RESUMO
Over the years, rapamycin has attracted serious attention due to its remarkable biological properties and as a potent inhibitor of the mammalian target of rapamycin (mTOR) protein through its binding with FKBP-12. Several efficient strategies that utilize synthetic and biosynthetic approaches have been utilized to develop small molecule rapamycin analogs or for synthesizing hybrid compounds containing a partial rapamycin structure to improve pharmacokinetic properties. Herein, we report selected case studies related to the synthesis of rapamycin-derived compounds and hybrid molecules to explore their biological properties.
RESUMO
Inspired from geldanamycin, the synthesis of a new series of 20-membered macrocyclic compounds is developed. The key features in our design are (i) retention of the fragment having the precise chiral functional groups of geldanamycin at C10, C11, C12 and C14, and (ii) replacement of an olefin moiety with the ester group, and the quinoid sub-structure with the triazole ring. The southern fragment needed for the macrocyclic ring formation was obtained from Evans' syn aldol as the key reaction and with the use of D-mannitol as the cheap source of a chiral starting material. For the synthesis of the northern fragment, we utilized l-ascorbic acid, which provided the desired chiral functional groups at C6 and C7. Further, the chain extension completed the synthesis of the northern fragment. In our approach, the crucial 20 membered macrocyclic ring was formed employing the click chemistry. When tested for their ability to directly trans-differentiate human mesenchymal stem cells to neurons, two novel compounds (20a and 7) from this series were identified and this was further validated by the presence of specific neuronal biomarkers (i.e. nestin, agrin and RTN4).
Assuntos
Benzoquinonas/farmacologia , Lactamas Macrocíclicas/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Benzoquinonas/síntese química , Benzoquinonas/química , Diferenciação Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/química , Células-Tronco Mesenquimais/citologia , Estrutura Molecular , Neurônios/citologia , Relação Estrutura-AtividadeRESUMO
Aberrant apoptosis can lead to acute or chronic degenerative diseases. Mitochondrial outer membrane permeabilization (MOMP) triggered by the oligomerization of the Bcl-2 family proteins Bax/Bak is an irreversible step leading to execution of apoptosis. Here, we describe the discovery of small-molecule inhibitors of Bax/Bak oligomerization that prevent MOMP. We demonstrate that these molecules disrupt multiple, but not all, interactions between Bax dimer interfaces thereby interfering with the formation of higher-order oligomers in the MOM, but not recruitment of Bax to the MOM. Small-molecule inhibition of Bax/Bak oligomerization allowed cells to evade apoptotic stimuli and rescued neurons from death after excitotoxicity, demonstrating that oligomerization of Bax is essential for MOMP. Our discovery of small-molecule Bax/Bak inhibitors provides novel tools for the investigation of the mechanisms leading to MOMP and will ultimately facilitate development of compounds inhibiting Bax/Bak in acute and chronic degenerative diseases.
Assuntos
Apoptose/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , Animais , Sítios de Ligação , Células Cultivadas , Feminino , Ácido Glutâmico/toxicidade , Células HCT116 , Humanos , Lipossomos/metabolismo , Masculino , Camundongos , Membranas Mitocondriais/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Permeabilidade/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Proteína Killer-Antagonista Homóloga a bcl-2/antagonistas & inibidores , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/genéticaRESUMO
We developed a regio- and stereocontrolled Dieckmann cyclization approach to the synthesis of a novel, natural-product-like scaffold that was inspired from treprostinil (UT-15). This was further utilized in a diversity-based, 15-membered macrocyclic synthesis of two different sets of hybrid compounds. The amino acid moiety embedded in the macrocyclic skeleton allow exploring various chiral side chain groups within the ring.
Assuntos
Epoprostenol/análogos & derivados , Compostos Macrocíclicos/química , Cristalografia por Raios X , Epoprostenol/química , Compostos Macrocíclicos/síntese química , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
A practical stereoselective synthesis to obtain the substituted furan ring as the substructure of eribulin is developed. An asymmetric syn-aldol and intramolecular oxy-Michael were two key steps in our approach. The functionalized furan derivatives were then utilized further to build the 14- and 12-membered macrocyclic diversity as trans- and cis-fused (C-29 and C-30) compounds. This is the first report of building a chemical toolbox with macrocyclic small molecules having trans- or cis-fused 14- or 12-membered rings containing the substructure of eribulin and its diastereomer.
Assuntos
Furanos/síntese química , Cetonas/síntese química , Compostos Macrocíclicos/síntese química , Aldeídos/química , Ciclização , Furanos/química , Cetonas/química , Compostos Macrocíclicos/química , Estrutura Molecular , EstereoisomerismoRESUMO
A divergent approach to obtain a latrunculin family based hybrid macrocyclic toolbox is developed. A practical, stereoselective synthesis of a common substructure present in latrunculin A and latrunculol A was achieved. This was further utilized in the macrocyclic diversity synthesis. The amino acid moiety embedded in the 15-membered macrocyclic ring allows for the exploration of various chiral side chains as one of the diversity sites.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Macrolídeos/síntese química , Tiazolidinas/síntese química , Aminoácidos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Desenho de Fármacos , Macrolídeos/química , Modelos Moleculares , Estrutura Molecular , Tiazolidinas/químicaRESUMO
A stereoselective synthesis of a rapamycin fragment is developed and further utilized toward building a macrocyclic chemical toolbox. The amino alcohol moiety embedded in the 22-membered macrocyclic ring allowed for the addition of a variation in the chiral side chain. The key reactions leading to the synthesis of the rapamycin-derived pyran fragment include the following: (i) Paterson aldol, (ii) stereoselective ß-OH carbonyl reduction, and (iii) regio- and stereoselective intramolecular oxy-Michael reaction. The other piece needed for building the macrocyclic diversity was obtained from the coupling of various amino alcohol moieties with S-pipecolic acid.
Assuntos
Sirolimo/síntese química , Amino Álcoois/química , Estrutura Molecular , Ácidos Pipecólicos/química , Piranos/química , Sirolimo/química , EstereoisomerismoRESUMO
Modulators of microtubule dynamics have received increasing attention because of their potential to stop cancer growth. Although it belongs to the category of complex protein-protein interactions (PPIs), which are generally considered difficult to modulate through small molecules, the use of microtubule is considered a well-validated target. There are a number of bioactive natural products and related compounds that are currently in use as drugs or in clinical trials as next generation anti-cancer agents. The present review article is focused on two such bioactive natural products, epothilone and halichondrin B, and covers some of the key papers published after 2005 that outline various synthetic approaches to obtain next generation structural analogs as well as the synthesis of hybrid compounds.
Assuntos
Produtos Biológicos/farmacologia , Epotilonas/farmacologia , Éteres Cíclicos/farmacologia , Macrolídeos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Epotilonas/síntese química , Epotilonas/química , Éteres Cíclicos/síntese química , Éteres Cíclicos/química , Humanos , Macrolídeos/síntese química , Macrolídeos/química , Estrutura Molecular , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaAssuntos
Proteínas/química , Bibliotecas de Moléculas Pequenas , Proteínas 14-3-3/química , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/química , Tubulina (Proteína)/químicaRESUMO
A practical and modular approach to obtain a diverse set of 14-membered macrocyclic compounds from carbohydrates is developed that utilizes functional groups at C-1 and C-5. The evaluation of this toolbox in various zebrafish assays led to the identification of 2.7f as an antiangiogenesis agent.
Assuntos
Inibidores da Angiogênese/síntese química , Carboidratos/química , Compostos Macrocíclicos/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Desenho de Fármacos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Estrutura Molecular , Peixe-ZebraRESUMO
A highly practical and modular synthesis to obtain a diverse 14-membered ring-based macrocyclic toolbox is achieved. These compounds were further tested in zebrafish assays related to early embryonic development, angiogenesis, and neurogenesis, respectively. 1.4c was identified as an antiangiogenesis agent.
Assuntos
Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Inibidores da Angiogênese/química , Animais , Desenho de Fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Compostos Macrocíclicos/química , Estrutura Molecular , Morfogênese/efeitos dos fármacos , Neovascularização Patológica , Gravidez , Relação Estrutura-Atividade , Peixe-Zebra/embriologiaRESUMO
A novel approach to incorporate the macrocyclic rings onto the privileged substructure, i.e., tetrahydroquinoline scaffold, is developed. The presence of an amino acid-derived moiety in the macrocyclic skeleton provides an opportunity to modulate the nature of the chiral side chain. Further, evaluation in a zebrafish screen identified three active small molecules (2.5b, 3.2d, and 4.2) as antiangiogenesis agents at 2.5 µM.
RESUMO
Cytoplasmic stress granules (SGs) are specialized regulatory sites of mRNA translation that form under different stress conditions known to inhibit translation initiation. The formation of SG occurs via two pathways; the eukaryotic initiation factor (eIF) 2alpha phosphorylation-dependent pathway mediated by stress and the eIF2alpha phosphorylation-independent pathway mediated by inactivation of the translation initiation factors eIF4A and eIF4G. In this study, we investigated the effects of targeting different translation initiation factors and steps in SG formation in HeLa cells. By depleting eIF2alpha, we demonstrate that reduced levels of the eIF2.GTP.Met-tRNAi(Met) ternary translation initiation complexes is sufficient to induce SGs. Likewise, reduced levels of eIF4B, eIF4H, or polyA-binding protein, also trigger SG formation. In contrast, depletion of the cap-binding protein eIF4E or preventing its assembly into eIF4F results in modest SG formation. Intriguingly, interfering with the last step of translation initiation by blocking the recruitment of 60S ribosome either with 2-(4-methyl-2,6-dinitroanilino)-N-methylpropionamideis or through depletion of the large ribosomal subunits protein L28 does not induce SG assembly. Our study identifies translation initiation steps and factors involved in SG formation as well as those that can be targeted without induction of SGs.
Assuntos
Grânulos Citoplasmáticos/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Biossíntese de Proteínas , Animais , Linhagem Celular Tumoral , Células Cultivadas , Grânulos Citoplasmáticos/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Fatores de Iniciação em Eucariotos/genética , Fatores de Iniciação em Eucariotos/metabolismo , Guanosina Trifosfato/metabolismo , Células HeLa , Humanos , Camundongos , Microscopia de Fluorescência , Iniciação Traducional da Cadeia Peptídica/efeitos dos fármacos , Fosforilação , Proteínas de Ligação a Poli(A)/genética , Proteínas de Ligação a Poli(A)/metabolismo , Polirribossomos/metabolismo , Propionatos/farmacologia , Ligação Proteica , Inibidores da Síntese de Proteínas/farmacologia , RNA Interferente Pequeno/genética , RNA de Transferência de Metionina/metabolismo , Ribossomos/metabolismo , TransfecçãoAssuntos
Técnicas de Química Combinatória , Preparações Farmacêuticas/síntese química , Alcaloides/síntese química , Alcaloides/química , Compostos Orgânicos/síntese química , Compostos Orgânicos/química , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Preparações Farmacêuticas/química , Bibliotecas de Moléculas PequenasRESUMO
With the goal of identifying small molecule modulators of protein-protein interactions, we developed a solid-phase synthesis method, which was then successfully utilized in a library generation of 164 aminoindoline-derived, natural-product-like compounds. This library and several other related intermediates synthesized during this project were then subjected to different biological assays in search of small molecule modulators of focal adhesion kinase (FAK)-mediated signaling pathways. This study included (i) an in vitro, full length FAK inhibition assay, (ii) a cell proliferation assay, and (iii) a wound healing assay. In FAK inhibition assay, eight library members (5-12) and three aminoindoline derivatives (13, 14, and 2) were identified as promising candidates. Compounds 13 and 2 inhibited the FAK activity by 25-45% at 10 microM. These two lead compounds also showed activity in a wound healing assay. To our knowledge, these aminoindoline-derived small molecules belong to a new family of FAK inhibitors.
Assuntos
Técnicas de Química Combinatória/métodos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Indóis/química , Indóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/química , Humanos , Modelos Moleculares , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Cicatrização/efeitos dos fármacosRESUMO
Inspired by bioactive indoline alkaloid natural products, here, we report a divergent synthesis approach that led to skeletally diverse indoline alkaloid-inspired compounds. The natural product-inspired compounds obtained were then subjected to a series of in vitro and cellular assays to examine their properties as modulators of focal adhesion kinase (FAK) activity. This study resulted in the identification of a promising lead inhibitor of FAK (42), which also showed activity in a wound healing and cell invasion assay. The in silico study of the lead compound (42) was also undertaken.
Assuntos
Inibidores Enzimáticos/farmacologia , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Alcaloides Indólicos/farmacologia , Indóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Indóis/síntese química , Indóis/química , Fosforilação/efeitos dos fármacos , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacosRESUMO
A tetrahydroaminoquinoline-based library was generated with the goals of finding small molecule modulators of protein-protein interactions. Several library members as well as other related intermediates were tested for their ability to bind to Bcl-X(L) and Mcl-1 by in silico and (15)N NMR studies. The NMR study led to the identification of the tetrahydroaminoquinoline-based nude scaffold, 7 as a weak binder (K(d)=200 microM for Bcl-X(L) and K(d)=300 microM for Mcl-1) to both proteins. Using this scaffold as the starting material, we then synthesized a focused library of only 9 derivatives by applying the principles of a fragment-based approach. All these derivatives were then tested by NMR and this led to the discovery of a novel, small molecule (MIPRALDEN, 17) as a binder to Mcl-1 and Bcl-X(L) (K(D)=25 and 70 microM). This finding is novel because to our knowledge there are not many small molecules known in the literature that bind to Mcl-1.
Assuntos
Proteínas Proto-Oncogênicas c-bcl-2/química , Quinolinas/química , Quinolinas/farmacologia , Proteína bcl-X/química , Simulação por Computador , Modelos Moleculares , Estrutura Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A modular, reagent-based approach to obtain different indoline alkaloid-inspired, tetracyclic architectures is developed. With the use of TBSOTf as a Lewis acid, we report here a tandem Michael-based approach that led to the synthesis of a diastereomeric mixture of tetracyclic derivatives with two additional six-membered rings. By simply changing the Lewis acid to TMSOTf, we were able to obtain a different tetracyclic compound having additional functionalized 5- and 7-membered rings with complete stereocontrol.
Assuntos
Alcaloides/química , Indóis/química , Mesilatos/química , Compostos Policíclicos/síntese química , Compostos de Trimetilsilil/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Indicadores e Reagentes , Modelos Moleculares , Estrutura Molecular , Compostos Policíclicos/química , EstereoisomerismoRESUMO
We report here a practical, enantioselective synthesis of benzofuran-derived, cyclic trans-beta-amino acid scaffold. In two cases, tricyclic derivatives having six- and eight-membered unsaturated lactams were obtained from this versatile scaffold. To explore the biological applications, these compounds were subjected to cell-based assays, using NIH3T3 mouse cells to examine their potency as cell motility inhibitors and identified 18 as a potent cell motility inhibitor (IC50 approximately 40 microM in chamber cell migration assay).
Assuntos
Aminoácidos Cíclicos/química , Benzofuranos/química , Movimento Celular/efeitos dos fármacos , Flavonoides/química , Animais , Flavonoides/farmacologia , Camundongos , Sondas Moleculares , Células NIH 3T3RESUMO
With the goal of developing a modular approach leading to different indoline alkaloid natural-product-like tricyclic derivatives having an unsaturated lactam (see compounds 13, 14, and 16), an aminoindoline-based bicyclic scaffold 10 was obtained from 9. The selective deprotection of the indoline NTeoc or benzylic NHAlloc in compound 10, followed by N-acryloylation and then subjection to a ring-closing metathesis reaction, successfully led to obtaining two different architectures (13/14 and 16) having an unsaturated lactam functionality. This modular solution-phase methodology was then developed on solid phase. To achieve this objective, the aminoindoline bicyclic scaffold having an additional hydroxyl group could be immobilized onto the solid support using alkylsilyl linker-based polystyrene macrobeads, giving 18. By applying a ring-closing metathesis approach, 20 (tricyclic derivative with seven-membered-ring unsaturated lactam) and 23 (tricyclic derivative with eight-membered-ring unsaturated lactam) were then obtained from 18 in a number of steps.