Synthesis of (S)‐cyano(3‐phenoxyphenyl)methyl (1R,3R)‐ 3‐[(1Z)‐2‐chloro‐3,3,3‐trifluoro‐1‐propenyl]‐2,2‐dimethylcyclopropanecarboxylate‐1‐14C

γ‐Cyhalothrin ( 1a ), (S)‐cyano(3‐phenoxyphenyl)methyl (1R,3R)‐3‐[(1Z)‐2‐chloro‐3,3,3‐trifluoro‐1‐propenyl]‐2,2‐dimethylcyclopropanecarboxylate, is a single‐isomer, synthetic pyrethroid insecticide marketed by Pytech Chemicals GmbH, a joint venture between Dow AgroSciences and Cheminova A/S. As a part of the registration process there was a need to incorporate a carbon‐14 label into the cyclopropyl ring of this molecule. A high yielding radiochemical synthesis of γ‐cyhalothrin was developed from readily available carbon‐14 labeled N‐t‐Boc protected glycine. This seven step synthesis, followed by a preparative normal phase HPLC separation of diastereomers, provided 21.8 mCi of γ‐cyhalothrin‐1‐¹⁴C ( 1b ) with >98% radiochemical purity. Copyright © 2007 John Wiley & Sons, Ltd.     

Design,Synthesis, and Antitumor Activity of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones

A series of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones ( C1 – C35 ) were designed and synthesized, and the structures of compounds (Z)‐ C27 and (Z)‐ C29 were confirmed by single‐crystal X‐ray diffraction. The antitumor activities of these novel compounds against cervical cancer (HeLa), lung cancer (A549), and breast cancer (MCF‐7) cell lines were evaluated in vitro. Majority of the title compounds exhibited strong antitumor activities and were much more promising than the positive control Taxol, which were also accompanied by lower cytotoxicity to normal cells. In particular, compounds (E,Z)‐ C24 exhibited the most consistent potent activities against three neoplastic cells with IC₅₀ values ranging from 3.2 to 7.1 μm . Further researches demonstrated that compounds (E,Z)‐ C24 could induce cell apoptosis and arrest cell cycle at the G2/M and S phases. Meanwhile, the structure–activity relationship between the configurations and cytotoxicity of the compounds was also investigated.     

Synthesis of 3,7,8‐15N3‐N1‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin

3,7,8‐¹⁵N₃‐N¹‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin was synthesized from the oxidation of 1,7,NH₂‐¹⁵N₃‐8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine with 2 equivalents of Ir(IV) in pH 4.5 potassium phosphate buffer. The synthesis of 1,7,NH₂‐¹⁵N₃‐8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine started with bromination of 1,7,NH₂‐¹⁵N₃‐2′‐deoxyguanosine. The resulting 1,7,NH₂‐¹⁵N₃‐8‐bromo‐7,8‐dihydro‐2′‐deoxyguanosine reacted with sodium benzyloxide to afford 1,7,NH₂‐¹⁵N₃‐8‐benzyloxy‐7,8‐dihydro‐2′‐deoxyguanosine. Subsequent catalytic transfer hydrogenation of 1,7,NH₂‐¹⁵N₃‐8‐benzyloxy‐7,8‐dihydro‐2′‐deoxyguanosine with cyclohexene and 10% Pd/C yielded 1,7,NH₂‐¹⁵N₃‐8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine. Purification of 3,7,8‐¹⁵N₃‐N¹‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin was first carried out on a C18 column and the product was further purified on a graphite column. ESI‐MS was used to confirm the identity and to determine the isotopic purity of all the labeled compounds. The isotopic purity of 3,7,8‐¹⁵N₃‐N¹‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin was 99.4 atom% based on LC‐MS measurements. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and radioiodination of 7‐(3′‐ammoniopropyl)‐7,8‐dicarba‐nido‐undecaborate(‐1), (ANC)

Derivatives of nido‐carborate have potential use in tumour targeting as hydrophilic boron‐rich compounds for boron neutron capture therapy (BNCT) and as pendant groups for attachment of radiohalogens to tumour‐seeking molecules. For this purpose, functionalized derivatives of nido‐carborates that can be conjugated to biomolecules should be synthesized and evaluated. In this study, racemic 1 , 7‐(3′‐ammoniopropyl)‐7,8‐dicarba‐nido‐undecaborate(‐1) (acronym ANC ) was obtained by degradation of the corresponding aminopropyl‐o‐carborane, which was synthesized in three steps from 1‐tert‐butyldimethylsilyl‐2‐(3‐bromopropyl)‐o‐carborane, with sodium hydroxide in absolute ethanol. The racemate 1 was radioiodinated (¹²⁵ I ) using the Chloramine‐T method. Radio‐TLC results showed that radiolabelling with ¹²⁵ I was achieved in a yield greater than 95%. Copyright © 2004 John Wiley & Sons, Ltd.     

A facile synthesis of 5,5‐dideutero‐4‐dimethyl(phenyl)silyl‐6‐undecyl‐tetrahydropyran‐2‐one as a deuterium labeled synthon for (−)‐tetrahydrolipstatin and (+)‐δ‐hexadecanolide

Deuterium‐labeled biologically active compounds are gaining importance because they can be utilized as tracers or surrogate compounds to understand the mechanism of action, absorption, distribution, metabolism, and excretion. Deuterated drug molecules (heavy drugs) become novel as well as popular because of better stability and bioavailability compared with their hydrogen analogs. Labeling of organic molecules with deuterium at specific positions is thus gaining popularity. In this work, we have exploited a highly regioselective and enantioselective direct Michael addition of methyl‐d₃ alkyl ketones to dimethyl(phenyl)silylmethylene malonate that was catalyzed by (S)‐N‐(2‐pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid/ D₂O combination with high yield and isotopic purity. The 5,5‐dideutero‐4‐dimethyl(phenyl)silyl‐6‐undecyl‐tetrahydropyran‐2‐one was obtained from the adduct of methyl‐d₃ undecanyl ketone and dimethyl(phenyl)silylmethylene malonate by a silicon controlled diastereoselective ketone reduction, lactonization, and deethoxycarbonylation. The dideuterated silylated tetrahydropyran‐2‐one is the precursor for geminal ²H₂‐labeled (+)‐4‐hydroxy‐6‐undecyl‐tetrahydropyran‐2‐one, an advanced intermediate for gem‐dideutero (–)‐tetrahydrolipstatin and (+)‐δ‐hexadecanolide syntheses.     

N‐2‐(4‐N‐(4‐[18F]Fluorobenzamido)phenyl)‐propyl‐2‐propanesulphonamide: synthesis and radiofluorination of a putative AMPA receptor ligand

Arylpropylsulphonamides are in the focus of research as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolpropionic acid (AMPA) receptor ligands. A new fluorine‐18‐labelled potentiator of AMPA receptors was synthesized as a potential radiotracer for cerebral imaging with positron emission tomography. Using N‐2‐(4‐N‐(4‐nitrobenzamido)phenyl)‐propyl‐2‐propanesulphonamide ( 7 ) as labelling precursor for a Kryptofix 2.2.2^®/K₂CO₃‐activated nucleophilic radiofluorination, the putative AMPA receptor ligand N‐2‐(4‐N‐(4‐[¹⁸F]fluorobenzamido)phenyl)‐propyl‐2‐propanesulphonamide [¹⁸F] 8 was obtained in one step. Optimization of the reaction parameters time, temperature, solvent and concentration gave a radiochemical yield of 38±8% at 180°C in dimethylsulphoxide within 30‐min reaction time. After a solid‐phase extraction followed by a high‐performance liquid chromatography separation, the product could be obtained in radiochemical yields of 5±1.5%. Radiochemical purity was higher than 95% and the specific activity amounted to 77±40 GBq/µmol. First in vitro assays with rat brain slices revealed a high non‐specific binding and a uniform distribution of [¹⁸F] 8 not lending it for in vivo imaging purposes. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis of morphine‐[N‐methyl‐14C]‐6‐β‐D‐glucuronide

Protected morphine‐6‐glucuronide was converted into morphine‐[N‐methyl‐¹⁴C]‐6‐glucuronide by a three‐step procedure. Methyl (3‐pivaloylmorphin‐6‐yl 2,3,4‐tri‐O‐isobutyryl‐β‐D‐glucopyranosid)uronate was N‐demethylated by treatment with 1‐chloroethyl chloroformate to afford protected normorphine‐6‐glucuronide as its hydrochloride salt. The normorphine‐6‐glucuronide derivative was alkylated with iodomethane‐[¹⁴C] in the presence of potassium carbonate to produce C‐14 labelled protected morphine‐6‐glucuronide. Finally, hydrolysis of the protecting groups using 5% sodium hydroxide solution gave morphine‐[N‐methyl‐¹⁴C]‐6‐β‐D‐glucuronide with a specific activity of 41.8 mCi mmol^?1 and radiochemical purity of 99.2% (HPLC). Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of (R)‐ and (S)‐[O‐methyl‐11C]N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐(4‐methoxy‐phenyl)‐urea as candidate high affinity β1‐adrenoceptor PET radioligands

Molecular imaging and quantification of myocardial β₁‐adrenoceptor (AR) rather than total β‐AR density is of great clinical interest since cardiac biopsy studies suggest that myocardial β₁‐AR density is reduced in patients with chronic heart failure whereas cardiac β₂‐AR density may vary. Positron emission tomography (PET), with appropriate radioligands, offers the possibility to assess β‐AR density non‐invasively in humans. However, no PET radioligand for the selective imaging of cardiac β₁‐ARs is clinically available. Here some derivatives of the well characterized β₁‐AR selective antagonist, ICI 89,406, namely the enantiomers of N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐(4‐hydroxy‐phenyl)‐urea ( 5a and 5b ) were synthesized and evaluated in vitro. The (R)‐isomer 5a was more β₁‐selective but has lower affinity than its (S)‐enantiomer 5b (β₁‐AR selectivity: 6100 vs 1240; β₁‐affinity: K₁ = 0.288 nM vs K₁ = 0.067 nM). Etherification of the analogous desmethyl precursors, 5e and 5f , respectively, with [¹¹C]iodomethane gave ¹¹C‐labelled versions of 5a and 5b , namely 5g and 5h , in 44 ± 5% radiochemical yield (decay‐corrected) and 97.4 ± 1.3% radiochemical purity with specific radioactivities of 26.4 ± 9.4 GBq/µmol within 41.2 ± 3.4 min from the end of bombardment (n = 14). 5g and 5h are now being evaluated as candidate radioligands for myocardial β₁‐ARs. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of C‐14‐labeled novel IKK inhibitor: 2‐[14C]‐N‐(6‐chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide

2‐[¹⁴C]‐N‐(6‐Chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide (9A , also referred to as [¹⁴C]‐PS‐1145) was synthesized from [¹⁴C]‐paraformaldehyde in five steps in an overall radiochemical yield of 15%. The key intermediate 1‐[¹⁴C]‐6‐chloro‐1,2,3,4‐tetrahydro‐β‐carboline was obtained by Pictet–Spengler cyclization of chlorotryptamine with [¹⁴C]‐paraformaldehyde. Similar reactions were conducted with tryptamine to address the generality of the methodology. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of all‐trans‐[10′‐3H]‐8′‐apo‐β‐carotenoic acid

The enzyme, 15,15′‐β‐carotene dioxygenase (BCDOX), facilitates the oxidation of β‐carotene to yield retinal. This is a remarkable process in which one of 11 double bonds in β‐carotene is selectively oxidized. To further probe the mechanistic aspects of BCDOX, the synthesis of all‐trans‐[10′‐³H]‐8′‐apo‐β‐carotenoic acid is reported. This compound will be used as a photoaffinity labeling reagent to probe the β‐carotene binding pocket within BCDOX. The synthesis outlines a simple and efficient route for the incorporation of tritium at the 10′ olefinic carbon of 8′‐apo‐β‐carotenoic acid. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of C‐14 and C‐13, H‐2‐labeled IKK inhibitor: [14C] and [13C4,D3]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido[3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide

[¹⁴C]‐N‐(6‐Chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5B ), an IKK inhibitor, was synthesized from [¹⁴C]‐barium carbonate in two steps in an overall radiochemical yield of 41%. The intermediate, [carboxyl‐¹⁴C]‐2‐methylnicotinic acid, was prepared by the lithiation and carbonation of 3‐bromo‐2‐methylpyridine. [¹³C₄,D₃]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5C ) was synthesized from [1,2,3,4‐¹³C₄]‐ethyl acetoacetate and [D₄]‐methanol in six steps in an overall yield of 2%. [¹³C₄]‐2‐methylnicotic acid, was prepared by condensation of [¹³C₄]‐ethyl 3‐aminocrotonate and acrolein, followed by hydrolysis with lithium hydroxide. Copyright © 2006 John Wiley & Sons, Ltd.     

From β‐N‐tert‐butyloxycarbonyl N‐carboxyanhydrides to β‐aminoacid derivatives

Abstract: β‐N‐tert‐butyloxycarbonyl‐N‐carboxyanhydrides are very reactive β‐amino acid derivatives. They react cleanly and smoothly with different nucleophiles like aminoesters, enolates, N‐methyl‐d ‐glucamine, amidoximes to afford in good to excellent yields peptides, β‐amino ketocompounds, β‐aminosugars and functionalized disubstituted 1,2,4‐oxadiazoles.     

13C‐ and 14C‐labelling of N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐methyleneamino] guanidinium acetate

N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐¹³C₄‐methyleneamino]guanidinium acetate has been synthesized by a four‐step procedure. This involved reduction of the Weinreb amide N,N′‐dimethyl‐N,N′‐dimethyloxybutane‐1,4‐diamide‐1,2,3,4‐¹³C₄ by Dibal‐H to give the corresponding unstable dialdehyde which is reacted in situ with 4‐chloroaniline to form 1‐(4‐chlorophenyl)‐1H‐pyrrole‐¹³C₄. This pyrrole analogue underwent a Vilsmeyer acylation with POCl₃/DMF followed by final reaction with aminoguanidine bicarbonate to produce the desired labelled compound with 99% atom ¹³C. By using DMF [α‐¹⁴C] a radio‐labelled analogue was synthesized with a specific activity of 60 mCi/mmol. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis and mycobacterial evaluation of 5‐substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido‐[2,3‐d]pyrimidin‐4(3H)‐one derivatives

5‐Substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido[2,3‐d]pyrimidin‐4(3H)‐one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte‐derived macrophage (THP‐1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95–125 µg/ml against M. tuberculosis but showed no activity against M. aurum, E. coli, and S. aureus, indicating selectivity towards slow‐growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l , showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole‐cell mycobacterial drug‐efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.     

N‐[9‐(ortho‐Fluorobenzyl)‐2‐Phenyl‐8‐Azapurin‐6‐yl]‐Amides as Potent and Selective Ligands for A1 Adenosine Receptors

A series of N‐[9‐(ortho‐fluorobenzyl)‐2‐phenyl‐8‐azapurin‐6‐yl]‐amides were synthesized and tested for their affinity toward A₁, A_2A, and A₃ adenosine receptor subtypes. Biological results demonstrated that the introduction of a fluorine atom at the ortho position of the 9‐benzyl group generally enhanced affinity toward A₁ subtype and did not significantly affect A_2A and A₃ affinity. Very interesting is the compound bearing a meta‐fluorophenyl substituent on the carbonyl carbon of the amide group, which shows significantly high A₁/A_2A‐A₃ selectivity. Compounds of this new series, together with the previously published analogs without the fluorine atom on the 9‐benzyl group, constituted the starting dataset for the development of QSAR models. The models obtained were able to rationally describe the affinity trends resulting from biological testing and to enable investigation of the role of different substituents on the 8‐azapurine scaffold, as well as the influence of the newly introduced fluorine atom on the benzyl moiety. The said QSAR models can also assist in the design of new compounds selectively active on A₁ adenosine receptors. Furthermore, a molecular docking study was carried out to assess hypothetical binding mode of N‐[9‐(ortho‐fluorobenzyl)‐2‐phenyl‐8‐azapurin‐6‐yl]‐amides to A₁ adenosine receptors.     

Synthesis of deuterium and 15N‐labelled 2,5‐Bis[5‐amidino‐2‐pyridyl]furan and 2,5‐Bis[5‐(methoxyamidino)‐2‐pyridyl]furan

The acetate salt of 2,5‐bis[5‐amidino‐2‐pyridyl]furan‐d₂/¹⁵N₂ ( 4) was synthesized from 2,5‐bis[5‐cyano‐2‐pyridyl]furan‐d₂ ( 2 ), through the bis‐O‐acetoxyamidoxime followed by hydrogenation. Compound 2 was obtained via a Stille coupling reaction of 6‐chloronicotinonitrile with 2,5‐bis[tri‐n‐butyltin]‐furan‐d₂ ( 1 ). 2,5‐bis[5‐amidino‐2‐pyridyl)furan‐d₆ ( 10) was synthesized from 2,5‐bis[5‐cyano‐2‐pyridyl)furan‐d₆ ( 9 ) via a direct reaction with lithium bis(trimethylsilyl)amide, followed by deprotection with ethanolic HCl. ¹⁵N and/or deuterium‐labelled methoxy‐amidines 5a ‐d₂/¹⁵N₂, 5b ‐d₈, 12 , 14 ‐d₆ were prepared in good yield via direct methylation of their respective diamidoximes with either dimethylsulfate‐d₀ or dimethylsulfate‐d₆ in DMF solution and using LiOH as a base. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of N1‐tritylethane‐1,1,2,2‐d4‐1,2‐diamine: a novel mono‐protected C‐deuterated ethylenediamine synthon

A convenient and high‐yield synthesis for N¹‐tritylethane‐1,1,2,2‐d₄‐1,2‐diamine, a novel mono‐protected ethylenediamine‐C‐d₄, is reported. N¹‐tritylethane‐1,1,2,2‐d₄‐1,2‐diamine was prepared in three steps from ethylene oxide‐d₄ in a combined yield in the range 68–76%. Also reported is a synthesis of ethylenediamine‐C‐d₄ in two steps from 1,2‐dibromoethane‐d₄ in a combined yield in the range 61–65%.     

Synthesis of deuterium‐labeled 3‐O‐methyldopa and 4‐O‐methyldopa

Concise methods for the synthesis of 4‐hydroxy‐3‐[²H₃]‐methoxyphenylalanine (3‐O‐[²H₃]‐methydopa) and 3‐hydroxy‐4‐[²H₃]‐methoxyphenylalanine (4‐O‐[²H₃]‐methydopa) are described. The 3‐O‐[²H₃]‐methydopa is a valuable internal standard for the tandem MS quantification of 3‐O‐methyldopa, a metabolite of value in the diagnosis of aromatic l‐amino acid decarboxylase (AADC) deficiency. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of [1‐13C]‐para‐xylene and [2‐13C]‐para‐xylene

An efficient synthesis of [1‐¹³C]‐para‐xylene ( 1a ) and [2‐¹³C]‐para‐xylene ( 1b ) is described. The incorporation of the label has been achieved by cyclocondensation of suitable 1,5‐bis(bromomagnesio)alkanes with either ethyl [1‐¹³C]acetate or ethyl [¹³C]formate which gave [ring‐¹³C]‐labelled dimethylcyclohexanols. Dehydration of these alcohols followed by dehydrogenation of the intermediate dimethylcyclohexenes furnished the title compounds in 32 and 40% overall yield, respectively. Copyright © 2001 John Wiley & Sons, Ltd.     

Preparation and in‐vitro Evaluation of 4‐Benzylsulfanylpyridine‐2‐carbohydrazides as Potential Antituberculosis Agents

A set of 4‐benzylsulfanylpyridine‐2‐carbohydrazides was synthesized and evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, non‐tuberculous mycobacteria, and multidrug‐resistant M. tuberculosis. The activities expressed as the minimum inhibitory concentration (MIC) fall into a range of 2 to 125 μmol/L, most often 4 to 32 μmol/L. The results revealed that the substituents on the benzyl moiety do not influence the antimycobacterial efficacy. The substances exhibited similar activities against sensitive and resistant strains of M. tuberculosis. Furthermore, compounds show low antiproliferative effect and cytotoxicity.