Animals; Aziridines; Chemical Phenomena; Chemistry; Cricetinae; DNA; Humans; Mutagenicity Tests; Mutagens
PubMed: 2406584
DOI: 10.1016/0165-1110(90)90038-d -
Organic Letters Oct 2006An unprecedented stereo- and regioselective trisubstituted aziridine ring-opening by phenol derivatives was discovered. The reaction features very mild reaction...
An unprecedented stereo- and regioselective trisubstituted aziridine ring-opening by phenol derivatives was discovered. The reaction features very mild reaction conditions and broad functional group compatibility, which provides a good method for the stereoselective formation of tertiary alkyl-aryl ethers in highly functionalized systems. [reaction: see text]
Topics: Aziridines; Catalysis; Ethers; Molecular Structure; Phenols; Stereoisomerism
PubMed: 17048854
DOI: 10.1021/ol062010w -
Bioorganic & Medicinal Chemistry Jul 2013The concept of pharmacophore hybridization is attracting an increasing interest from medicinal chemists. Whereas the main motivation for the application of this...
The concept of pharmacophore hybridization is attracting an increasing interest from medicinal chemists. Whereas the main motivation for the application of this methodology relates to the pharmacological advantages associated with hybrid molecules, molecular hybridization can also deliver a synthetic advantage through selective chemical modification of the more reactive entity within hybrid systems. Moreover, if both features are combined, new hybrid structures result displaying both a biological and a synthetic benefit, and elaboration of this methodology might culminate in structural diversity and chemical novelty. In this perspective, a new approach based on hybrid structures combining a biologically interesting yet rather chemically reactive nucleus with a privileged heterocyclic scaffold is discussed by means of β-lactam-purine chimeras useful in antiviral research and aziridine-(iso)quinoline hybrids for antimalarial purposes.
Topics: Animals; Antimalarials; Antiviral Agents; Aziridines; Chemistry, Pharmaceutical; Drug Discovery; Humans; Malaria, Falciparum; Plasmodium falciparum; Purines; Quinolines; beta-Lactams
PubMed: 23684232
DOI: 10.1016/j.bmc.2013.04.033