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1.
Biochemistry ; 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34845903

RESUMO

Catalytic promiscuity is the coincidental ability to catalyze nonbiological reactions in the same active site as the native biological reaction. Several lines of evidence show that catalytic promiscuity plays a role in the evolution of new enzyme functions. Thus, studying catalytic promiscuity can help identify structural features that predispose an enzyme to evolve new functions. This study identifies a potentially preadaptive residue in a promiscuous N-succinylamino acid racemase/o-succinylbenzoate synthase (NSAR/OSBS) enzyme from Amycolatopsis sp. T-1-60. This enzyme belongs to a branch of the OSBS family which includes many catalytically promiscuous NSAR/OSBS enzymes. R266 is conserved in all members of the NSAR/OSBS subfamily. However, the homologous position is usually hydrophobic in other OSBS subfamilies, whose enzymes lack NSAR activity. The second-shell amino acid R266 is close to the catalytic acid/base K263, but it does not contact the substrate, suggesting that R266 could affect the catalytic mechanism. Mutating R266 to glutamine in Amycolatopsis NSAR/OSBS profoundly reduces NSAR activity but moderately reduces OSBS activity. This is due to a 1000-fold decrease in the rate of proton exchange between the substrate and the general acid/base catalyst K263. This mutation is less deleterious for the OSBS reaction because K263 forms a cation-π interaction with the OSBS substrate and/or the intermediate, rather than acting as a general acid/base catalyst. Together, the data explain how R266 contributes to NSAR reaction specificity and was likely an essential preadaptation for the evolution of NSAR activity.

2.
Org Lett ; 23(17): 6622-6627, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34436913

RESUMO

An enantioselective three-component reaction was developed for the synthesis of tetrahydropyridazinones employing chiral α,ß-unsaturated acylammonium salts, malonates, and azodicarboxylates. An initial α-amination of a malonate with an azodicarboxylate and a subsequent chiral Lewis-base-catalyzed Michael/proton transfer/lactamization process delivered optically active tetrahydropyridazinones (up to 99:1 er). Subsequent transformations of these adducts were explored, revealing some unexpected rearrangements, and the use of an allyl methyl malonate enabled a subsequent deallylative decarboxylation and the introduction of a second stereocenter.

3.
Sci Rep ; 11(1): 10652, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34017048

RESUMO

The epithelial-mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapies, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover prolonged, sub-cytotoxic exposure to OpA is sufficient to suppress EMT-imparted CSC features including sphere formation and resistance to doxorubicin. In vivo growth of CSC-rich mammary cell tumors, is suppressed by OpA treatment. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features.


Assuntos
Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal , Fungos/química , Sesterterpenos/farmacologia , Animais , Neoplasias da Mama/genética , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Nucleares/metabolismo , Fenótipo , Proteína 1 Relacionada a Twist/metabolismo
4.
Cell Chem Biol ; 28(6): 825-834.e6, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33412110

RESUMO

Interfacial inhibitors exert their biological effects through co-association with two macromolecules. The pateamine A (PatA) class of molecules function by stabilizing eukaryotic initiation factor (eIF) 4A RNA helicase onto RNA, resulting in translation initiation inhibition. Here, we present the crystal structure of an eIF4A1:RNA complex bound to an analog of the marine sponge-derived natural product PatA, C5-desmethyl PatA (DMPatA). One end of this small molecule wedges itself between two RNA bases while the other end is cradled by several protein residues. Strikingly, DMPatA interacts with the eIF4A1:RNA complex in an almost identical fashion as rocaglamide A (RocA), despite being completely unrelated from a structural standpoint. The structural data rationalize the ability of PatA analogs to target a wider range of RNA substrates compared to RocA. We define the molecular basis of how DMPatA is able to clamp eIF4A1 onto RNA, imparting potent inhibitory properties to this molecule.


Assuntos
Compostos de Epóxi/química , Fator de Iniciação 4A em Eucariotos/química , Macrolídeos/química , RNA/química , Tiazóis/química , Linhagem Celular , Cristalografia por Raios X , Humanos , Modelos Moleculares , Conformação Molecular
5.
Nat Prod Rep ; 38(4): 843-860, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33146205

RESUMO

Covering: 2000 to 2020 Triptolide is a bioactive diterpene triepoxide isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal plant whose extracts have been used as anti-inflammatory and immunosuppressive remedies for centuries. Although triptolide and its analogs exhibit potent bioactivities against various cancers, and inflammatory and autoimmune diseases, none of them has been approved to be used in the clinic. This review highlights advances in material sourcing, molecular mechanisms, clinical progress and new drug design strategies for triptolide over the past two decades, along with some prospects for the future course of development of triptolide.


Assuntos
Diterpenos/farmacologia , Fenantrenos/farmacologia , Animais , Doenças Autoimunes/tratamento farmacológico , Diterpenos/isolamento & purificação , Desenho de Fármacos , Descoberta de Drogas , Compostos de Epóxi/isolamento & purificação , Compostos de Epóxi/farmacologia , Previsões , Humanos , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Fenantrenos/isolamento & purificação , Tripterygium/química
7.
Org Lett ; 22(23): 9282-9286, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33226820

RESUMO

A concise, organocatalytic, enantioselective route to the γ-lactam core of the oxazolomycins was developed. Key steps include a Lewis base-catalyzed, Michael proton transfer-lactamization organocascade, a one-pot N-methylation and diastereoselective α-alkylation, a diastereotopic group-selective reduction, a substrate-directed allylic hydroxylation, and a lanthanide-mediated organolithium addition to append the side chain. A formal synthesis of (+)-neooxazolomycin via interception of a Kende intermediate, accessed in 10 steps (previously 24 steps from α-d-glucose), enabled confirmation of the relative and absolute stereochemistry.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Oxazóis/química , Oxazóis/síntese química , Pirrolidinonas/química , Compostos de Espiro/química , Alquilação , Compostos Bicíclicos Heterocíclicos com Pontes/química , Catálise , Estrutura Molecular , Estereoisomerismo
8.
Nat Prod Rep ; 37(11): 1436-1453, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-33104139

RESUMO

Covering: 1986 to 2020Natural products are an enduring source of chemical information useful for probing biologically relevant chemical space. Toward gathering further structure-activity relationship (SAR) information for a particular natural product, synthetic chemists traditionally proceeded first by a total synthesis effort followed by the synthesis of simplified derivatives. While this approach has proven fruitful, it often does not incorporate hypotheses regarding structural features necessary for bioactivity at the synthetic planning stage, but rather focuses on the rapid assembly of the targeted natural product; a goal that often supersedes the opportunity to gather SAR information en route to the natural product. Furthermore, access to simplified variants of a natural product possessing only the proposed essential structural features necessary for bioactivity, typically at lower oxidation states overall, is sometimes non-trivial from the original established synthetic route. In recent years, several synthetic design strategies were described to streamline the process of finding bioactive molecules in concert with fathering further SAR studies for targeted natural products. This review article will briefly discuss traditional retrosynthetic strategies and contrast them to selected examples of recent synthetic strategies for the investigation of biologically relevant chemical space revealed by natural products. These strategies include: diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS), diverted-total synthesis (DTS), analogue-oriented synthesis (AOS), two-phase synthesis, function-oriented synthesis (FOS), and computed affinity/dynamically ordered retrosynthesis (CANDOR). Finally, a description of pharmacophore-directed retrosynthesis (PDR) developed in our laboratory and initial applications will be presented that was initially inspired by a retrospective analysis of our synthetic route to pateamine A completed in 1998.


Assuntos
Produtos Biológicos/síntese química , Descoberta de Drogas , Produtos Biológicos/farmacologia , Sondas Moleculares , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
9.
Org Lett ; 22(21): 8307-8312, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33034457

RESUMO

Pharmacophore-directed retrosynthesis applied to ophiobolin A led to bicyclic derivatives that were synthesized and display anticancer activity. Key features of the ultimate defensive synthetic strategy include a Michael addition/facially selective protonation sequence to set the critical C6 stereocenter and a ring-closing metathesis to form the cyclooctene. Cytotoxicity assays toward a breast cancer cell line (MDA-MB-231) confirm the anticipated importance of structural complexity for selectivity (vs MCF10A cells) while C3 variations modulate stability.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sesterterpenos/síntese química , Sesterterpenos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Sesterterpenos/química , Relação Estrutura-Atividade
10.
Acta Pharmacol Sin ; 41(12): 1519-1524, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32994545

RESUMO

Ion channels are the third largest class of targets for therapeutic drugs. The pharmacology of ion channels is an important research area for identifying new treatment options for human diseases. The past decade or so has seen increasing interest in an ion channel protein belonging to the transient receptor potential (TRP) family, namely the melastatin subfamily member 7 (TRPM7), as an emerging drug target. TRPM7 is a bifunctional protein with a magnesium and calcium-conducting divalent ion channel fused with an active kinase domain. TRPM7 is ubiquitously expressed in human tissues, including the brain, and regulates various cell biology processes such as magnesium and calcium homeostasis, cell growth and proliferation, and embryonic development. TRPM7 provides a link between cellular metabolic status and intracellular calcium homeostasis in neurons due to TRPM7's unique sensitivity to fluctuating intracellular Mg·ATP levels. Thus, the protein plays a key role in ischemic and hypoxic neuronal cell death and brain injury, and is one of the key nonglutamate mechanisms in cerebral ischemia and stroke. Currently, the most potent and specific TRPM7 inhibitor is waixenicin A, a xenicane diterpenoid from the Hawaiian soft coral Sarcothelia edmondsoni. Using waixenicin A as a pharmacological tool, we demonstrated that TRPM7 is involved in promoting neurite outgrowth in vitro. Most recently, we found that waixenicin A reduced hypoxic-ischemic brain injury and preserved long-term behavioral outcomes in mouse neonates. We here suggest that TRPM7 is an emerging drug target for CNS diseases and disorders, and waixenicin A is a viable drug lead for these disorders.


Assuntos
Acetatos/farmacologia , Acetatos/uso terapêutico , Fármacos do Sistema Nervoso Central/farmacologia , Fármacos do Sistema Nervoso Central/uso terapêutico , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Linhagem Celular , Humanos
11.
Chemistry ; 26(59): 13372-13377, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-32991008

RESUMO

The tigliane ring system, which encompasses iconic members such as phorbol and TPA, is widely renowned due to numerous observations of displaying potent biological activity, and subsequent use as mainstream biochemical tools. Traditionally, naturally occurring phorboids are regarded as tumor promotors through PKC activation, although in recent times more highly oxidized natural derivatives have been identified as anti-tumor agents. In the view that only limited synthetic investigations toward skeletal stereochemical modification have been undertaken, non-natural systems could be useful for a better understanding of the tigliane pharmacophore via interrogation of cellular sensitivity. In this context the concise construction of a number of highly functionalized non-natural D-ring inverted phorbol esters were synthesized, via a rhodium-catalyzed [4+3] cycloaddition, and biologically evaluated using a range of cancer cell lines. The biological results highlight the notion that subtle changes in structure have dramatic effects on potency. Furthermore, although the non-natural derivatives did not outcompete the natural systems in the PKC-activation sensitive MCF7 cancer cell line, they outperformed in other cancer cell lines (MM96L and CAL27). This observation strongly suggested an alternate mode of action not involving activation of PKC, but instead involves thiol addition as indicated by glutathione addition and NF-κB reporter activity.


Assuntos
Neoplasias , Forbóis , Proteína Quinase C/química , Compostos de Sulfidrila/química , Linhagem Celular , Humanos
12.
Biochem Cell Biol ; 98(4): 502-510, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32008367

RESUMO

The natural product pateamineA (PatA) is a highly potent antiproliferative agent. PatA and the simplified analog desmethyl, desamino pateamineA (DMDAPatA) have exhibited cytotoxicity selective for rapidly proliferating cells, and have been shown to inhibit cap-dependent translation initiation through binding to eIF4A (eukaryotic initiation factor 4A) of the eIF4F complex. PatA and DMDAPatA are both known to stimulate the RNA-dependent ATPase, and ATP-dependent RNA helicase activities of eIF4A. The impact of other eIF4F components, eIF4E and eIF4G, on DMDAPatA action were investigated in vitro and in cultured mammalian cells. The perturbation of the eIF4A-eIF4G association was found to be eIF4E- and mRNA cap-dependent. An inhibitory effect on helicase activity of eIF4A was observed when it was part of a complex that mimicked the eIF4F complex. We propose a model of action for DMDAPatA (and by supposition PatA) where the cellular activity of the compound is dependent on an "active" eIF4F complex.


Assuntos
Adenosina Trifosfatases/metabolismo , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Macrolídeos/química , Macrolídeos/farmacologia , Neoplasias/tratamento farmacológico , RNA Mensageiro/metabolismo , Tiazóis/química , Tiazóis/farmacologia , Adenosina Trifosfatases/genética , Produtos Biológicos , Linhagem Celular , Proliferação de Células , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , RNA Mensageiro/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
13.
Org Lett ; 22(4): 1407-1413, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32009413

RESUMO

Toward a method for direct conversion of alkenes to cyclic guanidines, we report that 1,3-dipolar cycloadditions of 2-amido-1,3-diamino allylic cations with alkenes provide a new method for direct cyclic guanidine annulation. Generated under oxidative conditions, the 2-amido-1,3-diaminoallyl cations react as 1,3-dipoles providing rapid access to 2-amino imidazolines through net (3 + 2) cycloadditions. The utility is demonstrated through a concise synthesis of the oroidin alkaloid, phakellin. The described 1,3-dipole also participates in net (4 + 3) cycloadditions with dienes.


Assuntos
Compostos Alílicos/química , Amidas/química , Guanidina/síntese química , Alcenos/química , Cátions/química , Reação de Cicloadição , Guanidina/análogos & derivados , Guanidina/química , Estrutura Molecular , Estereoisomerismo
14.
Mol Biochem Parasitol ; 236: 111258, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31968220

RESUMO

Translation initiation factor eIF4F is essential for cap-dependent translation initiation in eukaryotes. eIF4F is a trimeric complex consisting of a scaffold protein eIF4G, cap-binding protein eIF4E and DEAD-box RNA helicase eIF4A. eIF4F binds to the 5' cap structure of the mRNA through eIF4E and facilitates the binding of the preinitiation complex (PIC) via protein-protein interactions of eIF4G with eIF3 in mammals or with eIF5 in yeast. Initiation factor eIF4A is known to unwind the secondary structures of the 5'UTRs encountered by the PIC during its initial binding to the mRNA and while scanning for the initiation codon. In Giardia, homologs for eIF4E (GleIF4E2) and eIF4A (GleIF4A) have been identified but not for eIF4G. To address how PIC is recruited to the 5' end of mRNA in the absence of eIF4G homolog, we have used yeast two-hybrid assays to identify potential interactions of GleIF4E2 with the components of the PIC. The results show that GleIF4E2 can interact with the ß subunit of the initiation factor GleIF2, a component of the PIC. ZDOCK modeling of the GleIF4E2-GleIF2ß complex revealed that the dorsal side of GleIF4E2 is likely involved in binding to GleIF2ß, which mimics the interaction of mammalian eIF4E with eIF4G, and with eIF4E binding proteins. These results suggest that GleIF4E2 can facilitate the recruitment of the PIC to the 5'end of the mRNA by binding directly to the components of the PIC. The role of GleIF4A in translation initiation in Giardia is not clearly understood as the short 5' UTRs of the mRNA are unlikely to form secondary structures. Interestingly, Pateamine A, a specific inhibitor of human eIF4A, inhibited the growth of Giardia in a dose-dependent manner, suggesting that the activity of GleIF4A is probably required for translation. Using yeast two-hybrid assays, we have identified a novel interaction of GleIF4A with i subunit of the initiation factor GleIF3 (GleIF3i), another component of the PIC. These results indicate that the GleIF4A can also interact directly with the components of the PIC. ZDOCK modeling of the GleIF3i-GleIF4A complex suggests that GleIF3i could serve as a stimulator of GleIF4A activity.


Assuntos
Fator de Iniciação 4A em Eucariotos , Fator de Iniciação 4E em Eucariotos , Biossíntese de Proteínas/fisiologia , Linhagem Celular Transformada , Códon de Iniciação/metabolismo , Fator de Iniciação 4A em Eucariotos/química , Fator de Iniciação 4A em Eucariotos/metabolismo , Fator de Iniciação 4E em Eucariotos/química , Fator de Iniciação 4E em Eucariotos/metabolismo , Fator de Iniciação 4G em Eucariotos/química , Fator de Iniciação 4G em Eucariotos/metabolismo , Giardia lamblia/genética , Humanos , Modelos Estruturais , Ligação Proteica , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
15.
Front Chem ; 8: 608296, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33392151

RESUMO

During their infective stages, hookworms release excretory-secretory (E-S) products, small molecules, and proteins to help evade and suppress the host's immune system. Small molecules found in E-S products of mammalian hookworms include nematode derived metabolites like ascarosides, which are composed of the sugar ascarylose linked to a fatty acid side chain. The most abundant proteins found in hookworm E-S products are members of the protein family known as Ancylostoma secreted protein (ASP). In this study, two ascarosides and their fatty acid moieties were synthesized and tested for in vitro binding to Na-ASP-2 using both a ligand competition assay and microscale thermophoresis. The fatty acid moieties of both ascarosides tested and ascr#3, an ascaroside found in rat hookworm E-S products, bind to Na-ASP-2's palmitate binding cavity. These molecules were confirmed to bind to the palmitate but not the sterol binding sites. An ascaroside, oscr#10, which is not found in hookworm E-S products, does not bind to Na-ASP-2. More studies are required to determine the structural basis of ascarosides binding by Na-ASP-2 and to understand the physiological significance of these observations.

16.
Biophys J ; 118(2): 492-504, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31839263

RESUMO

The attractant chemotaxis response of Escherichia coli to norepinephrine requires that it be converted to 3,4-dihydroxymandelic acid (DHMA) by the monoamine oxidase TynA and the aromatic aldehyde dehydrogenase FeaB. DHMA is sensed by the serine chemoreceptor Tsr, and the attractant response requires that at least one subunit of the periplasmic domain of the Tsr homodimer (pTsr) has an intact serine-binding site. DHMA that is generated in vivo by E. coli is expected to be a racemic mixture of the (R) and (S) enantiomers, so it has been unclear whether one or both chiral forms are active. Here, we used a combination of state-of-the-art tools in molecular docking and simulations, including an in-house simulation-based docking protocol, to investigate the binding properties of (R)-DHMA and (S)-DHMA to E. coli pTsr. Our studies computationally predicted that (R)-DHMA should promote a stronger attractant response than (S)-DHMA because of a consistently greater-magnitude piston-like pushdown of the pTsr α-helix 4 toward the membrane upon binding of (R)-DHMA than upon binding of (S)-DHMA. This displacement is caused primarily by interaction of DHMA with Tsr residue Thr156, which has been shown by genetic studies to be critical for the attractant response to L-serine and DHMA. These findings led us to separate the two chiral species and test their effectiveness as chemoattractants. Both the tethered cell and motility migration coefficient assays validated the prediction that (R)-DHMA is a stronger attractant than (S)-DHMA. Our study demonstrates that refined computational docking and simulation studies combined with experiments can be used to investigate situations in which subtle differences between ligands may lead to diverse chemotactic responses.


Assuntos
Proteínas de Bactérias/metabolismo , Quimiotaxia , Escherichia coli/citologia , Escherichia coli/metabolismo , Ácidos Mandélicos/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Proteínas de Bactérias/química , Proteínas de Membrana/química , Simulação de Dinâmica Molecular , Conformação Proteica
17.
Org Lett ; 21(18): 7394-7399, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31498642

RESUMO

A pharmacophore-directed retrosynthesis strategy applied to rameswaralide provided simplified precursors bearing the common 5,5,6 (red) and 5,5,7 (blue) skeleton present in several cembranoid and norcembranoids from Sinularia soft corals. Key steps include a Diels-Alder lactonization organocascade delivering the common 5,5,6 core and a subsequent ring expansion affording a 5,5,7 core serviceable for the synthesis of rameswaralide. Initial structure-activity relationships of intermediates en route to the natural product have revealed interesting differential and selective cytotoxicity.


Assuntos
Antozoários/química , Produtos Biológicos/farmacologia , Diterpenos/farmacologia , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos/síntese química , Diterpenos/química , Humanos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade
18.
ACS Chem Neurosci ; 10(9): 4102-4111, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31387354

RESUMO

The search for compounds capable of targeting early pathological changes of Alzheimer̀s disease (AD), such as oxidative stress and neuroinflammation, is an important challenge. Gracilin A derivatives were recently synthesized, using a pharmacophore-directed retrosynthesis (PDR) strategy, and found to possess potent neuroprotective effects. In this work, the previously described derivatives 1-7 which demonstrated mitochondrial-mediated, antioxidant effects were chosen for further study. The ability of compounds to modulate the expression of antioxidant genes (CAT, GPx, SODs, and Nrf2) was determined in SH-SY5Y cells, and the simplified derivatives 2 and 3 were found to be the most effective. The anti-neuroinflammatory properties of all derivatives were assessed in BV2 microglial cells activated with lipopolysaccharide (LPS). Several derivatives decreased the release of cytokines (Il-1ß, IL-6, GM-CSF, and TNF-α) and other damaging molecules (ROS, NO) and also regulated the translocation of Nrf2 and NFκB, and reduced p38 activation. These protective effects were confirmed in a trans-well coculture with BV2 and SH-SY5Y cells and several derivatives increased SH-SY5Y survival. This present work demonstrates the neuroprotective properties of gracilin A derivatives, making them promising candidate drugs for AD. Particularly, derivatives 2 and 3 showed the greatest potential as lead compounds for further development.


Assuntos
Acetatos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Diterpenos/farmacologia , Furanos/farmacologia , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/farmacologia , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia
19.
Nat Chem ; 11(4): 342-350, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30903037

RESUMO

The architecture and bioactivity of natural products frequently serve as embarkation points for the exploration of biologically relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure-activity relationships. However, synthetic strategies towards a natural product are not always guided by hypotheses regarding the structural features required for bioactivity. Here, we report an approach to natural product total synthesis that we term 'pharmacophore-directed retrosynthesis'. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in the structural complexity of this minimal structure enable development of a structure-activity relationship profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort, as demonstrated here for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activity.


Assuntos
Acetatos/química , Diterpenos/química , Furanos/química , Imunossupressores/química , Fármacos Neuroprotetores/química , Acetatos/síntese química , Acetatos/farmacologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Reação de Cicloadição , Diterpenos/síntese química , Diterpenos/farmacologia , Desenho de Fármacos , Furanos/síntese química , Furanos/farmacologia , Humanos , Imunossupressores/síntese química , Imunossupressores/farmacologia , Membranas Mitocondriais/metabolismo , Conformação Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
20.
Leukemia ; 33(7): 1663-1674, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30700841

RESUMO

The viability of chronic lymphocytic leukemia (CLL) is critically dependent upon staving off death by apoptosis, a hallmark of CLL pathophysiology. The recognition that Mcl-1, a major component of the anti-apoptotic response, is intrinsically short-lived and must be continually resynthesized suggested a novel therapeutic approach. Pateamine A (PatA), a macrolide marine natural product, inhibits cap-dependent translation by binding to the initiation factor eIF4A. In this study, we demonstrated that a synthetic derivative of PatA, des-methyl des-amino PatA (DMDAPatA), blocked mRNA translation, reduced Mcl-1 protein and initiated apoptosis in CLL cells. This action was synergistic with the Bcl-2 antagonist ABT-199. However, avid binding to human plasma proteins limited DMDAPatA potency, precluding further development. To address this, we synthesized a new series of PatA analogs and identified three new leads with potent inhibition of translation. They exhibited less plasma protein binding and increased cytotoxic potency toward CLL cells than DMDAPatA, with greater selectivity towards CLL cells over normal lymphocytes. Computer modeling analysis correlated their structure-activity relationships and suggested that these compounds may act by stabilizing the closed conformation of eIF4A. Thus, these novel PatA analogs hold promise for application to cancers within the appropriate biological context, such as CLL.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos de Epóxi/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Macrolídeos/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Tiazóis/farmacologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada , Fator de Iniciação 4A em Eucariotos/química , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Prognóstico , Conformação Proteica , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Tumorais Cultivadas
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