ABSTRACT
A bis-tert-alcohol-functionalized crown-6-calix[4]arene (BACCA) was designed and prepared as a multifunctional organic promoter for nucleophilic fluorinations with CsF. By formation of a CsF/BACCA complex, BACCA could release a significantly active and selective fluoride source for SN2 fluorination reactions. The origin of the promoting effects of BACCA was studied by quantum chemical methods. The role of BACCA was revealed to be separation of the metal fluoride to a large distance (>8 Å), thereby producing an essentially "free" F(-). The synergistic actions of the crown-6-calix[4]arene subunit (whose O atoms coordinate the counter-cation Cs(+)) and the terminal tert-alcohol OH groups (forming controlled hydrogen bonds with F(-)) of BACCA led to tremendous efficiency in SN2 fluorination of base-sensitive substrates.
Subject(s)
Alcohols/chemistry , Calixarenes/chemistry , Cations/chemistry , Crown Ethers/chemistry , Ethanol/chemistry , Fluorides/chemistry , Hydrocarbons, Fluorinated/chemistry , Phosphates/chemistry , Sulfhydryl Compounds/chemistry , Halogenation , Hydrogen Bonding , Metals/chemistry , Molecular StructureABSTRACT
Hexaethylene glycol bis(3-hexaethylene glycol imidazolium) dimesylate ionic liquid (hexaEG-DHIM) was designed and prepared as a highly efficient promoter for the nucleophilic hydroxylation of alkyl halides to the corresponding alcohol products in neat water media. It was observed that hexaEG-DHIM promoter enhanced the nucleophilicity of water significantly in the reaction. In addition, the hexaEG-DHIM could be reused several times without loss of activity. Moreover, the hydroxylation reactions of base-sensitive and/or polar alkyl halide substrates proceeded highly chemoselectively in excellent yields.
Subject(s)
Cations/chemistry , Ethylene Glycol/chemical synthesis , Ethylene Glycols/chemical synthesis , Hydrocarbons, Halogenated/chemistry , Ionic Liquids/chemistry , Mesylates/chemical synthesis , Water/chemistry , Catalysis , Ethylene Glycol/chemistry , Ethylene Glycols/chemistry , Hydroxylation , Mesylates/chemistry , Molecular StructureABSTRACT
We introduce the high-throughput synthesis of various (18)F-labeled peptide tracers by a straightforward (18)F-labeling protocol based on a chemo-orthogonal strain-promoted alkyne azide cycloaddition (SPAAC) using aza-dibenzocyclootyne-substituted peptides as precursors with (18)F-azide synthon to develop peptide based positron emission tomography (PET) molecular imaging probes. The SPAAC reaction and subsequent chemo-orthogonal purification reaction with azide resin proceeded quickly and selectively under physiologically friendly reaction conditions (i.e., toxic chemical reagents-free, aqueous medium, room temperature, and pH ≈7), and provided four (18)F-labeled tumor targetable bioactive peptides such as cyclic Arg-Gly-Asp (cRGD) peptide, bombesin (BBN), c-Met binding peptide (cMBP), and apoptosis targeting peptide (ApoPep) in high radiochemical yields as direct injectable solutions without any HPLC purification and/or formulation processes. In vitro binding assay and in vivo PET molecular imaging study using the (18)F-labeled cRGD peptide also demonstrated a successful application of our (18)F-labeling protocol.
Subject(s)
Cycloaddition Reaction/methods , Isotope Labeling/methods , Peptides/chemistry , Alkynes/chemistry , Animals , Aza Compounds/chemistry , Azides/chemistry , Female , Iodine Radioisotopes/chemistry , Mice , Peptides/pharmacokinetics , Positron-Emission Tomography , Radioactive TracersABSTRACT
Herein, we report the promising use of n-oligoethylene glycols (oligoEGs) as mutifunctional promoters for nucleophilic-substitution reactions employing alkali metal salts. Among the various oligoEGs tested, pentaethylene glycol (pentaEG) had the most efficient catalytic activity. In particular, when compared with other nucleophiles examined, a fluorine nucleophile generated from CsF was significantly activated by the pentaEG promoter. We also performed various facile nucleophilic-displacement reactions, such as the halogenation, acetoxylation, thioacetoxylation, nitrilation, and azidation of various substrates with potassium halides, acetate, thioacetate, cyanide, and sodium azide, respectively, in the presence of the pentaEG promoter. All of these reactions provided their desired products in excellent yields. Furthermore, the combination of pentaEG and a tert-alcohol medium showed tremendous efficiency in the nucleophilic-displacement reactions (fluorination and methoxylation) of base-sensitive substrates with basic nucleophiles (cesium fluoride and potassium methoxide, respectively). The catalytic role of oligoEGs was examined by quantum-chemical methods. The oxygen atoms in oligoEGs were found to act as Lewis bases on the metal cations to produce the "flexible" nucleophile, whereas the two terminal hydroxy (OH) groups acted as "anchors" to orientate the nucleophile and the substrate into an ideal configuration for the reaction.
Subject(s)
Ethylenes/chemistry , Fluorine/chemistry , Glycols/chemistry , Alcohols/chemistry , Catalysis , Combinatorial Chemistry Techniques , Metals, Alkali/chemistry , Molecular Conformation , Molecular StructureABSTRACT
Hexaethylene glycol substituted imidazolium based ionic liquids (hexaEGILs) were designed and prepared well-tailored to a specific organic reaction using alkali-metal fluorides (MFs) as multifunctional organic catalysts. These hexaEGIL catalysts could significantly enhance the reactivity of MF, even KF. Furthermore, the hexaEGIL systems showed tremendous efficiency in the nucleophilic fluorination of base-sensitive substrates.
Subject(s)
Ethylene Glycols/chemistry , Ionic Liquids/chemistry , Alkalies/chemistry , Catalysis , Fluorides/chemistry , Hydrogen-Ion Concentration , Molecular StructureABSTRACT
Polymer-supported pentaethylene glycols (PSpentaEG) as promising catalysts for nucleophilic fluorination with alkali metal fluoride (MF) could significantly enhance the nucleophilicity of MF and provide simple purification and recycling in the reaction. Furthermore, by their synergistic effect, the combination of PSpentaEG and a tert-alcohol media system showed tremendous efficiency in the fluorination of base-sensitive substrates such as sec-alkyl halide.
Subject(s)
Glycols/chemistry , Polymers/chemistry , Catalysis , Combinatorial Chemistry Techniques , Halogenation , Molecular StructureABSTRACT
A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.
Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis , Cyclopentanes/chemical synthesis , Stilbenes/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cyclopentanes/pharmacokinetics , Cyclopentanes/pharmacology , DNA Fragmentation , Drug Screening Assays, Antitumor , Endothelial Cells/drug effects , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Solubility , Stilbenes/pharmacokinetics , Stilbenes/pharmacology , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacokinetics , Tubulin Modulators/pharmacologyABSTRACT
The enantiomers of 5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-one, a novel anticancer agent, were separated by derivatisation with caronaldehyde, separation of the resulting diastereoisomers of the corresponding esters by silica gel column chromatography and regeneration of alcohols (S)-5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-one and (R)-5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-one under aqueous conditions. The absolute configuration of the enantiomers was determined by 1H NMR studies of the corresponding Mosher esters. Alternatively, the enantiomers were separated by preparative HPLC to collect the (S)- and (R)-5-hydroxy-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-1-ones with high purity which was comparable with that obtained by the chemical method. The details of these methods have been presented herein.
