Regioselective ring opening of 2-methylaziridine derivatives with F- and F-fluoride

Regioselectivity of the nucleophilic ring opening of N-benzoyl (Bz) and N-benzyloxycarbonyl (Cbz) activated 2-methylaziridines with anhydrous tetramethylammonium fluoride, anhydrous hydrogen fluoride, and ¹⁹F or [¹⁸F]-labelled potassium cryptand fluoride ([K₂₂₂][^18/19F]) were investigated. Whereas all reactions with rigorously anhydrous N(CH₃)₄F did not ring-open the aziridines, reactions with anhydrous HF exclusively yielded the 2-fluoropropanamine derivatives. Reactions of Bz-protected and Cbz-protected 2-methylaziridine with [K₂₂₂][^18/19F] yielded the 2-fluoropropanamine and 1-fluoro-2-propanamine derivatives as the major products, respectively, and represents the first example of regiocontrol during ring opening of aziridines with [¹⁸F]-fluoride.     

Radiolabeling of HER2-specific Affibody molecule with F-18

The presence of human epidermal growth factor type 2 (HER2) on 20-30% of human breast cancer is a prognostic indicator of more rapid disease progression and a therapeutic indicator for anti-HER2 monoclonal antibodies. Because the literature has demonstrated some discordance between primary and metastatic tumors in the same patient for expression of the HER2 marker, we set out to develop an imaging agent that could be used to assess the marker concentration in vivo in an individual patient. The pharmaceutical company Affibody^® AB has optimized the specificity of Affibody^® molecules for HER2. Two Affibody^® molecules, a 7 kDa and an 8 kDa protein, were designed with a single carboxy terminal cysteine in order to provide a specific location for the purposes of labeling for various types of imaging. We have prepared [¹⁸F]FBEM utilizing a coupling reaction between [¹⁸F]fluorobenzoic acid and aminoethylmaleimide. We then optimized the conjugation of this radiolabeled maleimide to the free sulfhydryl of cysteine by incubating at pH 7.4 in phosphate buffered saline containing 0.1% sodium ascorbate. An overall uncorrected yield of radiolabeled Affibody^® molecule of approximately 10% from [¹⁸F]fluoride was achieved in a 2 h synthesis. These conjugated Affibody^® molecules were obtained with a specific activity of 2.51 ± 0.92 MBq/μg. Characterization of the product by HPLC-MS supported the conjugation of [¹⁸F]FBEM with the Affibody^® molecule. The radiolabeled Affibody^® molecule retained its binding specificity as demonstrated by successful imaging of xenografts expressing HER2.     

Nucleophilic 18F-fluorination of heteroaromatic iodonium salts with no-carrier-added [18F]fluoride

Diaryliodonium salts containing the 2-thienyl group as an example of an electron-rich heteroaromatic moiety proved to be very potent precursors for the nucleophilic, regioselective no-carrier-added (nca) radiofluorination of various arenes. It even allowed the nucleophilic introduction of nca [18F]fluoride into electron-rich arene compounds in one step. The influences of the substitution pattern, of counteranions, and of different reaction conditions were studied. Effects of counterions could be explained by the influence of solvent on ion pair separation of precursor salts. Different aryl(2-thienyl)iodonium salts were used as precursors, where the homoaromatic group systematically varied from bearing electron-deficient to electron-rich substituents. Relative rates of exchange kinetics correlated linearly with Hammett constants of the appropriate substituents confirming a nucleophilic aromatic substitution reaction of high reactivity and low selectivity.     

Synthesis of no-carrier-added 4-[18F]fluorophenol from 4-benzyloxyphenyl-(2-thienyl)iodonium bromide

4-[(18)F]Fluorophenol is a versatile synthon for the synthesis of more complex radiopharmaceuticals bearing a 4-[(18)F]fluorophenoxy moiety. In order to prepare 4-[(18)F]fluorophenol in no-carrier-added (n.c.a.) form only a nucleophilic labelling method starting from [(18)F]fluoride is suitable. In this paper a new, two step radiosynthesis starting from 4-benzyloxyphenyl-(2-thienyl)iodonium bromide and [(18)F]fluoride with subsequent deprotection is described, yielding n.c.a. [(18)F]fluorophenol in 34 to 36% radiochemical yield.     

Synthesis of Methyl 2-Acetamido-4,6-di-O-acetyl-3-S-acetyl-2-deoxy-3-thio-α-D-mannopyranoside

Methyl-2-acetamido-4,6-di-O-acetyl-3-S-acetyl-2-deoxy-3-thio-α-D-mannopy-ranoside has been synthesized by conversion of methyl 2-amino-2-deoxy-4,6-O-benzylidene-α-D-altropyranoside into the corresponding 3-O-methanesulfony1-2-N-[(methylthio)thiocarbonyl]derivative followed by intramolecular displacement of the 3-O-methanesulfonyloxy group with the (methylthio)thiocarbamoyl group.     

Influence of labelling with radiohalogens in 2−18F-, 6−18F- and 6−123I-nicotinic acid diethylamide on biodistribution in mice

By comparison of three halogenated nicotinic acid derivatives, viz. 2–¹⁸F-, 6–¹⁸F-and 6–¹²³I-nicotinic acid diethylamide (2–¹⁸F-NADA, 6–¹⁸F-NADA, 6–¹²³I-NADA) the biodistribution of¹⁸F-and¹²³I-radioactivity in mice was determined. For the two fluoro-compounds the results indicate nearly similar time-activity curves in almost all organs investigated, while the iodo-derivative exhibits significant differences: for the brain and the heart a complete elimination of¹²³I-radioactivity takes place within 4 hours, time-activity curves of the liver and the kidneys show higher maximal accumulations compared to the fluorinated derivatives and activity in the stomach increases continously within a time period of 2 hours to a maximum which is about 5 times higher than that of 6–¹⁸F-NADA. For the lung drastic differences can also be observed in case of 6–¹²³I-NADA which accumulates with a dose of about 40%/g already 30 seconds after injection and exceeds the corresponding values for 2–¹⁸F-NADA and 6–¹⁸F-NADA by a factor of about 6, followed by a biexponential decrease. De-fluorination reactions from the aromatic ring can be excluded, as could be shown by the low accumulation of¹⁸F-radioactivity in bones after application of 6–¹⁸F-NADA.     

Synthesis of novel 3-deoxy-3-C-triazolylmethyl-allose derivatives and evaluation of their biological activity

Recently, monosaccharide-triazole conjugates have proved to possess a large variety of useful biological activities. This paper describes synthesis of a new series of 3-deoxy-3-C-triazolylmethyl-allose derivatives. These new compounds are obtained from acetonide-protected 3-deoxy-3-azidomethyl allose and commercial alkynes via Cu(I) catalyzed 1,3-dipolar cycloaddition. The obtained molecular scaffolds differ from those described earlier by the presence of a methylene linker (-CH₂-) between the C(3) of allose and the triazole moiety. It was demonstrated that acetonide-protected monosaccharide, 3-deoxy-3-C-(4-phenyl-1H-1,2,3-triazol-1-yl)methyl-1,2:5,6-di-O-isopropylidene-α-d-allofuranose, inhibited α-L-fucosidase for 26% at 0.1 mM concentration, but a deprotected analog, 3-deoxy-3-C-(4-(4-tert-butylphenyl)-1H-1,2,3-triazol-1-yl)methyl-β-d-allofuranose, showed 15% inhibition of β-glucosidase at 1 mM concentration.      

Synthesis of 2-deoxy-2-c-alkyl glycal and glycopyranosides from 2-hydroxy glycal ester

A method to convert 2-hydroxy glycal ester to the corresponding 2-deoxy-2-C-alkyl glycal in a facile manner, through key reactions including (i) C-allylation at C-1, (ii) Wittig reaction, and (iii) Cope rearrangement of a 1,5-diene derivative, is reported. The α-anomer of the 1,5-diene derivative underwent Cope rearrangement to afford 2-deoxy-2-C-glycal derivative, whereas the β-anomer was found to be unreactive. Employing this sequence, 3,4,6-tri-O-benzyl-2-O-acetyl-1,5-anhydro-d-arabino-hex-1-enitol was transformed to 3,4,6-tri-O-benzyl-2-deoxy-2-C-alkyl-1,5-anhydro-D-arabino-hex-1-enitol. 2-Deoxy-2-C-alkyl glycal derivative is a suitable glycosyl donor to prepare 2-deoxy-2-C-alkyl glycosides, mediated through haloglycosylation and a subsequent dehalogenation. A number of 2-deoxy-2-C-alkyl glycosides, with both glycosyl and nonglycosyl moieties at the reducing end, are thus prepared from the glycal.     

Synthesis and γ-radiolysis of 2′-deoxy-5-fluorouridine and 5-fluorouridine derivatives

Seventeen compounds having a variety of substituents at the 3- and 5′-positions of 2′-deoxy-5-fluorouridine (5-FUdR) and 5-fluorouridine (5-FUR) were synthesized, and their γ-radiolysis in aqueous solutions were studied. The compounds having thioureido (RNHCSNH, R  H, PhCH₂, acyl) and thiocarbonylamino (XCSNH, X  PhCH₂S, PhO) groups at the 3-position of 5-FUdR were efficiently cleaved to give 5-FUdR with high G values upon γ-irradiation of their aqueous solutions. The active species for these cleavage reactions were hydrated electron (e⁻ _aq), H^• and HO^•. However, the compounds having a dimethylsulfoxyimino group at 3-position of 5-FUdR and 5-FUR afforded 5-FUdR and 5-FUR only under the radiolysis conditions where e⁻ _aq becomes a principal active species. The compound having a 2-benzoylthiazoylthiocarbonylamino group at the 3-position of 5-FUdR showed the highest reactivity toward HO^.. The mechanisms of these γ-radiolysis reactions are discussed. The examination of anticellular activities of γ-irradiated compounds having a thiocarbonylamino group at the 3-position of 5-FUdR toward murine Sarcoma 180 cells revealed that these compounds may be utilized as a candidate for a radiation-induced drug (RID).     

Fluorocarbohydrates-XXVIII: Synthesis and characterisation of 2-deoxy-2-fluoro-derivatives of l-rhamnose and l-epirhamnose

Addition of CF₃OF to 3,4-di-O-acetyl-l-rhamnal gave four products separable by fractional crystallisation and column chromatography. The two principal products were in the epirhamnose series, i.e. trifluoromethyl 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-α-l-glucoside and 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-α-l-glucosyl fluoride. The lesser products were in the rhamnose series viz. trifluoromethyl 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-β-1-mannoside and 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-β-l-mannosyl fluoride. The structures were confirmed by ¹H and ¹⁹F NMR spectral measurements. Deacylation and acidic hydrolysis gave the free 2-deoxy-2-fluoro sugars of both series.     

Synthesis of methyl ethers of methyl 2-acetamido-2-deoxy-α-D-glucopyranoside

A convenient method is proposed for the synthesis of all the individual methyl ethers of methyl 2-acetamido-2-deoxy-α-D-glucopyranoside based on the partial methylation of 2-acetamido-2-deoxy-α-D-glucopyranoside with dimethyl sulfate in an alkaline medium followed by preparative liquid column chromatography on silica gel of the resulting mixture of methyl ethers.     

4,6-O-benzylidene-directed beta-mannopyranosylation and alpha-glucopyranosylation: the 2-deoxy-2-fluoro and 3-deoxy-3-fluoro series of donors and the importance of the O2-C2-C3-O3 interaction

A series of 4,6-O-benzylidene-protected 2-O-benzyl-3-deoxy-3-fluoro- and 3-O-benzyl-2-deoxy-2-fluorogluco- and mannopyranosyl thioglycosides were synthesized and their coupling reactions with a series of alcohols, on preactivation with 1-benzenesulfinylpiperidine and trifluoromethanesulfonic anhydride, investigated. In all cases, the selectivities were lower than those observed with the corresponding simple 4,6-O-benzylidene 2,3-di-O-benzylgluco- and mannopyranosyl thioglycosides. This leads to the conclusion that the high beta-selectivity observed with 4,6-O-benzylidene 2,3-di-O-benzylmannopyranosyl donors under the same conditions is in large part derived from the compression of the O2-C2-C3-O3 torsion angle on going from the intermediate covalent glycosyl triflate to the oxacarbenium ion, as compared to the relaxation of this torsion angle in the gluco series.     

Syntheses of 4, 5-Di-O-bexzyl-2-deoxy-2-C-methyl L-lyxose and Methyl 4, 5-Di-O-bexzyl-2-deoxy-2-C-methyl-3-O-metkyl-L-lyxonate

The title compounds, which possess C-methyl groups at the α-position of carbonyl groups and vicinal hydroxyl groups with syn (three) relationship, were synthesized efficiently from known 3-decxy-1, 2-O-isopropylidene-3-C-methyl-α-D-allofuranose. The synthetic routes involve: 1) inversion of C-5 configuration of the starting sugar, 2) suitable protection of the 5, 6-diol, and 3) glycol cleavage of the 1, 2-diol to an aldehyde or direct oxidation of the diol to carboxylic acid.     

Synthesis and in vivo distribution of 2-deoxy-2-aminodiglucose-prednisolone conjugate(DPC)

In order to develop a novel kidney-targeted drug delivery system,a small molecular carrier(2-deoxy-2-aminodiglucose) was synthesized,and then the 2-deoxy-2-aminodiglucose-prednisolone conjugate(DPC) was synthesized to verify the kidney targeting capability of the carrier.Both 2-deoxy-2-aminodiglucose and DPC were confirmed by NMR and MS spectrum.The tissue distribution studies showed that DPC presented an excellent kidney targeting property in vivo,compared with prednisolone group, 4.9-fold of drug concentration in kidney was observed in the DPC group.Thus,it indicated that 2-deoxy-2-aminodiglucose could be a potential carrier for kidney-targeted drug delivery.     

Stereoselective synthesis of 2-deoxy-beta-galactosides via 2-deoxy-2-bromo- and 2-deoxy-2-iodo-galactopyranosyl donors

[reaction: see text] A series of 2-bromo- and 2-iodo-galactopyranosyl acetates and trichloroacetimidates were evaluated as glycosyl donors for the synthesis of 2-deoxygalactopyranosides. The best selectivity for the beta-glycosidic linkage was achieved by using 6-deoxy-3,4-carbonate-protected galactosyl donors.