RESUMO
Chromatographic behavior of novel chiral stationary phases with bonded selectors based on Cinchona alkaloids modified with dipeptides was studied using dipeptides as probe molecules. Buffer-free and salt containing hydro-organic solutions were used as the mobile phases. The selectors exhibit pseudoenantiomeric behavior with respect to the L/D or LL/DD enantiomers and do not behave so with respect to the LD/DL enantiomers. The alkaloid part of the selectors is the driver of enantioselectivity, while the dipeptide substituent plays a modulating role. The quinidine-based selectors demonstrate stronger adsorption affinity and higher enantioselectivity as compared to the quinine-based selectors. The dipeptide analytes containing a glycyl fragment are weaker retained and their enantiomers are worse separated comparing to dipeptides with both units being larger amino acids. Moreover, a phenyl group in the structure of a dipeptide analyte facilitates enantioseparation. The effect of the mobile phase composition on retention depends on the hydrophobicity of an analyte. Hydrophobic dipeptides are better eluted by methanol-rich solvents, hydrophilic dipeptides are better eluted with water-rich solvents, and dipeptides with an intermediate hydrophobicity demonstrate a U-shaped or more complicated dependence of the retention factor on the percentage of methanol. Even a small buffer addition to the mobile phase decreases retention, but the ion-exchange mechanism was not confirmed. The effect of an electrolyte is rather due to the shielding of the charged groups of the selector reducing thereby electrostatic interaction between the selector and analyte. Efficiency of the novel columns is comparable to that of other brush-type chiral columns, the highest achieved number of the theoretical plates per 1 m varying between 30,000 and 40,000.
Assuntos
Cromatografia de Fase Reversa , Alcaloides de Cinchona , Dipeptídeos , Interações Hidrofóbicas e Hidrofílicas , Alcaloides de Cinchona/química , Dipeptídeos/química , Dipeptídeos/isolamento & purificação , Estereoisomerismo , Cromatografia de Fase Reversa/métodos , Cromatografia Líquida de Alta Pressão/métodos , Quinina/química , Quinina/isolamento & purificaçãoRESUMO
Chiral resolution of polar organic compounds such as amino acids and peptides represents an important chromatographic task due to increasing significance of natural species, which play important signaling and regulatory roles in the living organisms. Despite the number of available chiral stationary phases, this task remains challenging, since not many of the commercially available systems are capable to resolve non-derivatized zwitterionic species. In this study, we present a target-oriented design of a new class of chiral selectors. Pursuing the goal to separate amino acids, and especially short peptides, we have combined Cinchona alkaloids - quinine and quinidine - with three different biogenic dipeptides. We have synthesized six different chiral stationary phases, with selector loading of â¼200 µmol g-1, and tested their chiral recognition capabilities for acidic, basic and zwitterionic analytes using various mobile phases. We have observed that all chiral stationary phases retain the chiral anion exchange capability known for commercially available Cinchona-based columns leading to baseline or partial resolution of six out of ten analytes. The performance in chiral resolution of basic analytes is not optimum due to the weak cation exchange character of the peptidic residue. However, we report on encouraging results in the chiral resolution of short peptides, for which, depending on their structure, we see the chiral resolution of up to three stereoisomers (from four possible) in a preliminary screening.
Assuntos
Alcaloides de Cinchona , Cinchona , Dipeptídeos , Alcaloides de Cinchona/química , Quinina/química , Quinidina , Aminoácidos/química , Aminas , Estereoisomerismo , Cromatografia Líquida de Alta Pressão/métodosRESUMO
About 247 million cases of malaria occurred in 2021 with Plasmodium falciparum accounting for the majority of 619,000 deaths. In the absence of a widely available vaccine, chemotherapy remains crucial to prevent, treat, and contain the disease. The efficacy of several drugs currently used in the clinic is likely to suffer from the emergence of resistant parasites. A global effort to identify lead compounds led to several initiatives such as the Medicine for Malaria Ventures (MMV), a repository of compounds showing promising efficacy in killing the parasite in cell-based assays. Here, we used mass spectrometry coupled with cellular thermal shift assay to identify putative protein targets of MMV000848, a compound with an in vitro EC50 of 0.5 µM against the parasite. Thermal shift assays showed a strong increase of P. falciparum purine nucleoside phosphorylase (PfPNP) melting temperature by up to 15 °C upon incubation with MMV000848. Binding and enzymatic assays returned a KD of 1.52 ± 0.495 µM and an IC50 value of 21.5 ± 2.36 µM. The inhibition is competitive with respect to the substrate, as confirmed by a cocrystal structure of PfPNP bound with MMV000848 at the active site, determined at 1.85 Å resolution. In contrast to transition states inhibitors, MMV000848 specifically inhibits the parasite enzyme but not the human ortholog. An isobologram analysis shows subadditivity with immucillin H and with quinine respectively, suggesting overlapping modes of action between these compounds. These results point to PfPNP as a promising antimalarial target and suggest avenues to improve inhibitor potency.
Assuntos
Antimaláricos , Plasmodium falciparum , Purina-Núcleosídeo Fosforilase , Antimaláricos/química , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Purina-Núcleosídeo Fosforilase/química , Quinina/química , Espectrometria de Massas , Ligação ProteicaRESUMO
Isothermal titration calorimetry (ITC) is a technique where the heat given off, or absorbed, during a binding event is measured and used to determine the binding thermodynamics and affinity associated with binding. This protocol focuses on ITC applications for studying aptamer interactions with small molecule ligands where ITC has the advantage of being a label-free solution-based technique. The limitation of ITC using a relatively large amount of material compared to other analytical techniques is not applicable here as large amounts of nucleic acids, especially DNA, can be readily obtained. In this chapter we describe how to use ITC methods to measure the thermodynamics and affinity of binding using the interaction of quinine with a DNA cocaine-binding aptamer as an example.
Assuntos
Aptâmeros de Nucleotídeos , Cocaína , Ácidos Nucleicos , Aptâmeros de Nucleotídeos/química , Calorimetria/métodos , Cocaína/química , Ligantes , Ácidos Nucleicos/metabolismo , Ligação Proteica , Quinina/química , TermodinâmicaRESUMO
A series of N-Boc ketimines derived from pyrazolin-5-ones have been used as electrophiles in enantioselective Mannich reactions with different 1,3-dicarbonyl compounds. This method provides a direct pathway to access the 4-amino-5-pyrazolone derivatives bearing a quaternary substituted stereocenter and containing two privileged structure motifs, the ß-diketone and pyrazolinone substructures. The adducts were obtained in excellent yields (up to 90%) and enantioselectivities (up to 94:6 er) by employing a very low loading of 2 mol% of a quinine-derived bifunctional squaramide as an organocatalyst for a wide range of substrates. In addition, the utility of the obtained products was demonstrated through one step transformations to enantioenriched diheterocyclic systems (4-pyrazolyl-pyrazolone and 4-isoxazolyl-pyrazolone), potentially promising candidates for drug discovery.
Assuntos
Pirazolonas , Quinina , Quinina/química , Estereoisomerismo , Estrutura Molecular , Catálise , Pirazolonas/químicaRESUMO
This study developed a simple flow injection (FI) method based on diperiodatonickelate(IV)-sulfuric acid reaction using chemiluminescence (CL) detection for the determination of thiram (THI) fungicide in fresh water using quinine as the sensitizer. The possible mechanism of the CL reaction was described using UV-Vis. absorption and CL spectra. Experimental variables were optimized by applying a univariate approach, and a linear calibration curve was obtained in the range of 1.0 × 10-3 -2.0 mg L-1 (R2 = 0.9994, n = 9) with a limit of detection of 5.0 × 10-4 mg L-1 (S/N = 3) and an injection throughput of 200 h-1 . This approach was successfully applied to determine THI in fresh water by using solid-phase extraction and achieved a good recovery rate of 94%-110% with a relative standard deviation of 1.9%-3.7% (n = 4). The results obtained were compared with the reported FI-CL and high-performance liquid chromatography-ultraviolet methods, and the three methods did not differ significantly at the 95% confidence limit.
Assuntos
Análise de Injeção de Fluxo , Tiram , Análise de Injeção de Fluxo/métodos , Quinina/química , Medições Luminescentes/métodos , Água DoceRESUMO
In contrast to monotopic receptor 3, the anthracene functionalized squaramide dual-host receptor 1 is capable of selectively extracting sulfate salts, as was evidenced unambiguously by DOSY, mass spectrometry, fluorescent and ion chromatography measurements. The receptors were investigated in terms of anion and ion pair binding using the UV-vis and 1H NMR titrations method in acetonitrile. The reference anion receptor 3, lacking a crown ether unit, was found to lose the enhancement in anion binding induced by the presence of cations. Besides the ability to bind anions in an enhanced manner exhibited by ion pair receptors 2 and 4, changing the 1-aminoanthracene substituent resulted in their exhibiting a lower anion affinity than receptor 1. By using receptor 1 and adjusting the water content in organic phase it was possible to selectively detect sulfates both by "turn-off" and "turn-on" fluorescence, and to do so homogenously and under interfacial conditions. Such properties of receptor 1 have allowed the development of a new type of sensor capable of recognizing and extracting potassium sulfate from the aqueous medium across a phase boundary, resulting in an appropriate fluorescent response in the organic solution.
Assuntos
Ânions/química , Antracenos/química , Acetonitrilas/química , Cátions/química , Éteres de Coroa/química , Cristalografia por Raios X/métodos , Fluorescência , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Modelos Moleculares , Quinina/análogos & derivados , Quinina/química , Sulfatos/químicaRESUMO
Cooperative asymmetric catalysis with hydrogen chloride (HCl) and chiral dual-hydrogen-bond donors (HBDs) is applied successfully to highly enantioselective Prins cyclization reactions of a wide variety of simple alkenyl aldehydes. The optimal chiral catalysts were designed to withstand the strongly acidic reaction conditions and were found to induce rate accelerations of 2 orders of magnitude over reactions catalyzed by HCl alone. We propose that the combination of strong mineral acids and chiral hydrogen-bond-donor catalysts may represent a general strategy for inducing enantioselectivity in reactions that require highly acidic conditions.
Assuntos
Álcoois/síntese química , Aldeídos/química , Alcenos/química , Ácido Clorídrico/química , Benzopiranos/síntese química , Catálise , Ciclização , Ligação de Hidrogênio , Quinina/análogos & derivados , Quinina/química , Estereoisomerismo , Tioureia/análogos & derivados , Ureia/análogos & derivadosRESUMO
Organocatalysts, which are less toxic than metal catalysis, as well as inexpensive, environmentally benign, and stable against moisture and oxygen compared to metal-based catalysts, have received considerable attention for being efficient and clean catalysts. With respect to green chemistry, the development of organocatalysis is a significant research subject for a sustainable society. This article reviews studies on the development of novel organocatalysts and the reactions achieved from using them. Focusing on the push-pull ethylene moiety, in which two electron-withdrawing groups (EWGs) were introduced, we proposed that the vinylogous amide proton (N-H) will lead to the design of organocatalysts. We have developed the diaminomethylenemalononitrile (DMM) organocatalysts, which are push-pull ethylenes having two cyano groups as EWGs, and proved that they are effective for highly stereoselective hydrophosphonylation with aldehydes. The catalytic ability of the DMM organocatalyst was demonstrated in the development of the first asymmetric hydrophosphonylation of ketones using organocatalysts. The DMM organocatalyst can be applied to the selective 1,4-addition asymmetric hydrophosphonylation of enones. In addition, we designed and synthesized novel organocatalysts bearing squaramide-sulfonamide motif as multiple hydrogen bond donors. Squaramide-sulfonamide organocatalysts efficiently catalyzed the asymmetric direct vinylogous aldol reactions of furan-2(5H)-one with aldehydes. Successively, we achieved the synthesis of γ,γ-disubstituted-δ-hydroxy-γ-butenolide via asymmetric direct vinylogous aldol reaction of furanone derivatives using the squaramide-sulfonamide organocatalysts.
Assuntos
Química Orgânica/métodos , Química Verde/métodos , Quinina/análogos & derivados , Sulfonamidas/química , Aldeídos/química , Amidas/química , Catálise , Elétrons , Etilenos/química , Ligação de Hidrogênio , Nitrilas/química , Fenômenos de Química Orgânica , Prótons , Quinina/químicaRESUMO
SNM1A is a zinc-dependent nuclease involved in the removal of interstrand crosslink lesions from DNA. Inhibition of interstrand crosslink repair enzymes such as SNM1A is a promising strategy for improving the efficacy of crosslinking chemotherapy drugs. Initial studies have demonstrated the feasibility of developing SNM1A inhibitors, but the full potential of this enzyme as a drug target has yet to be explored. Herein, the synthesis of a family of squaramide- and thiosquaramide-bearing nucleoside derivatives and their evaluation as SNM1A inhibitors is reported. A gel electrophoresis assay was used to identify nucleoside derivatives bearing an N-hydroxysquaramide or squaric acid moiety at the 3'-position, and a thymidine derivative bearing a 5'-thiosquaramide, as candidate SNM1A inhibitors. Quantitative IC50 determination showed that a thymidine derivative bearing a 5'-thiosquaramide was the most potent inhibitor, followed by a thymidine derivative bearing a 3'-squaric acid. UV-Vis titrations were carried out to evaluate the binding of the (thio)squaramides to zinc ions, allowing the order of inhibitory potency to be rationalised. The membrane permeability of the active inhibitors was investigated, with several compounds showing promise for future in vivo applications.
Assuntos
Enzimas Reparadoras do DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Quinina/análogos & derivados , Enzimas Reparadoras do DNA/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Quinina/síntese química , Quinina/química , Quinina/farmacologia , Relação Estrutura-AtividadeRESUMO
Quinine (an antimalarial) and aspirin (a nonsteroidal anti-inflammatory drug) were combined into a new drug-drug salt, quininium aspirinate, C20H25N2O2+·C9H7O4-, by liquid-assisted grinding using stoichiometric amounts of the reactants in a 1:1 molar ratio, and water, EtOH, toluene, or heptane as additives. A tetrahydrofuran (THF) solution of the mechanochemical product prepared using EtOH as additive led to a single crystal of the same material obtained by mechanochemistry, which was used for crystal structure determination at 100â K. Powder X-ray diffraction ruled out crystallographic phase transitions in the 100-295â K interval. Neat mechanical treatment (in a mortar and pestle, or in a ball mill at 20 or 30â Hz milling frequencies) gave rise to an amorphous phase, as shown by powder X-ray diffraction; however, FT-IR spectroscopy unambiguously indicates that a mechanochemical reaction has occurred. Neat milling the reactants at 10 and 15â Hz led to incomplete reactions. Thermogravimetry and differential scanning calorimetry indicate that the amorphous and crystalline mechanochemical products form glasses/supercooled liquids before melting, and do not recrystallize upon cooling. However, the amorphous material obtained by neat grinding crystallizes upon storage into the salt reported. The mechanochemical synthesis, crystal structure analysis, Hirshfeld surfaces, powder X-ray diffraction, thermogravimetry, differential scanning calorimetry, FT-IR spectroscopy, and aqueous solubility of quininium aspirinate are herein reported.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Aspirina/síntese química , Quinina/síntese química , Anti-Inflamatórios não Esteroides/química , Aspirina/química , Varredura Diferencial de Calorimetria , Cristalografia por Raios X , Ligação de Hidrogênio , Preparações Farmacêuticas , Transição de Fase , Quinina/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Difração de Raios XRESUMO
Herein, we report the encapsulation and release of antimalarial drug quinine (QN) using three nanocarriers, including MCM-41 (1), and its 3-aminopropyl silane (aMCM-41 (2)) and 3-phenylpropyl silane (pMCM-41 (3)) surface functionalized derivatives. The pH and thermal optimization effects on QN adsorption and release from 1, 2 and 3 were investigated.
Assuntos
Antimaláricos/química , Nanopartículas/química , Quinina/química , Dióxido de Silício/química , Cápsulas/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Estrutura Molecular , Tamanho da Partícula , Porosidade , Propriedades de SuperfícieRESUMO
Chiral ion exchangers based on quinine (QN) and quinidine (QD), namely Chiralpak QN-AX and QD-AX as anionic and ZWIX(+) and ZWIX(-) as zwitterionic ion exchanger chiral stationary phases (CSPs) have been investigated with respect to their retention and chiral resolution characteristics. For the evaluation of the effects of the composition of the polar organic bulk solvents of the mobile phase (MP) and those of the organic acid and base additives acting as displacers necessary for a liquid chromatographic ion-exchange process, racemic N-(3,5-dinitrobenzoyl)leucine and other related analytes were applied. The main aim was to evaluate the impact of the MP variations on the observed, and thus the apparent enantioselectivity (αapp), and the retention factor. Significant differences were found using either polar protic methanol (MeOH) or polar non-protic acetonitrile (MeCN) solvents in combination with the acid and base additives as counter- and co-ions. It became clear, that the charged sites of both the chiral selectors of the CSPs and the analytes get specifically solvated, accompanied by the adsorption of all MP components on the CSP, thereby building a stagnant "stationary phase layer" with a composition different from the bulk MP. Via a systematic change of the MP composition, trends of resulting αapp and retention factors have been identified and discussed. In a detailed set of experiments, the effect of the concentration of the acid component in the MP containing MeOH or MeCN was specifically investigated, with the acid considered to be a displacer in anion-exchange type chromatographic systems. Surprisingly, all four chiral columns retained and resolved the tested N-acyl-Leu analytes with αapp values up to 21 within a retention factor window of 0.03 and 10 with pure MeOH as eluent. However, using pure MeCN as eluent, an almost infinite-long retention of the acidic analyte was noticed in all cases. We suggest that the rather different thickness of the solvation shells generated by MeOH or MeCN around the charged/chargeable sites of the chiral selector determines eventually the strength of the electrostatic selector-selectand interactions. As a control experiment we included the non-chiral N-acylglycine derivatives as analyte in all cases to support the interpretations with respect to the contribution of the enantioselective and non-enantioselective retention factor increments as a part of the observed αapp.
Assuntos
Cinchona/química , Leucina/química , Solventes/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia por Troca Iônica/métodos , Troca Iônica , Quinidina/química , Quinina/química , EstereoisomerismoRESUMO
The taste-modifying properties of nanofibrillar cellulose (NFC) and carboxymethyl cellulose (CMC) are compared for the first time. The samples were prepared in the form of gels, with and without added sweet and bitter taste components. As viscosity itself is known to affect taste perception, the viscosities of NFC and CMC samples were set to the same level as shear rates commonly found in the oral cavity. A trained panel of 10 assessors evaluated the bitterness and sweetness of the samples. Further, the assessors were given an opportunity to describe the samples in free words. The taste-modifying capacities of the thickening agents were at the same level when sweet compounds were added. However, CMC was better able to reduce the bitterness of quinine hydrochloride than NFC, which did not show any bitterness-reduction ability with the compound. This was unexpected, as our previous studies of NFC showed fairly high binding capacity with quinine. The open-ended responses revealed that the NFC-containing samples had an astringent sensation, while certain assessors observed a sensation of saltiness in the CMC samples. This may explain the inability of NFC to mask the bitterness of quinine hydrochloride, as astringency may act as a bitterness enhancer, while saltiness may suppress it. Both thickening agents were perceived as slightly bitter. Our study reveals the need for further assessment of the orosensory properties of NFC, particularly the magnitude and origin of its astringency, before it can be fully utilized in food industry applications.
Assuntos
Carboximetilcelulose Sódica/química , Celulose/química , Nanofibras/química , Sensação , Percepção Gustatória/fisiologia , Paladar/fisiologia , Adulto , Feminino , Humanos , Masculino , Quinina/química , ViscosidadeRESUMO
The new symmetric acyclic N,N'-bis(1-pyrenyl) squaramide (H2L) functionalized with the pyrene moiety as a fluorogenic fragment has been designed and its ability to selectively detect specific anions and metals investigated. H2L selectively binds Cl- both in solution (DMSO 0.5% H2O and MeCN) and in the solid state, and allows to selectively detect Cu2+ in MeCN with the formation of a 2:1 metal-receptor complex, with a green intense emission appreciable by naked eye under the UV lamp. The H2L copper complex preserves its emission properties in the presence of Cl-. The addition of basic anions (OH-, CN-, and F-) up to 10 equivalents caused the deprotonation of the squaramide NHs and a dramatic change of the emission properties of the H2L copper complex.
Assuntos
Complexos de Coordenação/química , Cobre/química , Pirenos/química , Quinina/análogos & derivados , Acetonitrilas/química , Ânions/química , Teoria da Densidade Funcional , Modelos Moleculares , Conformação Molecular , Quinina/química , Espectrometria de FluorescênciaRESUMO
A short RNA with the sequence of the antisense strand of Patisiran has been selected as test material for the investigation of its common impurities using three different two-dimensional liquid chromatography (2D-LC) platforms. On the one hand, a quinine (QN) carbamate-based weak anion-exchange (AX) stationary phase (QN-AX) and a classical C18 reversed phase (RP) stationary phase in ion-pair (IP) mode with tripropylammonium acetate, respectively, have been used in the first dimension (1D) to provide the selectivity for impurities formed during the synthesis of the RNA. In the next step, certain peaks of interest from 1D have been transferred by multiple-heart-cutting (MHC) into a 2D in which an ESI-MS-compatible non-ionpairing RP method has been used for desalting via a diverter valve to remove non-volatile phosphate buffer components and ion-pair agents, respectively. Thus, a sensitive electrospray-ionization quadrupole time of flight mass spectrometry (ESI-TOF-MS) analysis of resolved impurity peaks of the siRNA has become possible under MS-friendly conditions. With both 2D-LC setups, peak purity of the ON has been evaluated by selective comprehensive (high resolution) sampling of the main peak. In a third MHC 2D-LC approach, the QN-AX LC mode was online coupled with the IP-RPLC in the 2D using UV detection. It allows the separation of additional impurities which coeluted in the first dimension. The potential of these methods for comprehensive impurity profiling of ON therapeutics is illustrated and discussed.
Assuntos
Cromatografia por Troca Iônica/métodos , Cromatografia de Fase Reversa/métodos , RNA Interferente Pequeno/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Sequência de Bases , Carbamatos/química , Cromatografia Líquida de Alta Pressão , Quinina/química , RNA Interferente Pequeno/químicaRESUMO
Radiolabeled derivatives of Tyr3-octreotide and Tyr3-octreotate, synthetic analogues of the peptide hormone somatostatin, can be used for positron emission tomography (PET) imaging of somatostatin receptor expression in neuroendocrine tumors. In this work, a squaramide ester derivative of desferrioxamine B (H3DFOSq) was used attach either Tyr3-octreotide or Tyr3-octreotate to the metal binding ligand to give H3DFOSq-TIDE and H3DFOSq-TATE. These new peptide-H3DFOSq conjugates form stable complexes with either of the positron-emitting radionuclides gallium-68 (t1/2 = 68 min) or zirconium-89 (t1/2 = 3.3 days). The new complexes were evaluated in an AR42J xenograft model that has endogenous expression of SSTR2. All four agents displayed good tumor uptake and produced high-quality PET images. For both radionuclides, the complexes formed with H3DFOSq-TATE performed better, with higher tumor uptake and retention than the complexes formed with H3DFOSq-TIDE. The versatile ligands presented here can be radiolabeled with either gallium-68 or zirconium-89 at room temperature. The long radioactive half-life of zirconium-89 makes distribution of pre-synthesized tracers produced to certified standards feasible and could increase the number of clinical centers that can perform diagnostic PET imaging of neuroendocrine tumors.
Assuntos
Desferroxamina/química , Radioisótopos de Gálio/química , Octreotida/química , Quinina/análogos & derivados , Radioisótopos/química , Somatostatina/metabolismo , Zircônio/química , Animais , Camundongos , Quinina/químicaRESUMO
Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/síntese química , Descoberta de Drogas/métodos , Quimioinformática , Cromonas/química , Griseofulvina/química , Indóis/química , Morfinanos/química , Quinidina/química , Quinina/química , Bibliotecas de Moléculas Pequenas/químicaRESUMO
The enzymatic basis for quinine 1 biosynthesis was investigated. Transcriptomic data from the producing plant led to the discovery of three enzymes involved in the early and late steps of the pathway. A medium-chain alcohol dehydrogenase (CpDCS) and an esterase (CpDCE) yielded the biosynthetic intermediate dihydrocorynantheal 2 from strictosidine aglycone 3. Additionally, the discovery of an O-methyltransferase specific for 6'-hydroxycinchoninone 4 suggested the final step order to be cinchoninone 16/17 hydroxylation, methylation, and keto-reduction.
Assuntos
Metiltransferases/metabolismo , Quinina/química , Quinina/metabolismo , Alcaloides de Vinca/química , Hidroxilação , Estrutura MolecularRESUMO
Herein we report the design, synthesis and assessment of the first example of a squaramide-based self-immolative system triggered by an enzymatic reduction. We have proved that the release of the alkylating agent N',N'-(bis(2-chloroethyl)benzene)-1,4-diamine (ANM) provokes a dramatic reduction of the survival factor in glioblastoma cells, evidencing the suitability of the squaramide-based spacer for drug delivery applications.