Synthesis and biodistribution of p-iodophenyl analogues of a naturally occurring imidazole ribonucleoside

A model iodophenyl imidazole ribonucleoside has been synthesized to study biodistribution properties in laboratory animals. The key intermediate 5-amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-[N-(p-iodophenyl)carboxamide] ( 5 ) was synthesized by coupling N-succinimidyl-5-amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxylate ( 4 ) and p-iodoaniline. Deacetylation of the intermediate compound gave 5-amino-1-β-D-ribofuranosylimidazole-4-[N-(p-iodophenyl)]carboxamide ( 6 ). Ring annulation via diazotization of 5 gave 7-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazo[4,5-d]-v-triazin-[3-N-(p-iodophenyl)]-4-one ( 7 ). Subsequent deacetylation of 7 afforded 7-β-D-ribofuranosylimidazo[4,5-d]-v-triazin-[3-N-(p-iodophenyl)]-4-one ( 8 ). The radiolabeled compounds, [¹²⁵I] 5 and [¹²⁵I] 6 were prepared in a manner similar to the corresponding unlabeled compounds except that p-[¹²⁵I]iodoaniline was used for coupling with 4 . Biodistribution studies of iodine-125-labeled 5 and 6 were performed in female Fischer rats and tumor bearing nude mice. Compound 6 showed uptake in the brain and proliferating tissues such as tumor and bone-marrow.     

Potential cerebral perfusion agents. Synthesis and evaluation of new radioiodinated barbituric acid analogs

Two new ¹²⁵I-labeled barbituric acid analogs, 5-ethyl-5-(E-1-iodo-1-penten-5-yl)2-thiobarbituric acid ( 4 ) and 5-ethyl-5-( m -iodophenyl)barbituric acid ( 7 ), have been prepared and evaluated in rats as potential cerebral perfusion agents. Annulation of 2-ethyl-2-(E-1-iodo-1-penten-5-yl)malonate ( 3 ) with thiourea in the presence of sodium ethoxide gave the 5-ethyl-5-(E-1-iodo-1-penten-5-y1)-thiobarbituric acid ( 4 ). Diethyl 2-ethyl-2-phenyl-malonate was treated with thallium(III) trifluoroacetate followed by addition of aqueous potassium iodide to provide diethyl 2-ethyl-2-(m-iodophenyl)malonate ( 10 ). The malonic ester derivative 10 was condensed with urea in the presence of sodium hydride to give the desired 5-ethyl-5-(m-iodophenyl)barbituric acid ( 7 ), and a decarbethoxylation product, 2-(m-iodophenyl)butyric acid ( 11 ). Iodine-125-labeled 4 and 7 were synthesized in the same manner and the tissue distribution of these new agents evaluated in rats. Both [¹²⁵I] 4 and [¹²⁵I] 7 showed high brain uptake. Significant in vivo deiodination was detected with [¹²⁵I] 4 whereas [¹²⁵I] 7 was found to be stable to deiodination.     

Potential cerebral perfusion agents. Synthesis and evaluation of berberine analogues

The synthesis and tissue distribution studies in rats of tetra[³H]-hydroberberine ([³H] 2 ) and 8-(p-[¹²⁵I]iodobenzyl)tetrahydroberberine ([¹²⁵I] 6 ) are described. Compound 2 was synthesized by sodium borohydride reduction of berberine hydrochloride ( 1 ). Treatment of berberine hydrochloride with p-bromo-benzylmagnesium bromide gave 8-(p-bromobenzyl)dihydroberberine ( 4 ) which after sodium borohydride reduction and iodine-125 bromine exchange gave [¹²⁵I] 6 . The unsubstituted tetrahydro compound [³H] 2 showed significantly higher brain uptake (2.2% dose/gm after 5 minutes) as compared to the corresponding 8-substituted derivative [¹²⁵I] 6 . Both radiolabeled compounds washed out from the brain relatively quickly.     

Photolytic Reactions of (o-Allylbenzyl)dicarbonyl(η5-cyclopentadienyl)iron

Photolysis of (o-allylbenzyl)dicarbonyl(η⁵-cyclopentadienyl)iron ( 4 ) at 20° in CH₂Cl₂ leads to carbon-monoxide loss followed by intramolecular complexation to [η²-(o-allylbenzyl)]carbonyl(η⁵-cyclopentadienyl)iron ( 13 ). At 50° in C₆D₆, a photochemical rearrangement proceeds forming carbonyl (η⁵-cyclopentadienyl){η³-[3-(2-methylphenyl)allyl]}iron ( 17 ). Depending on the temperature, photolysis of 4 leads to intermolecular reactions at the benzylic or allylic position of the π complexes 13 and 17 , respectively.     

New azomycin acyclonucleoside. Synthesis and biodistribution of radiohalogenated analogues in tumor-bearing mice

The design, synthesis and biological activities of several acyclonucleoside analogues related to misoni-dazole are described. The hydroxy- 5 , bromo- 6 , iodo- 7 , and fluoro- 8 derivatives of ethoxymethylazomycin and iodopropenyloxymethylazomycin ( 12 ) have been prepared. Alkylation of silylated azomycin with haloethoxy-methylene chloride gave the corresponding acyclonucleosides. Similarly, propargyloxymethylene chloride gave propargyloxymethylazomycin ( 10 ), which after hydrostannylation and subsequent iododestannylation yielded iodopropenyloxymethylazomycin ( 12 ). The radiolabeled [¹²⁵I] or [¹⁸F] compounds were prepared from the corresponding substrates. Biodistribution results of the radiolabeled analogues in mice showed that compound 7 had good tumor uptake (2.0% injected dose/g at 1 hour). The high radioactive levels in blood and stomach, however, were perhaps due to in vivo deiodination or metabolism. Compound [¹²⁵I]- 12 showed the highest tumor uptake (4.8 and 3.6% injected dose/g at 1 and 4 hours respectively) of all of the compounds tested. Relatively low thyroid uptake of radioactivity in mice dosed with compound [¹²⁵I]- 12 indicates significantly reduced in vivo deiodination in comparison to compound [¹²⁵I]- 7.     

Synthesis of 2,3‐Disubstituted 5‐Iodo‐1H‐Pyrrolo[2,3‐b]pyridines via Fischer Cyclization

A simple and convenient procedure for the preparation of some unknown 2,3‐disubstituted 5‐iodo‐1H‐pyrrolo[2,3‐b ]pyridines from readily available starting materials by Fischer indole cyclization in polyphosphoric acid is described. The present methodology provides an alternative synthetic approach to the synthesis of 5‐iodo‐7‐azaindole scaffold. All synthesized compounds were characterized by IR, MS, ¹H and ¹³C NMR, and elemental analysis.     

Enantioselective Copper-Catalyzed 1,4-Addition of Grignard Reagents to α,β-Unsaturated Carbonyl Compounds

The enantioselective copper-catalyzed 1,4-addition of Grignard reagents to α,β-unsaturated carbonyl compounds was studied with the following Cu^I compounds as catalyst precursor and 1,2:5,6-di-O-isopropylidene-3-thio-α-D -glucofuranose (Hsiig) as chiral ligand: CuI, iodo[bis(dibutylsulfide)]copper(I), [Cu(siig)], [Cu(siig)(pp)] (pp =1,2-bis)(diphenylphosphinoethene), and tetrakis[iodo(tributylphosphine)]copper(I). The addition of BuMg halides to cyclohex-2-en-1-one was tested under several reaction conditions. The chemical yields and regioselectivities for this reaction were, in all cases, larger than 90 and 98%, respectively, and independent of the experimental conditions. The enantioselectivity was strongly dependent on the reaction conditions and reached a maximum of 60%. Several other substrates were also tested in the above reaction. The X-ray crystal structure for [Cu(siig)(pp)] was determined by X-ray crystallography.     

The synthesis of novel polycyclic heterocyclic ring systems. 2. Naphmo[2,1-b:4,3-g]bisbenzo[b]thiophene

The novel polycyclic heterocyclic ring system, naphtho[2,1-b:4,3-g]bisbenzo[b]thiophene was synthesized from 5-[2-(2-bromo-3-thienyl)ethenyl]naphtho[2,1-b][1]benzothiophene. The assignment of its ¹H and ¹³C nmr spectra was also accomplished by utilizing two-dimensional nmr methods.     

Über die Biosynthese von γ-Dodecanolacton in reifenden Früchten: Aroma-Komponenten der Erdbeere (Fragaria ananassa) und des Pfirsichs (Prunus persica)

On the Biosynthesis of γ-Dodecanolactone in Ripening Fruits: Flavor Constituents from Strawberries (Fragaria ananassa) and Peaches (Prunus persica) Administration of deuterium-labelled 9,10-expoxy[8,8-²H₂]heptadecanoic acid 8a / b and 9,10-dihydroxy-[8,8-²H₂]methylheptadecanoate 9 as lower analogues of oleic acid 1 to ripening fruits of strawberries (Fragaria ananassa) and peaches (Prunus persica) results in the emission of labelled γ-undecanolactone ( 5 ) as the lower analog of γ-dodecanolactone ( 2 ). The transformation proceeds with loss of a single D-atom from C(8) of the precursors. Early precursors, like the C₁₇-epoxy-acids 8a / b yield (4R)-γ-undecanolactone ( 5 ) of high enantiomeric purity, while later intermediates results in (4R)-γ-undecanolactone ( 5 ) of low purity. The data support a biosynthetic sequence involving the consecutive action of an epoxide hydrolase and β-oxidation to generate the correct chain length of the lactone percursor. The final steps proceed via cyclization of the 3,4-dihydroxyundecanoic acid 13 to the 3-hydroxy-γ-undecanolactone 14 . Elimination of H₂O and reduction of the intermediate γ-undec-2-enolactone 15 terminate the biosynthesis of 5 . The sequence is representative for the biosynthesis of naturally occurring γ-dodecanolactone ( 2 ).     

Studies on C-heterocyclic tin compounds. The synthesis and spectral characterization of some thienyl tetraorganotin(IV) compounds

The synthesis of a series of tetraorganotin(IV) compounds containing selectively the 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 5-t-butyl-2-thienyl, 4-methyl-2-thienyl and 3-(2-pyridyl)-2-thienyl groups [L], of formula R_4-nSn[L]_n (R = Ph, p-tolyl, Me, cyclopentyl, cyclohexyl; n = 1–4) is reported. Features of structural interest deduced from ^119mSn Mössbauer and NMR (¹³C and ¹¹⁹Sn modes) spectra are considered.     

Synthesis and 13C-NMR study of novel pyrazolo[5′,1′:3, 4][1, 2, 4]triazino[5, 6-d]pyrimidines

The pyrazolo[5′, 1′:3, 4][1, 2, 4]triazino[5, 6-d]pyrimidines 5a-c, 6 were synthesized from the pyrazolo[5, 1-c]-[1, 2, 4]triazines 1a, c and the ring carbon signals of 5a-c, 6 were assigned by the aid of coupling constant [J( 13 C-¹H)] data.     

Potential cerebral perfusion agents. Synthesis and evaluation of a 1,4-disubstituted dihydropyridine analogue

The synthesis of a 1,4-disubstituted dihydropyridine, 1-(E-1[¹²⁵I]iodo-1-penten-5-yl)-4-(β-N-acetylaminoethyl)-1,4-dihydropyridine ([¹²⁵I] 10 ), is described. Acetylation of 4-(β-aminoethylpyridine) with acetic anhydride followed by condensation with E-1-borono-5-iodo-1-pentene ( 7 ) gave 1-(E-1-borono-1-penten-5-yl)-4-(β-N-acetylaminoethyl)pyridinium iodide ( 8 ). Chloramine-T and sodium iodide iodination of 8 gave the corresponding E-1-iodo compound 9 which was reduced with sodium borohydride to furnish 1-(E-1-iodo-1-penten-5-yl)-4-(β-N-acetylaminoethyl)-1,4-dihydropyridine ( 10 ). The corresponding radioiodinated compound was prepared similarly using Na[¹²⁵I]. The tissue distribution studies in rats indicate that [¹²⁵I] 10 crosses the blood brain barrier (0.49% dose/g in the brain) but gradually washes out from the brain.     

A CONVENIENT SYNTHESIS OF 4-SUBSTITUTED-4′-(2-THIENYL)- 2,2′-BITHIAZOLES AS POTENTIAL PHOTOTOXIC AGENTS

Alpha-tosyloxyacetylthiophene (3), obtained by the hypervalent iodine oxidation of 2-acetylthiophene (2) using [hydroxy- (tosyloxy)iodo]benzene (HTIB), on treatment with rubeanic acid exclusively generates 4-(2-thienyl)thiazole-2-thiocarboxamide (4) which upon subsequent treatment with a variety of alpha-tosyloxyketones (5) affords the title compounds (6) in excellent yields.     

Radioiodinated fatty acids for myocardial scanning

A simple method for labelling fatty acids with iodine radionuclides is reported. 16-[¹²³I]iodohexadecanoic, 17-[¹²³I]iodoheptadecanoic and 18-[¹²³I]iodooctadecanoic acids were prepared by exchange reaction in ethanolic solution. The best results in biodistribution studies were obtained with 18-[¹²³I]iodooctanoic acid.     

Reactions of coordinated molecules : XXV. The preparation of several bis[(hydroxy)(methyl)]carbenoid complexes of rhenium

When the rhenium(I) complexes, XRe(CO)₅ (where X is Cl, Br or I), are treated with two molar-equivalents of methyllithium, dianionic complexes of the type, fac-(OC)₃(X)Re[C(CH₃)O]₂^–, are formed. The diprotonation of these dianions with HX affords the neutral, bis-carbenoid complexes, fac-(OC)₃(X)Re[C(CH₃)(OH)]₂. When X is methyl, the reaction with methyllithium gives only a monoanion. The iodo, bis-carbenoid complex decomposes in solution with the elimination of acetaldehyde and with the formation of the known dimeric complex, [Re(CO)₄I]₂. The X-ray molecular structure determination of this dimeric complex is reported. The ^13C NMR data of the chloro and bromo biscarbenoid complexes are also presented.     

The syntheses and NMR spectra of the twelve isomeric thieno[b]fused naphthyridines

Through the use of Pd(0)-catalyzed couplings between 2-(2-trimethylstannyl-3-pyridyl)-1,3-dioxolane, 3-trimethylstannyl-2-pyridine carboxaldehyde, 3-trimethylstannyl-4-pyridine carboxaldehyde and 4-trimethyl-stannyl-3-pyridine carboxaldehyde with t-butyl-N-(3-bromo-2-thienyl)carbamate, t-butyl-N-(2-bromo-3-thienyl)carbamate and t-butyl-N-(4-bromo-3-thienyl)carbamate in N,N-dimethylformamide at 100°, using cupric oxide as a coreagent, all twelve isomeric thieno[b]naphthyridines have been synthesized in an one-pot procedure. A detailed study of the ¹H and ¹³C nmr spectra of these isomers has been undertaken.     

Synthesis,characterization, and biological activities of some novel thienylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines and related heterocycles

3-Cyano-5-ethoxycarbonyl-6-methyl-4-(2′-thienyl)-pyridine-2(1H)-thione ( 1 ) is synthesized and reacted with chloroacetamide or chloroacetonitrile to give 3-amino-5-ethoxycarbonyl-6-methyl-4(2′-thienyl)-thieno[2,3-b]pyridine-2-carboxamide 3a or its 2-carbonitrile analog 3b , respectively. Cyclocondensation of 3a with triethylorthoformate produced the corresponding pyridothienopyrimidineone 4 , which on heating with phosphorus oxychloride gave 4-chloropyrimidine derivative 5 . Compound 5 was used as key intermediate for synthesizing compounds 6 , 9 , 10 , 11 , and 12 upon treatment with some nucleophilic reagents such as thiourea, 5-phenyl-s-triazole-3(1H)-thione, piperidine, morpholine, or hydrazine hydrate, respectively. Reaction of pyridothienopyrimidinethione 6 with N-(4-tolyl)-2-chloroacetamide or ethyl bromoacetate afforded the corresponding S-substituted methylsulfanylpyrimidines 7 or 8 . The condensation of 3b with triethylorthoformate gave azomethine derivative 13 , which was reacted with hydrazine hydrate to give ethyl 3-amino-3,4-dihydro-4-imino-7-methyl-9-(2′-thienyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-8-carboxylate ( 14 ). Compounds 12 and 14 were used as precursors for synthesizing other new thienylpyridothienopyrimidines as well as isomeric thienyl-s-triazolopyridothieno- pyrimidines. All synthesized compounds were characterized by elemental and spectral analyses such as IR, ¹H NMR, and ¹³C NMR. In addition, majority of synthesized compounds were tested for their antifungal activity against five strains of fungi. Moreover, compounds 3a , 5 , 6 , 8 , and 22 were screened for their anticancer activity against HEPG-2 and MCF-7 cell lines.     

Synthesis and Physicochemical Characterization of New C‐Functionalized Derivatives of the Gadolinium(III) Complex with 3,6,10‐Tris(carboxymethyl)‐3,6,10‐triazadodecanedioic Acid (H5ttda) Exhibiting Fast Water Exchange – Potential Paramagnetic Reporters for Molecular Imaging

To confirm the observation that [Gd(ttda)] derivatives have a significantly shorter residence time τ_M of the coordinated H₂O molecule than [Gd(dtpa)], four new C‐functionalized [Gd(ttda)] complexes, [Gd(4‐Me‐ttda)] ( 1 ), [Gd(4‐Ph‐ttda)] ( 2 ), [Gd(9‐Me‐ttda)] ( 3 ), and [Gd(9‐Ph‐ttda)] ( 4 ), were prepared and characterized (H₅ttda=3,6,10‐tris(carboxymethyl)‐3,6,10‐triazadodecanedioic acid; H₅dtpa=3,6,9‐tris(carboxymethyl)‐3,6,9‐triazaundecanedioic acid). The temperature dependence of the proton relaxivity for these complexes at 0.47 T and of the ¹⁷O transverse relaxation rate of H₂¹⁷O at 7.05 T confirm that the proton relaxivity is not limited by the H₂O‐exchange rate. The residence time of the H₂O molecules in the first coordination sphere of the gadolinium complexes at 310 K, as calculated from ¹⁷O‐NMR data, is 13, 43, 2.9, and 56 ns for 1, 2, 3 , and 4 , respectively. At 310 K, the longitudinal relaxivity of 2 is higher than for the parent compound [Gd(ttda)] and the other complexes of the series. The stability of the new compounds was studied by transmetallation with Zn²⁺ ions. All the new complexes are more stable than the parent compound [Gd(ttda)].     

Chiral [2H]-Labelled Methylene Groups in Trienoic- and Dienoic Fatty Acids: A Facile Approach via Asymmetric Epoxidation of [2H] Allyl Alcohols

Chiral [²H] -labelled methylene groups flanked by two double bonds within (poly)unsaturated fatty acids are readily available from trans-2,3-epoxy[2,3-²H₂] alk-4-yn-l-ols, obtained in their turn by asymmetric epoxidation of the corresponding (E)-[2,3-²H₂] alk-2-en-4-yn-l-ols (see Scheme 3). The procedure is exemplified for (8S,3Z,6Z,9Z)-[7,8-²H₂] trideca-3,6,9-trienoic acid ((8S)- 11 ) and (8R)- 11 (Scheme 4) as well as for (5S,3Z,6Z)-[4,5^?2H₂]deca-3,6-dienoic acid ((5S)- 13 ) and (5R)- 13 (Scheme 5).     

Kinetics of 17-(123I) iodoheptadecanoic acid in myocardium of rats

Myocardial uptake and turnover of 17-(¹²³I)-iodoheptadecanoic acid, injected i.v., was studied in rats. Kinetics of radioactivity incorporated into myocardial tissue and heart lipids as well as myocardial radioactivity recovered as¹²³I iodide were determined. Maximal heart uptake of IHA (7.9% dose/g heart) was observed as early as 30 sec., p.i., followed by mono-component elimination period. Already 10 to 30 sec p.i. 70 to 80% of total myocardial radioactivity was recovered as¹²³I iodide. IHA was incorporated only in modest amounts into myocardial phospholipids and triglycerides. Time course of total myocardial radioactivity grossly paralleled that recovered as¹²³I iodide. These findings indicate stringent limitations in utility of IHA as a tracer for assessment of β-oxidation.