RESUMO
The novel synthetic strategy for dolabellane skeleton was realized, which allowed the synthesis of clavulactone analogues 26 and 27 in a concise and efficient manner. Salient transformations include a diastereoselective Mukaiyama aldol reaction, an intramolecular nucleophilic addition reaction, a Grob fragmentation reaction, and an efficient Mukaiyama-Michael addition reaction.
RESUMO
The asymmetric total syntheses of hedyosumin E aglycon, 7,10-epoxyhedyosminolide and ent-zedolactone A were realized, with the first two being achieved for the first time.
Assuntos
4-Butirolactona/análogos & derivados , Sesquiterpenos de Guaiano/síntese química , 4-Butirolactona/síntese química , 4-Butirolactona/química , Catálise , Cristalografia por Raios X , Reação de Cicloadição , Modelos Moleculares , Sesquiterpenos de Guaiano/química , EstereoisomerismoRESUMO
The clinical success of cancer nanomedicines critically depends on availability of simple, safe and highly efficient nanocarriers. Here, we report that robust and multifunctional nanoparticles self-assembled from hyaluronic acid-g-poly(γ-benzyl-l-glutamate)-lipoic acid conjugates achieve a remarkably high loading (up to 25.8wt.%) and active targeted delivery of doxorubicin (DOX) to human breast tumor xenograft in vivo. DOX-loaded nanoparticles following auto-crosslinking (DOX-CLNPs) are highly stable with little drug leakage under physiological conditions while quickly release ca. 92% DOX in 30h under a cytoplasmic-mimicking reductive environment. The in vitro assays reveal that DOX-CLNPs possess a superior selectivity and antitumor activity to clinically used pegylated liposomal doxorubicin hydrochloride (DOX-LPs) in CD44 receptor overexpressing MCF-7 human breast cancer cells. Strikingly, DOX-CLNPs exhibit a superb tolerated dose of over 100mg DOX equiv./kg, which is more than 5 times higher than DOX-LPs, and an extraordinary breast tumor accumulation of 8.6%ID/g in mice. The in vivo therapeutic studies in MCF-7 human breast tumor-bearing nude mice show that DOX-CLNPs effectively inhibit tumor growth, improve survival rate, and significantly decrease adverse effects as compared to DOX-LPs. DOX-CLNPs based on natural endogenous materials with high drug loading, great stability and CD44-targetability are highly promising for precision cancer chemotherapy. STATEMENT OF SIGNIFICANCE: We demonstrate that with rational design, simple and multifunctional anticancer nanotherapeutics can be developed to achieve highly efficient and targeted cancer chemotherapy. Doxorubicin-loaded multifunctional nanoparticles based on hyaluronic acid-g-poly(γ-benzyl-l-glutamate)-lipoic acid conjugates exhibit a high drug loading, superior stability, fast bioresponsivity, high tolerability, and obvious selectivity toward CD44-overexpressing tumors in vivo. These nanotherapeutics achieve effective tumor suppression, drastically improved survival rate and reduced side effects as compared to clinically used pegylated liposomal doxorubicin in MCF-7 human breast tumor-bearing nude mice. Unlike previously reported multifunctional nanomedicines, the present nanotherapeutics primarily based on natural endogenous materials are simple and straightforward to fabricate, which makes them potentially interesting for clinical translation.
Assuntos
Antineoplásicos/uso terapêutico , Materiais Biocompatíveis/química , Neoplasias da Mama/tratamento farmacológico , Nanopartículas/química , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Reagentes de Ligações Cruzadas/química , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Feminino , Humanos , Ácido Hialurônico/química , Células MCF-7 , Camundongos Nus , Peptídeos/síntese química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Ácido Poliglutâmico/análogos & derivados , Ácido Poliglutâmico/síntese química , Ácido Poliglutâmico/química , Espectroscopia de Prótons por Ressonância Magnética , Ácido Tióctico/síntese química , Ácido Tióctico/química , Distribuição Tecidual/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
An organocatalytic formal [4 + 2] cycloaddition reaction has been realized that permits rapid access to a wide range of bicyclo[2.2.1]heptane-1-carboxylates in a highly enantioselective manner from simple starting materials under mild and operationally simple conditions.
RESUMO
A pharmaceutical-oriented, transition-metal-free, cyanide-free one-step direct transformation of methylarenes to aryl nitriles is described. For the dimethylarenes, the selectivity can be well-controlled to form mononitriles or dinitriles. Enantioenriched nitriles can also be synthesized by this method. As a pharmaceutically practical method, the antidepressant drug citalopram was synthesized from cheap and commercially abundant m-xylene on a gram scale in high yield, avoiding transition-metal residues and toxic cyanides.
Assuntos
Citalopram/síntese química , Nitrilas/síntese química , Xilenos/química , Antidepressivos de Segunda Geração/síntese química , Química Farmacêutica , EstereoisomerismoRESUMO
The first and asymmetric total synthesis of hedyosumins A, B, and C was accomplished in 13-14 steps from simple starting materials. The essential tools that allow us to access the tetracyclic skeleton include an organocatalytic [4 + 3] cycloaddition reaction, an intramolecular aldol condensation, and an intramolecular carboxymercuration/demercuration enabled lactonization. A CBS-catalyzed asymmetric reduction was employed to boost the ee of the synthetic natural products to an excellent level. This synthesis established the absolute configurations of hedyosumins A, B, and C.
Assuntos
Produtos Biológicos/síntese química , Medicamentos de Ervas Chinesas/síntese química , Magnoliopsida/química , Sesquiterpenos de Guaiano/síntese química , Aldeídos/química , Produtos Biológicos/química , Catálise , Cristalografia por Raios X , Medicamentos de Ervas Chinesas/química , Conformação Molecular , Estrutura Molecular , Sesquiterpenos de Guaiano/químicaRESUMO
The first synthetic attempt commencing from an eight-membered ring to approach the [5.3.1] bicyclic core of vinigrol has demonstrated the feasibility of using the conformational bias of the cyclooctane-ring system to realize highly diastereoselective reactions. The synthetic potential of the newly disclosed access to in/out isomerism may stimulate broader interests.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Química Orgânica/métodos , Diterpenos/síntese química , Alquilação , Catálise , Cristalografia por Raios X , Diterpenos/química , Oxirredução , Paclitaxel/química , Paládio , EstereoisomerismoRESUMO
Huperzine A, huperzine B, and huperzine U are congeners isolated from the Chinese herb Huperzia serrata (= Lycopodium serratum ) in minuscule amounts. The most efficient total synthesis of huperzine A, the first asymmetric total syntheses of huperzine B, and the first total synthesis of huperzine U have been achieved efficiently in overall yields of 17%, 10%, and 9%, respectively, each spanning 10-13 steps from (R)-pulegone. The featured steps include palladium-catalyzed Buchwald-Hartwig coupling and Heck cyclization reactions and an Ir-catalyzed olefin isomerization reaction. This work has established the absolute configurations of huperzine B and huperzine U and revealed that natural huperzine A, huperzine B, and huperzine U possess the same set of absolute stereochemistries, thus providing support for the potential role of huperzine B and huperzine U in the biosynthesis of huperzine A.
Assuntos
Alcaloides/síntese química , Medicamentos de Ervas Chinesas/síntese química , Lycopodium/química , Monoterpenos/química , Sesquiterpenos/síntese química , Alcaloides/química , Monoterpenos Cicloexânicos , Medicamentos de Ervas Chinesas/química , Estrutura Molecular , Sesquiterpenos/química , EstereoisomerismoRESUMO
The concise collective total synthesis of englerinâ A and B, orientalolâ E and F, and oxyphyllol has been accomplished in 10-15 steps, with the total synthesis of orientalolâ E and oxyphyllol being achieved for the first time. The success obtained was enabled by the realization of the [4+3] cycloaddition reaction of 9 and 10. Other features of the synthesis include 1)â the intramolecular Heck reaction to access the azulene core, 2)â the epoxidation-S(N)2' reduction sequence to access the allylic alcohol, 3)â the efficient regioselective and stereoselective formal hydration of the bridging C=C bond in the synthesis of englerins, and 4)â the late-stage chemo- and stereoselective C-H oxidation in the synthesis of orientalolâ E. The total synthesis of these natural products has enabled the structural revision of oxyphyllol and established the absolute stereochemical features of the organocatalytic [4+3] cycloaddition reaction. The identification of 5 as the natural product oxyphyllol, the success in converting 5 to orientalolâ E, along with the fact that englerins and oxyphyllol were isolated from plants of the same genus Phyllanthus gives support to our proposed biosynthetic pathways. This work may enable detailed biological evaluations of these natural products and their analogues and derivatives, especially of their potential in the fight against renal cell carcinoma (RCC).
Assuntos
Antineoplásicos Fitogênicos/síntese química , Produtos Biológicos/síntese química , Carcinoma de Células Renais/química , Carcinoma de Células Renais/tratamento farmacológico , Sesquiterpenos de Guaiano/síntese química , Antineoplásicos Fitogênicos/química , Produtos Biológicos/química , Catálise , Ciclização , Reação de Cicloadição , Oxirredução , Sesquiterpenos de Guaiano/química , EstereoisomerismoRESUMO
An efficient total synthesis of (-)-epothilone B has been achieved in ca. 8% yield over 11 steps from 9 (or 10 steps from 7/8), which features a bissiloxane-tethered ring closing metathesis reaction to approach the trisubstituted (Z) double bond and forms a new basis for further development of an industrial process for epothilone B and ixabepilone.
Assuntos
Epotilonas/síntese química , Ciclização , Epotilonas/química , Estrutura Molecular , EstereoisomerismoRESUMO
The total synthesis of Lycopodium alkaloid (-)-huperzine A has been accomplished in 10 steps with 17% overall yield from commercially abundant (R)-pulegone. The synthetic route features an efficient synthesis of 4 via a Buchwald-Hartwig coupling reaction, a dianion-mediated highly stereoselective alkylation of 4, and a rare example of an intramolecular Heck reaction of an enamine-type substrate. The stereoselective ß-elimination and the accompanying Wagner-Meerwein rearrangement are of particular interest.
Assuntos
Alcaloides/síntese química , Monoterpenos/química , Sesquiterpenos/síntese química , Alcaloides/química , Alquilação , Ciclização , Monoterpenos Cicloexânicos , Lycopodium/química , Estrutura Molecular , Sesquiterpenos/química , EstereoisomerismoRESUMO
Δ2-Pyrazolines are of significant medicinal and synthetic interest due to their therapeutic properties and utility in the synthesis of 1,3-diamines, yet few asymmetric methods exist to prepare them. An unprecedented highly enantioselective organocatalytic synthesis of 2-pyrazolines was achieved through an asymmetric conjugate addition catalyzed by 9-epi-amino cinchona alkaloids followed by deprotection-cyclization, which furnished chiral 2-pyrazolines in 46-78% yield and 59-91% ee. This bifunctional catalytic methodology thus provides easy access to considerable range of optically active 3,5-dialkyl 2-pyrazolines.
RESUMO
The first total synthesis of (-)-plicatic acid has been achieved by a concise and enantioselective route. In this synthesis, a conceptually new strategy featuring an asymmetric epoxidation-intramolecular epoxy-ring-opening Friedel-Crafts reaction sequence was developed for the stereoselective construction of the 2,7'-cyclolignane skeleton bearing contiguous quaternary-quaternary-tertiary stereocenters. The implementation of this strategy was enabled by the development of a modified protocol for the Seebach epoxidation with TADOOH, which affords an unprecedented, highly enantioselective and diastereoselective epoxidation with a range of alpha-carbonyl-beta-substituted acrylates 3.
Assuntos
Alcenos/química , Compostos de Epóxi/química , Lignanas/química , Lignanas/síntese química , Naftóis/química , Naftóis/síntese química , Estereoisomerismo , Especificidade por SubstratoRESUMO
AIMS: We synthesized a novel system of docetaxel-loaded, trastuzumab-functionalized nanoparticles (NPs) of biodegradable copolymers for targeted and synergistic chemotherapy. MATERIALS & METHODS: NPs of two component biodegradable copolymers were prepared by a modified solvent extraction/evaporation method with D-alpha-tocopheryl polyethylene glycol succinate (TPGS) as emulsifier. One component copolymer is poly(lactide)-TPGS, which is of desired hydrophobic-lipophilic balance for cellular adhesion, and another is carboxyl group-terminated TPGS, which facilitates the conjugation of trastuzumab on the NP surface for targeting. RESULTS: In vitro investigation with SK-BR-3 breast cancer cells of HER2 overexpression showed that the trastuzumab-functionalized NPs have great advantages over nude NPs in cellular uptake and cytotoxicity. CONCLUSION: Trastuzumab conjugated onto the NP surface has two functions: one is to target HER2-overexpressing cancer cells and the other is to enhance the cytotoxicity of docetaxel through synergistic effects. The trastuzumab-functionalized, docetaxel-loaded NPs have great potential for targeted chemotherapy to treat HER2-overexpressing cancer.
Assuntos
Anticorpos Monoclonais/química , Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/química , Polímeros/química , Taxoides/administração & dosagem , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel , Portadores de Fármacos/administração & dosagem , Humanos , Nanopartículas/administração & dosagem , Nanopartículas/toxicidade , Taxoides/farmacologia , TrastuzumabRESUMO
Highly enantioselective aminations of acyclic α-alkyl ß-keto thioesters and trifluoroethyl α-methyl α-cyanoacetate (12) with as low as 0.05 mol % of a bifunctional cinchona alkaloid catalyst were established. This ability to afford highly enantioselectivity for the amination of α-alkyl ß-carbonyl compounds renders the 6'-OH cinchona alkaloid-catalyzed amination applicable for the enantioselective synthesis of acyclic chiral compounds bearing N-substituted quaternary stereocenters. The synthetic application of this reaction is illustrated in a concise asymmetric synthesis of α-methylserine, a key intermediate previously utilized in the total synthesis of a small molecule immunomodulator, conagenin.
RESUMO
In this communication, we describe an unprecedented highly enantioselective catalytic conjugate addition of simple alkyl thiols to alpha,beta-unsaturated N-acylated oxazolidin-2-ones catalyzed by acid-base bifunctional catalysis. This reaction provides a useful catalytic method for the synthesis of optically active chiral sulfur compounds that are otherwise difficult to prepare by asymmetric catalysis. The successful development of this reaction resulted from a discovery that, upon proper modification, a cinchona alkaloid bearing a thiourea functionality at 6' position can afford highly efficient catalysis for asymmetric conjugate additions.
Assuntos
Oxazolidinonas/química , Compostos de Sulfidrila/síntese química , Acilação , Catálise , Alcaloides de Cinchona/química , Ésteres/síntese química , Estereoisomerismo , Compostos de Sulfidrila/químicaRESUMO
Despite the potential of chiral peroxides as biologically interesting or even clinically important compounds, no catalytic enantioselective peroxidation has been reported. With a chiral catalyst not only to induce enantioselectivity but also to convert a well established epoxidation pathway into a peroxidation pathway, the first efficient catalytic peroxidation has been successfully developed. Employing readily available alpha,beta-unsaturated ketones and hydroperoxides and an easily accessible cinchona alkaloid catalyst, this novel reaction will open new possibilities in the asymmetric synthesis of chiral peroxides. Under different conditions a highly enantioselective epoxidation with the same starting materials, reagents, and catalyst has was also established.
Assuntos
Peróxido de Hidrogênio/química , Cetonas/química , Catálise , Alcaloides de Cinchona/química , Oxirredução , Peróxidos/síntese química , EstereoisomerismoRESUMO
This paper continued our earlier work on the poly(D,L-lactide-co-glycolide)/montmorillonite nanoparticles (PLGA/MMT NPs), which were further decorated by human epidermal growth factor receptor-2 (HER2) antibody Trastuzumab for targeted breast cancer chemotherapy with paclitaxel as a model anticancer drug. Such a NP system is multifunctional, which formulates anticancer drugs with no harmful adjuvant, reduces the side effects of the formulated anticancer drug, promotes synergistic therapeutic effects, and achieves targeted delivery of the therapy. The paclitaxel-loaded PLGA/MMT NPs were prepared by a modified solvent extraction/evaporation technique, which were then decorated with Trastuzumab. The effects of the surface decoration on particle size and size distribution, surface morphology, drug encapsulation efficiency, as well as the drug release kinetics, were investigated. The NP formulation exhibited a biphasic drug release with a moderate initial burst followed by a sustained release profile. The surface decoration speeded the drug release. Surface chemistry analysis was conducted by X-ray photoelectron spectroscopy (XPS), which confirmed the presence of Trastuzumab on the NP surface. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed the stability of the antibody in the NP preparation process. Internalization of the coumarin-6-loaded PLGA/MMT NPs with or without the antibody decoration by both of Caco-2 colon adeno carcinoma cells and SK-BR-3 breast cancer cells was visualized by confocal laser scanning microscopy and quantitatively analyzed, which shows that the antibody decoration achieved significantly higher cellular uptake of the NPs. The results of in vitro cytotoxicity experiment on SK-BR-3 cells further proved the targeting effects of the antibody decoration. Judged by IC50 after 24h culture, the therapeutic effects of the drug formulated in the NPs with surface decoration could be 12.74 times higher than that of the bare NPs and 13.11 times higher than Taxol.