RESUMO
Aberrant hedgehog (Hh) pathway signaling is implicated in multiple cancer types and targeting the Smoothened (SMO) receptor, a key protein of the Hh pathway, has proven effective in treating metastasized basal cell carcinoma. Our lead optimization effort focused on a series of heteroarylamides. We observed that a methyl substitution ortho to the heteroaryl groups on an aniline core significantly improved the potency of this series of compounds. These findings predated the availability of SMO crystal structure in 2013. Here we retrospectively applied quantum mechanics calculations to demonstrate the o-Me substitution favors the bioactive conformation by inducing a dihedral twist between the heteroaryl rings and the core aniline. The o-Me also makes favorable hydrophobic interactions with key residue side chains in the binding pocket. From this effort, two compounds (AZD8542 and AZD7254) showed excellent pharmacokinetics across multiple preclinical species and demonstrated in vivo activity in abrogating the Hh paracrine pathway as well as anti- tumor effects.
Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Descoberta de Drogas , Imidazóis/farmacologia , Receptor Smoothened/antagonistas & inibidores , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/síntese química , Imidazóis/química , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , Receptor Smoothened/metabolismo , Relação Estrutura-Atividade , Proteína GLI1 em Dedos de Zinco/metabolismoRESUMO
The design and synthesis of a novel series of 2,6-disubstituted pyrazine derivatives as CK2 kinase inhibitors is described. Structure-guided optimization of a 5-substituted-3-thiophene carboxylic acid screening hit (3a) led to the development of a lead compound (12b), which shows inhibition in both enzymatic and cellular assays. Subsequent design and hybridization efforts also led to the unexpected identification of analogs with potent PIM kinase activity (14f).
Assuntos
Caseína Quinase II/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirazinas/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/síntese química , Pirazinas/química , Pirazinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 µM, cellular EC50 = 0.032 µM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.
Assuntos
Antineoplásicos/farmacologia , Ensaios Clínicos Fase I como Assunto , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Indóis/farmacologia , Linfoma de Células B/tratamento farmacológico , Piperidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Piperidinas/síntese química , Piperidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.
Assuntos
Histona Acetiltransferases/antagonistas & inibidores , Proteínas Nucleares/antagonistas & inibidores , Piridonas/farmacologia , Pirróis/farmacologia , Fatores Associados à Proteína de Ligação a TATA/antagonistas & inibidores , Fator de Transcrição TFIID/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Água/química , Sítios de Ligação/efeitos dos fármacos , Proteínas de Ciclo Celular , Relação Dose-Resposta a Droga , Transferência Ressonante de Energia de Fluorescência , Fluorometria , Histona Acetiltransferases/metabolismo , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Proteínas Nucleares/metabolismo , Piridonas/síntese química , Piridonas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Fator de Transcrição TFIID/metabolismo , Fatores de Transcrição/metabolismoRESUMO
The discovery and optimization of a series of small molecule EZH2 inhibitors is described. Starting from dimethylpyridone HTS hit (2), a series of indole-based EZH2 inhibitors were identified. Biochemical potency and microsomal stability were optimized during these studies and afforded compound 22. This compound demonstrates nanomolar levels of biochemical potency (IC50=0.002 µM), cellular potency (EC50=0.080 µM), and afforded tumor regression when dosed (200 mpk SC BID) in an EZH2 dependent tumor xenograft model.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Indóis/química , Complexo Repressor Polycomb 2/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Técnicas de Química Sintética , Desenho de Fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Proteína Potenciadora do Homólogo 2 de Zeste , Células HeLa/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Terapia de Alvo Molecular/métodos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The histone lysine methyltransferase (MT) Enhancer of Zeste Homolog 2 (EZH2) is considered an oncogenic driver in a subset of germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) and follicular lymphoma due to the presence of recurrent, monoallelic mutations in the EZH2 catalytic domain. These genomic data suggest that targeting the EZH2 MT activity is a valid therapeutic strategy for the treatment of lymphoma patients with EZH2 mutations. Here we report the identification of highly potent and selective EZH2 small molecule inhibitors, their validation by a cellular thermal shift assay, application across a large cell panel representing various non-Hodgkin's lymphoma (NHL) subtypes, and their efficacy in EZH2mutant-containing GCB-DLBCL xenograft models. Surprisingly, our EZH2 inhibitors selectively affect the turnover of trimethylated, but not monomethylated histone H3 lysine 27 at pharmacologically relevant doses. Importantly, we find that these inhibitors are broadly efficacious also in NHL models with wild-type EZH2.
Assuntos
Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/toxicidade , Histonas/metabolismo , Complexo Repressor Polycomb 2/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/toxicidade , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Histonas/química , Humanos , Cinética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Metilação , Camundongos , Camundongos Nus , Mutação , Peptídeos/análise , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Transplante HeterólogoRESUMO
A method for the synthesis of N-functionalized C2-/C3-substituted indoles via Pd-catalyzed C-N bond coupling of halo-aryl enamines is described. The general strategy utilizes a variety of amines and ß-keto esters which are elaborated into halo-aryl enamines as latent precursors to indoles. The preferred conditions comprising the RuPhos precatalyst and RuPhos in the presence of NaOMe in 1,4-dioxane tolerate a variety of substituents and are scalable for the construction of indoles in multigram quantities.
Assuntos
Indóis/síntese química , Paládio/química , Aminas/química , Catálise , Ciclização , Indóis/química , Estrutura MolecularRESUMO
Upregulation of Pim kinases is observed in several types of leukemias and lymphomas. Pim-1, -2, and -3 promote cell proliferation and survival downstream of cytokine and growth factor signaling pathways. AZD1208 is a potent, highly selective, and orally available Pim kinase inhibitor that effectively inhibits all three isoforms at <5 nM or <150 nM in enzyme and cell assays, respectively. AZD1208 inhibited the growth of 5 of 14 acute myeloid leukemia (AML) cell lines tested, and sensitivity correlates with Pim-1 expression and STAT5 activation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells, accompanied by a dose-dependent reduction in phosphorylation of Bcl-2 antagonist of cell death, 4EBP1, p70S6K, and S6, as well as increases in cleaved caspase 3 and p27. Inhibition of p4EBP1 and p-p70S6K and suppression of translation are the most representative effects of Pim inhibition in sensitive AML cell lines. AZD1208 inhibits the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 also potently inhibits colony growth and Pim signaling substrates in primary AML cells from bone marrow that are Flt3 wild-type or Flt3 internal tandem duplication mutant. These results underscore the therapeutic potential of Pim kinase inhibition for the treatment of AML.
Assuntos
Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Proliferação de Células/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Tiazolidinas/farmacologia , Animais , Compostos de Bifenilo/farmacocinética , Western Blotting , Ciclo Celular , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos SCID , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Tiazolidinas/farmacocinética , Distribuição Tecidual , Células Tumorais CultivadasRESUMO
A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.
Assuntos
Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Receptores ErbB/genética , Modelos Moleculares , Mutação , Relação Estrutura-AtividadeRESUMO
The potent and selective 3-amido-4-anilinoquinoline CSF-1R inhibitor AZ683 suffered from cardiovascular liabilities, which were linked to the off-target activities of the compound and ion channel activity in particular. Less basic and less lipophilic examples from both the quinoline and cinnoline series demonstrated cleaner secondary pharmacology profiles. Cinnoline 31 retained the required potency and oral PK profile, and was progressed through the safety screening cascade to be nominated into development as AZD7507.
Assuntos
Aminoquinolinas/síntese química , Aminoquinolinas/toxicidade , Compostos de Anilina/síntese química , Compostos de Anilina/toxicidade , Sistema Cardiovascular/efeitos dos fármacos , Inibidores Enzimáticos/toxicidade , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/toxicidade , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cobaias , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Miócitos Cardíacos/efeitos dos fármacos , RatosRESUMO
Novel substituted benzylidene-1,3-thiazolidine-2,4-diones (TZDs) have been identified as potent and highly selective inhibitors of the PIM kinases. The synthesis and SAR of these compounds are described, along with X-ray crystallographic, anti-proliferative, and selectivity data.
Assuntos
Compostos de Benzilideno/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Tiazolidinedionas/química , Animais , Compostos de Benzilideno/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologiaRESUMO
Cell-based subset screening of compounds using a Gli transcription factor reporter cell assay and shh stimulated cell differentiation assay identified a series of bisamide compounds as hedgehog pathway inhibitors with good potency. Using a ligand-based optimization strategy, heteroaryl groups were utilized as conformationally restricted amide isosteres replacing one of the amides which significantly increased their potency against SMO and the hedgehog pathway while decreasing activity against p38α kinase. We report herein the identification of advanced lead compounds such as imidazole 11c and 11f encompassing good p38α selectivity, low nanomolar potency in both cell assays, excellent physiochemical properties and in vivo pharmacokinetics.
Assuntos
Amidas/química , Proteínas Hedgehog/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Amidas/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
3-Amido-4-anilinocinnolines have been identified as potent and highly selective inhibitors of CSF-1R. The synthesis and SAR of these compounds is reported, along with some physical property, pharmacokinetic and kinase selectivity data.
Assuntos
Amidas/síntese química , Compostos de Anilina/síntese química , Compostos Heterocíclicos com 2 Anéis/síntese química , Inibidores de Proteínas Quinases/síntese química , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Amidas/química , Compostos de Anilina/química , Animais , Cães , Compostos Heterocíclicos com 2 Anéis/química , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Ratos , Relação Estrutura-AtividadeRESUMO
The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified.
Assuntos
Química Farmacêutica/métodos , Neoplasias/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacocinética , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Receptor de Fator Estimulador de Colônias de Macrófagos/química , Aminas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Concentração Inibidora 50 , Cinética , Camundongos , Modelos Químicos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , RatosRESUMO
A series of amidoheteroaryl compounds were designed and synthesized as inhibitors of B-Raf kinase. Several compounds from the series show excellent potency in biochemical, phenotypic and mode of action cellular assays. Potent examples from the series have also demonstrated good plasma exposure following an oral dose in rodents and activity against the Ras-Raf pathway in tumor bearing mice.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Mutação , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Administração Oral , Animais , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Ratos , Relação Estrutura-Atividade , Quinases raf/metabolismo , Proteínas ras/metabolismoRESUMO
The bisamide class of kinase inhibitors was identified as being active against CSF-1R. The synthesis and SAR of pyridyl and thiazolyl bisamides are reported, along with the pharmacokinetic properties and in vivo activity of selected examples.
Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Tiazóis/farmacologia , Células 3T3 , Amidas/química , Amidas/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Feminino , Humanos , Camundongos , Camundongos Nus , Ratos , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different phenyl substituents, have been synthesized and tested in monoamine transporter assays. As predicted from a pharmacophore model, most of the RR/SS diastereomers showed high potency as dopamine reuptake inhibitors. Analogues with a 4-chlorophenyl group and an unbranched initial alkyl atom had consistently enhanced selectivity for the dopamine transporter. The most potent compounds were those with a three- or four-carbon chain. The "inactive" RS/SR diastereomers showed substantial activity when the phenyl substituent was 3,4-dichloro. On a locomotor assay, one compound was found to have a slow onset and a long duration of action. The activity of these compounds provides additional evidence for a conformational/superposition model of methylphenidate with cocaine-like structures. A ketone analogue, obtained by hydrogenating a previously described vinylogous amide, had activity similar to that of methylphenidate.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/síntese química , Metilfenidato/análogos & derivados , Metilfenidato/síntese química , Animais , Linhagem Celular , Cristalografia por Raios X , Inibidores da Captação de Dopamina/farmacologia , Humanos , Cetonas/síntese química , Cetonas/farmacologia , Masculino , Metilfenidato/farmacologia , Camundongos , Atividade Motora/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ensaio Radioligante , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Complete details of an asymmetric synthesis of leucascandrolide A (1) are described. The synthesis highlights the use of two diastereoselective [4 + 2]-annulations for the assembly of the functionalized bispyranyl macrolide 3. An efficient assembly and union of the oxazole-containing side chain 4 with macrolide 3 was carried out using a Mitsunobu reaction. A convergent route to the oxazole side chain was developed using a Sonogashira cross-coupling between 2-trifloyloxazole 16 and alkyne 17, which allowed for the installation of the C9'-C10' (Z)-olefin.
Assuntos
Sesquiterpenos/síntese química , Acetatos/química , Aldeídos/química , Alcenos/química , Alquilação , Alcinos/química , Éter/química , Indóis/química , Lactonas/química , Macrolídeos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxazóis/química , Propanóis/química , Sesquiterpenos/química , Silanos/química , EstereoisomerismoRESUMO
In an effort to produce compounds with longer durations of action, we attempted to synthesize ketone analogs of methylphenidate which, however, appear to be highly unstable due to a highly acidic proton alpha to the ketone and phenyl groups. Nevertheless, vinylogous amide by products have been synthesized and tested for activity at dopamine, norepinephrine, and serotonin transporters. The compounds were found to be weak inhibitors of monoamine reuptake despite rigid three dimensional structures that are quite similar to the global minimum of threo-(R,R)-methylphenidate. The structures were confirmed by X-ray crystallography.
Assuntos
Amidas/química , Amidas/farmacologia , Metilfenidato/análogos & derivados , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Amidas/síntese química , Células Cultivadas , Cristalografia por Raios X , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Glicoproteínas de Membrana/antagonistas & inibidores , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Metilfenidato/síntese química , Metilfenidato/farmacologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Inibidores da Captação de Neurotransmissores/química , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Proteínas Recombinantes/antagonistas & inibidores , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina , Simportadores/antagonistas & inibidoresRESUMO
[reaction: see text] The asymmetric synthesis of a C1-C22 fragment (2) of leucascandrolide A is described. Synthetic highlights include the construction of the C9-C22 pyran fragment using a formal [4 + 2]-annulation of a chiral organosilane. A diastereoselctive Mukaiyama aldol was used to introduce the C9 stereocenter and complete the assembly of the macrocycle's carbon skeleton.