Synthetic strategies that enable the efficient and selective combination of different biologically active entities hold great promise for the development of multifunctional hybrid conjugates useful for biochemical and medical applications. Starting from side‐chain‐functionalized N(α)‐propargyl lysine derivatives, conjugates containing a 99mTc‐based imaging probe for SPECT and two different moieties (e.g., tumor‐targeting vectors, pharmacological modifiers, affinity tags, or second imaging probes) can be assembled using the CuI‐catalyzed alkyne–azide cycloaddition in efficient one‐pot protocols. This strategy was successfully applied to the preparation of a 99mTc‐labeled conjugate comprising a tumor‐targeting peptide sequence (bombesin(7–14)) and a low‐molecular‐weight albumin binder, a pharmacological modifier that prolongs the blood circulation time of the conjugate. Evaluation of the conjugate in vitro and in vivo provided promising results for its use as an imaging agent for the visualization of tumors positive for the gastrin‐releasing peptide receptor. The methodology presented herein provides an attractive synthetic tool for the preparation of multifunctional 99mTc‐based radiopharmaceuticals with significant potential for a multitude of applications. 相似文献
Tetralin‐1,4‐dione, the stable tautomer of dihydroxynaphthalene, was reduced with catecholborane in the presence of 3,3‐diphenyl‐1‐butyltetrahydro‐3H‐pyrrolo[1,2‐c][1,3,2]oxazaborole as catalyst to give enantiomerically highly enriched 4‐hydroxy‐1‐tetralone (99% ee) in an efficient one‐pot procedure. The R‐enantiomer provided a rapid access to sertraline while the S‐enantiomer was converted into 2‐epicatalponol and catalponol. A more selective enantioselective route to the antithermitic catalponol made use of the planar chiral tricarbonylchromium complex of hydroxytetralone. Its precursor chromium(tricarbonyl)[η6‐(1‐4,4a,8a)‐tetralin‐5,8‐dione] was obtained via direct complexation of 1,4‐dihydroxynaphthalene using chromium(tricarbonyl)‐ tris(ammonia) and boron trifluoride etherate as source of the chromium(tricarbonyl) fragment. Enolate prenylation was best carried out in the presence of a tetraamine ligand. Complete inversion of the stereogenic center bearing the prenyl group of the initially obtained tetralone complex was achieved via enolate formation followed by protonation. 相似文献
Radionuclide imaging of HER2 expression in tumours may enable stratification of patients with breast, ovarian, and gastroesophageal cancers for HER2-targeting therapies. A first-generation HER2-binding affibody molecule [99mTc]Tc-ZHER2:V2 demonstrated favorable imaging properties in preclinical studies. Thereafter, the affibody scaffold has been extensively modified, which increased its melting point, improved storage stability, and increased hydrophilicity of the surface. In this study, a second-generation affibody molecule (designated ZHER2:41071) with a new improved scaffold has been prepared and characterized. HER2-binding, biodistribution, and tumour-targeting properties of [99mTc]Tc-labelled ZHER2:41071 were investigated. These properties were compared with properties of the first-generation affibody molecules, [99mTc]Tc-ZHER2:V2 and [99mTc]Tc-ZHER2:2395. [99mTc]Tc-ZHER2:41071 bound specifically to HER2 expressing cells with an affinity of 58 ± 2 pM. The renal uptake for [99mTc]Tc-ZHER2:41071 and [99mTc]Tc-ZHER2:V2 was 25–30 fold lower when compared with [99mTc]Tc-ZHER2:2395. The uptake in tumour and kidney for [99mTc]Tc-ZHER2:41071 and [99mTc]Tc-ZHER2:V2 in SKOV-3 xenografts was similar. In conclusion, an extensive re-engineering of the scaffold did not compromise imaging properties of the affibody molecule labelled with 99mTc using a GGGC chelator. The new probe, [99mTc]Tc-ZHER2:41071 provided the best tumour-to-blood ratio compared to HER2-imaging probes for single photon emission computed tomography (SPECT) described in the literature so far. [99mTc]Tc-ZHER2:41071 is a promising candidate for further clinical translation studies. 相似文献
Non-invasive radionuclide imaging of human epidermal growth factor receptor type 2 (HER2) expression in breast, gastroesophageal, and ovarian cancers may stratify patients for treatment using HER2-targeted therapeutics. Designed ankyrin repeat proteins (DARPins) are a promising type of targeting probe for radionuclide imaging. In clinical studies, the DARPin [99mTc]Tc-(HE)3-G3 labeled using a peptide-based chelator His-Glu-His-Glu-His-Glu ((HE)3), provided clear imaging of HER2 expressing breast cancer 2–4 h after injection. The goal of this study was to evaluate if the use of cysteine-containing peptide-based chelators Glu-Glu-Glu-Cys (E3C), Gly-Gly-Gly-Cys (G3C), and Gly-Gly-Gly-Ser-Cys connected via a (Gly-Gly-Gly-Ser)3-linker (designated as G3-(G3S)3C) would further improve the contrast of imaging using 99mTc-labeled derivatives of G3. The labeling of the new variants of G3 provided a radiochemical yield of over 95%. Labeled G3 variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 1.9–5 nM. Biodistribution of [99mTc]Tc-G3-G3C, [99mTc]Tc-G3-(G3S)3C, and [99mTc]Tc-G3-E3C in mice was compared with the biodistribution of [99mTc]Tc-(HE)3-G3. It was found that the novel variants provide specific accumulation in HER2-expressing human xenografts and enable discrimination between tumors with high and low HER2 expression. However, [99mTc]Tc-(HE)3-G3 provided better contrast between tumors and the most frequent metastatic sites of HER2-expressing cancers and is therefore more suitable for clinical applications. 相似文献
A method for the preparation of 11α‐hydroxy derivatives of lithocholic and chenodeoxycholic acids, recently discovered to be natural bile acids, is described. The principal reactions involved were (1) elimination of the 12α‐mesyloxy group of the methyl esters of 3α‐acetate‐12α‐mesylate and 3α,7α‐diacetate‐12α‐mesylate derivatives of deoxycholic acid and cholic acid with potassium acetate/hexamethylphosphoramide; (2) simultaneous reduction/hydrolysis of the resulting △11‐3α‐acetoxy and △11‐3α,7α‐diacetoxy methyl esters with lithium aluminum hydride; (3) stereoselective 11α‐hydroxylation of the △11‐3α,24‐diol and △11‐3α,7α,24‐triol intermediates with B2H6/tetrahydrofuran (THF); and (4) selective oxidation at C‐24 of the resulting 3α,11α,24‐triol and 3α,7α,11α,24‐tetrol to the corresponding C‐24 carboxylic acids with NaClO2 catalyzed by 2,2,6,6‐tetramethylpiperidine 1‐oxyl free radical (TEMPO) and NaClO. In summary, 3α,11α‐dihydroxy‐5β‐cholan‐24‐oic acid and 3α,7α,11α‐trihydroxy‐5β‐cholan‐24‐oic acid have been synthesized and their nuclear magnetic resonance (NMR) spectra characterized. These compounds are now available as reference standards to be used in biliary bile acid analysis. 相似文献
Triterpenes of betulinic acid type exhibit many interesting biological activities. Therefore a series of new 3α‐hydroxy‐lup‐20(29)‐ene‐23,28‐dioic acid derivatives 2a—22 with putative pharmacological activities were synthesized. As starting compounds 3α‐hydroxy‐lup‐20(29)‐ene‐23,28‐dioic acid ( 1a ), isolated from Schefflera octophylla, or its 3‐O‐acetyl derivative 1b were used. Mono‐ and diesters ( 2a—b from 1a , and 4d from 4c ) were prepared with CH2N2. Oxidation of the isopropenyl side chain with OsO4 yielded the 20,29‐diols ( 4a—b from 1b , and 19 from 17 ), which were in the case of 4b further transformed to the 29‐norketones 8a/mdash;b . Oxidation of the isopropenyl side chain with m‐chloroperbenzoic acid afforded the 20,29‐epoxide 12 (from 1b ) and the 29‐aldehydes and a‐hydroxy aldehydes ( 13a—c from 2a, 14a—c from 2b , and 16a—c from 15a ). Ring A was modified by a tosylation—elimination sequence using p‐TsCl/NaOAc, which afforded diolefin 15a (from 2a ) with Δ2,20(29) double bonds or 23‐nor‐Δ3,20(29)diolefin 17 (from 1a ). Compounds 4b, 4c , and 8a were coupled with L ‐methionin, L ‐phenylalanin, L ‐alanin, L ‐serin, and L ‐glutaminic acid via amide bonds at positions 23 and 28 to afford the amino acid conjugates 5a—7b and 9a—11 . 相似文献
α‐Hydroxylamino phosphonates are synthesised in a one‐pot operation by three‐component coupling reactions of aldehydes, hydroxylamines and diethyl phosphite using 1‐butyl‐3‐methylimidazolium tetrafluoroborate ([bmim]BF4) or 1‐butyl‐3‐methylimidazolium hexafluorophosphate ([bmim]PF6) ionic liquids under mild and neutral conditions. The recovered ionic liquids can be recycled for four to five runs without loss of activity. 相似文献
A facile three‐step synthesis of racemic cyclopropylglycine in multigram quantities from inexpensive cyclopropyl methyl ketone has been elaborated. Enzymatic hydrolysis of the N‐Boc‐protected methyl ester of cyclopropylglycine 9 with the inexpensive enzyme papain from Carica papaya affords both enantiomers of cyclopropylglycine ( 8 ) with enantiomeric excesses of 99 % or better after deprotection under acidic conditions. Furthermore, the new cyclopropyl group‐containing building block methyl 2‐cyclopropyl‐2‐N‐Boc‐iminoacetate ( 13 ) was prepared by N‐chlorination and subsequent dehydrochlorination with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU). Addition of nucleophiles to 13 offers a ready access to an unusual, orthogonally bisprotected α,α‐diamino acid derivative and interesting components of rigid peptide backbones. 相似文献
Diagnosis and localization of bacterial infections remains a significant clinical challenge. Harnessing bacteria‐specific metabolic pathways, such as the maltodextrin transport mechanism, may allow specific localization and imaging of small or hidden colonies. This requires that the intrabacterial tracer accumulation provided by the transporter is matched by high serum stability of the tracer molecule. Herein, radiolabeled maltodextrins of varying chain lengths and with free nonreducing/reducing ends are reported and their behavior against starch‐degrading enzymes in the blood, which compromise their serum stability, is evaluated. Successful single‐photon emission computed tomography (SPECT) imaging is shown in a footpad infection model in vivo by using the newly developed model tracer, [99mTc] MB1143 , and the signal is compared with that of 18F‐fluorodeoxyglucose positron emission tomography ([18F]FDG‐PET) as a nonbacterial specific marker for inflammation. Although the [99mTc] MB1143 imaging signal is highly specific, it is low, most probably due to insufficient serum stability of the tracer. A series of stability tests with different 18F‐labeled maltodextrins finally yielded clear structural guidelines regarding substitution patterns and chain lengths of maltodextrin‐based tracers for nuclear imaging of bacterial infections. 相似文献
The reaction conditions for the conversion of 6‐endo‐tosyloxybicyclo[2.2.2]octan‐2‐one ( 7b ) into 6‐exo‐acetoxy ( 8b ) and 6‐exo‐benzoyloxybicyclo[2.2.2]octan‐2‐one ( 8a ), respectively, were improved. Thus known 6‐endo‐tosyloxy‐bicyclo[2.2.2]octan‐2‐ones (+)‐(1RS,6SR,8SR,11RS)‐11‐[(4‐toluenesulfonyl)oxy]tricyclo[6.2.2.01,6]dodecan‐9‐one ( 1a ), 13‐methyl‐15‐oxo‐9β,13b‐ethano‐9β‐podocarpan‐12β‐yl‐4‐toluenesulfonate ( 3a ), and methyl (13R)‐16‐oxo‐13‐[(4‐tolylsulfonyl)oxy]‐17‐noratisan‐18‐oate ( 5 ), were converted,in comparable yields, as previously recorded, but much shorter times, into (+)‐(1RS,6SR,8SR,11SR)‐11‐(benzoyloxy) tricyclo[6.2.2.01,6]dodecan‐9‐one ( 2 ), 13‐methyl‐15‐oxo‐9β,13β‐ethano‐9β‐podocarpan‐12α‐yl benzoate ( 4 ), and methyl (13S)‐13‐(benzoyloxy)‐16‐oxo‐17‐noratisan‐18‐oate ( 6 ), respectively. 相似文献
A new tridentate bifunctional chelator, N‐(‐2‐picolyl)(‐4‐hydroxy)(‐3‐amino)benzoic acid (PHAB), was designed to efficiently coordinate the [99mTc(CO)3]+ core and facilitate coupling reactions to biomolecules. The chelator can be procured in the form of the corresponding benzotriazole ester (PHAB‐OBT), which can be stored and used as a bioconjugation kit. PHAB‐OBT reacts with modified carbohydrates with high selectivity and efficiency in a single step in both aqueous and organic media. As is desirable for a kit, no complicated chemical bench work is required. Glycoconjugate postlabeling resulted in neutral radiolabeled glycans with high radiochemical yields. Prelabeling approaches were assessed by successive reaction of PHAB‐OBT with the [99mTc(CO)3]+ core and a modified galactose model. The radiolabeled galactose was obtained in 84 % yield as defined by HPLC analysis. Biodistribution of the radioactive 99mTc‐labeled chelator, as well as the glycoconjugates, were examined in mice. Noticeably different biodistribution patterns were observed that reflect trends in the uptake of carbohydrate analogues by various organs. 相似文献
A method for the synthesis of two (23R)‐ and (23S)‐epimeric pairs of 23‐fluoro‐3α,7α,12α‐trihydroxy‐5β‐cholan‐24‐oic acid and 23‐fluoro‐3α,7α‐dihydroxy‐5β‐cholan‐24‐oic acid is described. The key intermediates, 23,24‐dinor‐22‐aldehyde peracetates were prepared from cholic and chenodeoxycholic acids via the 24‐nor‐22‐ene, 24‐nor‐22ξ,23‐epoxy, and 23,24‐dinor‐22‐aldehyde derivatives. The Horner–Wadsworth–Emmons reaction of the 23,24‐dinor‐22‐aldehydes using triethyl 2‐fluoro‐2‐phosphonoacetate in the presence of LiCl and 1,8‐diazabicyclo[5,4,0]undec‐7‐ene (DBU), and subsequent hydrogenation of the resulting 23ξ‐fluoro‐22‐ene ethyl esters, followed by hydrolysis, gave a mixture of the epimeric (23R)‐ and (23S)‐fluorinated bile acids which were resolved efficiently by preparative RP‐HPLC. The stereochemical configuration of the fluorine atom at C‐23 in the newly synthesized compounds was confirmed directly by the X‐ray crystallographic data. The 1H and 13C NMR spectral differences between the (23R)‐ and (23S)‐epimers were also discussed. 相似文献
Overexpression of the gastrin‐releasing peptide receptor (GRPR) in a variety of human carcinomas has provided a means of diagnosis and treatment. Previously we reported a metabolically stable (NαHis)Ac‐βAla‐βAla‐[Cha13,Nle14]BBS(7–14) analogue with high affinity for the GRPR. We have also shown that the biodistribution pattern of this fairly lipophilic, radiolabeled peptide can be enhanced by glycation, which is easily carried out by CuI‐catalyzed cycloaddition. Herein, we further elaborate this “click approach” in the synthesis of a new series of triazole‐based chelating systems as alternatives to the (NαHis)Ac chelator for labeling with the 99mTc(CO)3 core. The bombesin analogues, containing these new chelating systems, were evaluated with regard to their synthesis and in vitro and in vivo properties, and were compared with their (NαHis)Ac counterparts. The influence of the chelator on biodistribution properties was less than that of glycation, which clearly improved the tumor‐to‐background ratios.相似文献
Assemble & chelate : Click chemistry enables the efficient and selective synthesis of structurally diverse conjugates containing a central di‐1,2,3‐triazole chelator for complexation with [99mTc(CO)3]+. Use of appropriate building blocks allows the modulation of pharmacological relevant characteristics of the conjugate, or the introduction of secondary probes suitable for imaging modalities other than single photon emission computed tomography (SPECT).
The direct organocatalytic enantioselective epoxidation of α,β‐unsaturated aldehydes with different peroxides is presented. Proline, chiral pyrrolidine derivatives, and amino acid‐derived imidazolidinones catalyze the asymmetric epoxidation of α,β‐unsaturated aldehydes. In particular, protected commercially available α,α‐diphenyl‐ and α,α‐di(β‐naphthyl)‐2‐prolinols catalyze the asymmetric epoxidation reactions of α,β‐unsaturated aldehydes with high diastereo‐ and enantioselectivities to furnish the corresponding 2‐epoxy aldehydes in high yield with up to 97:3 dr and 98 % ee. The use of non‐toxic catalysts, water and hydrogen peroxide, urea hydroperoxide or sodium percarbonate as the oxygen sources could make this reaction environmentally benign. In addition, one‐pot direct organocatalytic asymmetric tandem epoxidation‐Wittig reactions are described. The reactions were highly diastereo‐ and enantioselective and provide a rapid access to 2,4‐diepoxy aldehydes. Moreover, a highly stereoselective one‐pot organocatalytic asymmetric cascade epoxidation‐Mannich reaction, which proceeds via the combination of iminium and enamine activation, is presented. The mechanism and stereochemistry of the amino acid‐ and chiral pyrrolidine‐catalyzed direct asymmetric epoxidation of α,β‐unsaturated aldehydes are also discussed. 相似文献