RESUMO
Strigolactones (SLs) are new plant hormones with various developmental functions. They are also soil signaling chemicals that are required for establishing beneficial mycorrhizal plant/fungus symbiosis. In addition, SLs play an essential role in inducing seed germination in root-parasitic weeds, which are one of the seven most serious biological threats to food security. There are around 20 natural SLs that are produced by plants in very low quantities. Therefore, most of the knowledge on SL signal transduction and associated molecular events is based on the application of synthetic analogues. Stereochemistry plays a crucial role in the structure-activity relationship of SLs, as compounds with an unnatural D-ring configuration may induce biological effects that are unrelated to SLs. We have synthesized a series of strigolactone analogues, whose absolute configuration has been elucidated and related with their biological activity, thus confirming the high specificity of the response. Analogues bearing the R-configured butenolide moiety showed enhanced biological activity, which highlights the importance of this stereochemical motif.
Assuntos
Lactonas/farmacologia , Reguladores de Crescimento de Plantas/química , Reguladores de Crescimento de Plantas/farmacologia , Germinação/efeitos dos fármacos , Lactonas/química , Estrutura Molecular , Raízes de Plantas/química , Plantas Daninhas/efeitos dos fármacos , Sementes/efeitos dos fármacos , Relação Estrutura-Atividade , SimbioseRESUMO
In this study the hydroboration reaction has been exploited to produce in only four steps a new lipophilic GdBNCT/MRI agent (PB01). As a matter of fact, the formation of a new BC bond to link the decaborane with the lipophilic moiety greatly simplifies the synthesis of PB01 with respect to the previously reported dual agents. The complexes obtained (PB01a and PB01b) have been fully characterised from the relaxometric point of view and, after disaggregation with HPßCD, both isomers display high affinity for low density lipoproteins (LDLs) that can be exploited as specific carriers of these therapeutic and diagnostic agents for tumour cells. The LDL loading capacity is different for the two isomers. In fact, LDL can be loaded with 75 and 300 units of PB01a and PB01b, respectively, and for this reason, the isomer PB01b results to be the best candidate to perform MRI guided BNCT.
Assuntos
Compostos de Boro/química , Meios de Contraste/síntese química , Imageamento por Ressonância Magnética , Terapia por Captura de Nêutron , Meios de Contraste/química , Estrutura MolecularRESUMO
The gold(I)-catalyzed cyclization of N-Boc-protected 6-alkynyl-3,4-dihydro-2H-pyridines, prepared by the Sonogashira coupling of lactam-derived enol triflates or phosphates, provides vinylogous amides, which are useful intermediates in the synthesis of natural compounds. The Au(I)-catalyzed reaction is carried out with Ph3PAuOTf as a catalyst and proceeds via a 6-endo-dig cyclization to form a vinylgold species that after protodeauration generates a cyclic carbamate intermediate. This intermediate is in most cases not isolated, but the addition of a base to the reaction mixture rapidly and quantitatively delivers the target vinylogous amide. The first synthesis of a natural compound from Sonneratia hainanensis has been accomplished by this approach.
RESUMO
Since the first report and due to its handiness and wide scope, the Suzuki-Miyaura (SM) cross coupling reaction has become a routine methodology in many laboratories worldwide. With respect to other common transition metal catalyzed cross couplings, the SM reaction has been so far less exploited as a tool to introduce an acyl function into a specific substrate. In this review, the various approaches found in the literature will be considered, starting from the direct SM acylative coupling to the recent developments of cross coupling between boronates and acyl chlorides or anhydrides. Special attention will be dedicated to the use of masked acyl boronates, alkoxy styryl and alkoxy dienyl boronates as coupling partners. A final section will be then focused on the acyl SM reaction as key synthetic step in the framework of natural products synthesis.
Assuntos
Cetonas/síntese química , Acilação , Amidas/síntese química , Ácidos Borônicos/química , Catálise , Cobre/química , Compostos Heterocíclicos/síntese química , Paládio/químicaRESUMO
In this study, the Huisgen reaction has been used to functionalise a carborane cage with a lipophilic moiety and a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) ligand to obtain a new Gd boron neutron-capture therapy (BNCT)/magnetic resonance imaging (MRI) agent. The introduction of the triazole units has been accomplished under both heterogeneous conditions, by the use of a Cu-supported ionic-liquid catalyst, and homogeneous conditions. The ability of the Gd complex of the synthesised ligand to form stable adducts with low-density lipoproteins (LDLs) has been evaluated and then MRI has been performed on tumour melanoma cells incubated in the presence of a Gd-complex/LDL imaging probe. It has been concluded that the high amount of intracellular boron necessary to perform BNCT can be reached even in the presence of a relatively low-boron-containing LDL concentration.
Assuntos
Boranos/química , Terapia por Captura de Nêutron de Boro/métodos , Química Click , Gadolínio/química , Imageamento por Ressonância Magnética/métodos , Animais , Transporte Biológico , Linhagem Celular Tumoral , Técnicas de Química Sintética , Cobre/química , Ciclização , Gadolínio/metabolismo , Gadolínio/uso terapêutico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipoproteínas LDL/metabolismo , Melanoma Experimental/diagnóstico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , CamundongosRESUMO
An initial study has been accomplished into the synthetic feasibility of the preparation of diarylcarbenium salt via the direct coupling of aryl (or heteroaryl) aldehydes and arenes (or heteroaryl analogues) in the presence of a strong organic Brønsted acid. A number of stabilized aryl or heteroaryl(3-indolyl)carbenium ions, never previously prepared in the solid state, have been isolated in excellent yields as highly stable o-benzenedisulfonimide salts and have been fully characterized. Their purity has been proven by spectroscopic methods and chemical reduction with NaBH(4). An X-ray crystal structure analysis has been performed on one of the products: an azafulvenium species was shown to be the exclusive structure in the solid state.
RESUMO
Boron neutron capture therapy (BNCT) is based on the capture of thermal neutrons by boron 10 ((10)B) nuclei that have been selectively delivered to tumor cells. The amount of 10-30 µg of boron for g of tumor mass is needed to attain an acceptable therapeutic advantage. Despite that the potentialities of BNCT have been demonstrated in several preclinical studies, this technique has not yet been fully accepted in the armory of tools for tumor treatment. This is partly due to the differences in the uptake and distribution of (10)B among patients and also to the uncertainty found in the determination of tumor-to-blood (10)B concentration ratio. Attention is now being payed to use the main imaging techniques to determine the in vivo biodistribution of BNCT agents. Most of the work has been devoted to the most promising BNCT agents, namely BPA, BSH and carborane derivatives. This review surveys studies carried out over the last decade, and outlines the role that NMR, PET and SPECT imaging may have to improve the efficacy of BNCT.
Assuntos
Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Terapia por Captura de Nêutron de Boro/métodos , Neoplasias/radioterapia , Animais , Compostos de Boro/química , Humanos , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular/métodos , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
An efficient and practical synthesis of triaryl and trisindolylmethanes is reported via the bisarylation of aryl aldehydes with activated arenes. The new method features mild solvent-free reaction conditions, in most cases nearly stoichiometric reagent ratios, catalytic amount of the readily available, easily-handled, recoverable and reusable Brønsted acid catalyst o-benzenedisulfonimide.
Assuntos
Metano/síntese química , Metano/análogos & derivados , Metano/química , Estrutura Molecular , EstereoisomerismoRESUMO
The upregulation of low-density lipoprotein (LDL) transporters in tumour cells has been exploited to deliver a sufficient amount of gadolinium/boron/ligand (Gd/B/L) probes for neutron capture therapy, a binary chemio-radiotherapy for cancer treatment. The Gd/B/L probe consists of a carborane unit (ten B atoms) bearing an aliphatic chain on one side (to bind LDL particles), and a Gd(III)/1,4,7,10-tetraazacyclododecane monoamide complex on the other (for detection by magnetic resonance imaging (MRI)). Up to 190 Gd/B/L probes were loaded per LDL particle. The uptake from tumour cells was initially assessed on cell cultures of human hepatoma (HepG2), murine melanoma (B16), and human glioblastoma (U87). The MRI assessment of the amount of Gd/B/L taken up by tumour cells was validated by inductively coupled plasma-mass-spectrometric measurements of the Gd and B content. Measurements were undertaken in vivo on mice bearing tumours in which B16 tumour cells were inoculated at the base of the neck. From the acquisition of magnetic resonance images, it was established that after 4-6 hours from the administration of the Gd/B/L-LDL particles (0.1 and 1 mmol kg(-1) of Gd and (10)B, respectively) the amount of boron taken up in the tumour region is above the threshold required for successful NCT treatment. After neutron irradiation, tumour growth was followed for 20 days by MRI. The group of treated mice showed markedly lower tumour growth with respect to the control group.
Assuntos
Boro/farmacologia , Proteínas de Transporte/metabolismo , Gadolínio/farmacologia , Imageamento por Ressonância Magnética , Terapia por Captura de Nêutron/métodos , Animais , Boro/química , Proteínas de Transporte/química , Linhagem Celular Tumoral , Gadolínio/química , Humanos , Melanoma Experimental , Camundongos , Estrutura Molecular , Regulação para CimaRESUMO
o-Benzenedisulfonimide, a new strong bench-stable Brønsted acid, has been shown to efficiently catalyze the Mukaiyama aldol reaction of aldehydes or dimethyl acetals with silyl enol ethers under mild solvent-free reaction conditions.
RESUMO
Alkoxydienamides 2 have been synthesized exploiting the reactivity of α,ß-unsaturated acetals 1 with isocyanates in the presence of Schlosser's superbase LIC-KOR. In a mild acidic medium, 2 can then be promptly converted both into α-ketoamides 3 and into substituted 2-pyrrolidinones 4 or imino ethers 5 by choosing the appropriate experimental conditions.
Assuntos
Amidas/síntese química , Éteres Cíclicos/química , Éteres/química , Iminas/química , Lactamas/química , Ciclização , Modelos Moleculares , Estrutura MolecularRESUMO
The direct addition of metalated alkoxydiene 2, obtained from α,ß-unsaturated acetal 1 through a LIC-KOR-promoted conjugated elimination reaction, to enantiopure sulfinimines 3 (both R and SN-sulfinyl imines) afforded N-sulfinyl alkoxydienyl amines 4 with high diastereoselectivity. Functionalized enantiopure alkoxydienyl amines 5 were then easily obtained upon the selective removal of the chiral auxiliary under mild conditions. Moreover, the further hydrolysis of the alkoxydienyl moiety gave access to protected enantiopure ß-keto amines 7.
RESUMO
This review is an overview of the last ten years' use of the Mizoroki-Heck coupling applied to 1,2- and 1,3-dienes. Since both these systems form pi-allyl palladium intermediates in Pd(0) coupling, they show particular chemical behavior. Many examples of 1,2-dienes Heck reactions are presented. 1,2-Dienes are important substrates because of their high reactivity that makes them useful building blocks for the synthesis of biologically relevant structures.
Assuntos
Alcadienos/química , Produtos Biológicos/síntese química , Paládio/química , Catálise , CiclizaçãoRESUMO
A phosphine-free annulation reaction has been exploited for the preparation of substituted 3-alkenylindoles, 2-alkoxy-3-alkylidene-2,3-dihydrobenzofuranes and -indolidines in good to excellent yields. This has been done by reaction of protected 3-alkyl-1,2-dienols with o-iodophenols or protected o-iodoanilines. Two different heterocyclic skeletons were obtained, depending on the electron-donating properties of the heteroatom involved in the annulation process.
Assuntos
Álcoois/química , Benzofuranos/síntese química , Indóis/síntese química , Benzofuranos/química , Ciclização , Indóis/química , Estrutura Molecular , EstereoisomerismoRESUMO
A stereoselective approach to the synthesis of (E)-alkoxydienylamines (2) is described, starting from alpha,beta-unsaturated acetals (1) and aryl imines, under superbasic conditions. These can be readily converted into alpha-arylglycine derivatives (3) by mild acidic hydrolysis or, in turn, cyclized under oxidative conditions in the presence of a Pd catalyst to 2,3,4,5-tetrasubstituted pyrroles (4).
Assuntos
Aminas/síntese química , Glicina/análogos & derivados , Glicina/síntese química , Iminas/química , Pirróis/síntese química , Acetais/química , Aminas/química , Catálise , Técnicas de Química Combinatória , Ciclização , Glicina/química , Estrutura Molecular , Oxirredução , Paládio/química , Pirróis/química , EstereoisomerismoRESUMO
A new class of strigolactone analogues has been synthesized. They differ from known molecules, both of natural and synthetic origin, in two main features. The conjugated system extends from the enol ether bridge to the A ring, the B ring is a heterocycle while the C ring is a cyclic ketone instead of a gamma-lactone. The key step of the synthesis is a Nazarov cyclization on activated substrates. Bioassays using Orobanche seeds have revealed that all the molecules strongly stimulate germination; in particular the oxygen containing analogues are the most active. Interestingly, some of the new molecules show fluorescent properties.
Assuntos
Lactonas/síntese química , Ciclização , Corantes Fluorescentes , Germinação/efeitos dos fármacos , Orobanche , Sementes/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Sodium borocaptate (BSH) is widely used for boron neutron capture therapy (BNCT) of brain tumors. One drawback is the large uptake by the liver causing a decrease of its availability at the tumor region as well as bringing about toxicity problems. A novel carborane-based compound containing a boron payload very similar to that of BSH has been synthesized and tested on rat glioma (C6) cells, hepatoma tissue culture (HTC) cells, and hepatocytes. The newly synthesized system consists of an o-carborane unit (C(2)B(10)H(11), o-CB) conjugated to a glutamine residue through a proper spacer, namely, o-CB-Gln. As compared with BSH, it showed the same uptake by C6 cells, but a 50% decrease in uptake by HTC cells and an 80% decrease in uptake by healthy hepatocytes. On this basis o-CB-Gln appears an interesting candidate for BNCT of brain tumors as it is expected to have a therapeutic index analogous to that of BSH accompanied by a much lower liver toxicity.
Assuntos
Compostos de Boro/química , Compostos de Boro/metabolismo , Terapia por Captura de Nêutron de Boro , Glutamina/química , Animais , Transporte Biológico , Boroidretos/uso terapêutico , Compostos de Boro/síntese química , Compostos de Boro/uso terapêutico , Bovinos , Linhagem Celular Tumoral , Masculino , Ratos , Ratos Wistar , Compostos de Sulfidrila/uso terapêuticoRESUMO
C-(2-Benzyloxy)-ethyl-C'-N-tert-butoxycarbonyl-aminomethyl-o-carborane (8), a potentially useful intermediate for BNCT, has been synthesised. This intermediate can be readily functionalised with several biological vectors and MRI contrast agents. In this work intermediate 8 has been functionalised with a palmityl chain for lipophilic targeting and with Gd(III)-DOTAMA-C(6)-NH(2) as MRI detector. This combination yielded Gd(III)-C-palmitamidomethyl-C'-DOTAMA-C(6)-o-carborane (14) as a dual MRI-BNCT agent.
Assuntos
Compostos de Boro/química , Gadolínio/química , Compostos Organometálicos/síntese química , Terapia por Captura de Nêutron de Boro , Imageamento por Ressonância Magnética , Compostos Organometálicos/química , Compostos Organometálicos/uso terapêuticoRESUMO
A new approach to the synthesis of pyrimidines and cyclopentenones is described. The method exploits the reactivity of alpha,beta-unsaturated acetals with aromatic nitriles in the presence of the Schlosser's superbase LIC-KOR.
Assuntos
Acetais/química , Butanos/química , Ciclopentanos/síntese química , Etil-Éteres/química , Iminas/síntese química , Lítio/química , Nitrilas/química , Potássio/química , Pirimidinas/síntese química , Ciclopentanos/química , Iminas/química , Estrutura Molecular , Pirimidinas/químicaRESUMO
The direct transformation of lactam-, lactone-, and thiolactone-derived triflates into N-methoxy-N-methyl or morpholine Weinreb amides has been realized using Pd-catalyzed aminocarbonylation under CO atmospheric pressure and at room temperature. The carbonylative coupling can be efficiently carried out with 2% of catalyst in the presence of Xantphos as a ligand. The amides smoothly react with nucleophiles to afford acylated aza-, oxa-, and thio-heterocycles. The proposed methodology could be advantageously exploited for the synthesis of dienones in which one of the double bonds is embedded in a heterocyclic moiety, as useful substrates for Nazarov cyclization.