RESUMO
A deâ novo asymmetric strategy for the synthesis of d-bradyrhizose diastereomers from an achiral ketoenolester precursor is described. Key transformations used in the stereodivergent approach include two Noyori asymmetric reductions, an Achmatowicz rearrangement, diastereoselective alkene oxidations, and the first example of a palladium(0)-catalyzed glycosylation of a vinylogous pyranone. The isomeric composition of the bicyclic reducing sugars obtained was analyzed and their behaviour was compared to the natural product, revealing key stereocentres that impact the overall distribution.
RESUMO
BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by an accumulation of immature leukemic myeloblasts initiating from leukemic stem cells (LSCs)-the subpopulation that is also considered the root cause of chemotherapy resistance. Repurposing cardiac glycosides to treat cancers has gained increasing attention and supporting evidence, but how cardiac glycosides effectively target LSCs, e.g., whether it involves cell differentiation, remains largely unexplored. METHODS: Digoxin, a user-designed digitoxigenin-α-L-rhamnoside (D6-MA), and ouabain were tested against various human AML-derived cells with different maturation phenotypes. Herein, we established two study models to specifically determine the effects of cardiac glycosides on LSC death and differentiation-one allowed change in dynamics of LSCs and leukemic progenitor cells (LPCs), while another maintained their undifferentiated status. Regulatory mechanisms underlying cardiac glycoside-induced cytotoxicity were investigated and linked to cell cycle distribution and apoptotic machinery. RESULTS: Primitive AML cells containing CD34+ LSCs/LPCs were very responsive to nanomolar concentrations of cardiac glycosides, with ouabain showing the greatest efficiency. Ouabain preferentially induces caspase-dependent apoptosis in LSCs, independent of its cell differentiation status, as evidenced by (i) the tremendous induction of apoptosis by ouabain in AML cells that acquired less than 15% differentiation and (ii) the higher rate of apoptosis in enriched LSCs than in LPCs. We sorted LSCs and LPCs according to their cell cycle distribution into G0/G1, S, and G2/M cells and revealed that G0/G1 cells in LSCs, which was its major subpopulation, were the top ouabain responders, indicating that the difference in ouabain sensitivity between LSCs and LPCs involved both distinct cell cycle distribution and intrinsic apoptosis regulatory mechanisms. Further, Mcl-1 and c-Myc, which were differentially expressed in LSCs and LPCs, were found to be the key apoptosis mediators that determined ouabain sensitivity in AML cells. Ouabain induces a more rapid loss of Mcl-1 and c-Myc in LSCs than in LPCs via the mechanisms that in part involve an inhibition of Mcl-1 protein synthesis and an induction of c-Myc degradation. CONCLUSIONS: Our data provide new insight for repurposing cardiac glycosides for the treatment of relapsed/refractory AML through targeting LSCs via distinct cell cycle and apoptosis machinery. Video Abstract.
Assuntos
Glicosídeos Cardíacos , Leucemia Mieloide Aguda , Humanos , Glicosídeos Cardíacos/farmacologia , Glicosídeos Cardíacos/metabolismo , Glicosídeos Cardíacos/uso terapêutico , Ouabaína/farmacologia , Ouabaína/metabolismo , Ouabaína/uso terapêutico , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Leucemia Mieloide Aguda/patologia , Diferenciação Celular , Células-Tronco/metabolismo , Células-Tronco Neoplásicas/metabolismo , ApoptoseRESUMO
An effort toward the total synthesis of the polyketide natural product EBC-23 is reported. The asymmetric approach is convergent and uses a late-stage Claisen-like enolate/acid chloride coupling to establish a key 1,3-diketone intermediate. The 1,3-diketone target is an oxidized form of the hydrated natural product, which fails to spiroketalize. The convergent asymmetric synthesis uses an asymmetric Noyori transfer hydrogenation of a ß-furyl ketoester to enantioselectively form a chiral furyl alcohol. An Achmatowicz/Jones/Luche three-step reaction sequence was used to stereoselectively convert the furyl alcohol into the 5-hydroxy-pyran-2-one. The absolute stereochemistry of the 1,3-polyol fragment was established by a Leighton allylation. A subsequent Grubbs cross-metathesis, and Evans acetalation were used to install the 1,3-syn-diol stereochemistry.
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Produtos Biológicos , Compostos de Espiro , Piranos , EstereoisomerismoRESUMO
A diastereoselective synthesis of the ß-anomer of glycinamide ribonucleotide (ß-GAR) has been developed. The synthesis was accomplished in nine steps from D-ribose and occurred in 5% overall yield. The route provided material on the multi-milligram scale. The synthetic ß-GAR formed was remarkably resistant to anomerization both in solution and as a solid.
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Hidroximetil e Formil Transferases , Glicina/análogos & derivados , Fosforribosilglicinamido Formiltransferase , RibonucleotídeosRESUMO
Cardiac glycosides, such as digoxin and digitoxin, are compounds that interact with Na+ /K+ -ATPase to induce anti-neoplastic effects; however, these cardiac glycosides have narrow therapeutic index. Thus, semi-synthetic analogs of digitoxin with modifications in the sugar moiety has been shown to be an interesting approach to obtain more selective and more effective analogs than the parent natural product. Therefore, the aim of this study was to assess the cytotoxic potential of novel digitoxigenin derivatives, digitoxigenin-α-L-rhamno-pyranoside (1) and digitoxigenin-α-L-amiceto-pyranoside (2), in cervical carcinoma cells (HeLa) and human diploid lung fibroblasts (Wi-26-VA4). In addition, we studied the anticancer mechanisms of action of these compounds by comparing its cytotoxic effects with the potential to modulate the activity of three P-type ATPases; Na+ /K+ -ATPase, sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA), and plasma membrane Ca2+ -ATPase (PMCA). Briefly, the results showed that compounds 1 and 2 were more cytotoxic and selectivity for HeLa tumor cells than the nontumor cells Wi-26-VA4. While the anticancer cytotoxicity in HeLa cells involves the modulation of Na+ /K+ -ATPase, PMCA and SERCA, the modulation of these P-type ATPases was completely absent in Wi-26-VA4 cells, which suggest the importance of their role in the cytotoxic effect of compounds 1 and 2 in HeLa cells. Furthermore, the compound 2 inhibited directly erythrocyte ghosts PMCA and both compounds were more cytotoxic than digitoxin in HeLa cells. These results provide a better understanding of the mode of action of the synthetic cardiac glycosides and highlights 1 and 2 as potential anticancer agents.
Assuntos
Membrana Celular/enzimologia , Digitoxigenina , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Membrana Celular/genética , Digitoxigenina/análogos & derivados , Digitoxigenina/farmacologia , Células HeLa , Humanos , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
Identifying isoform-specific inhibitors for closely related kinase family members remains a substantial challenge. The necessity for achieving this specificity is exemplified by the RSK family, downstream effectors of ERK1/2, which have divergent physiological effects. The natural product, SL0101, a flavonoid glycoside, binds specifically to RSK1/2 through a binding pocket generated by an extensive conformational rearrangement within the RSK N-terminal kinase domain (NTKD). In modelling experiments a single amino acid that is divergent in RSK3/4 most likely prevents the required conformational rearrangement necessary for SL0101 binding. Kinetic analysis of RSK2 association with SL0101 and its derivatives identified that regions outside of the NTKD contribute to stable inhibitor binding. An analogue with an n-propyl-carbamate at the 4" position on the rhamnose moiety was identified that forms a highly stable inhibitor complex with RSK2 but not with RSK1. These results identify a SL0101 modification that will aid the identification of RSK2 specific inhibitors.
Assuntos
Benzopiranos/síntese química , Monossacarídeos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Sequência de Aminoácidos , Benzopiranos/metabolismo , Carbamatos/química , Humanos , Cinética , Modelos Moleculares , Monossacarídeos/metabolismo , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Ramnose/química , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Relação Estrutura-AtividadeRESUMO
The synthesis of two series of five kaempfer-3-ols was described. The first set all have a C-3 hydroxyl group and the second has a carboxymethoxy ether at the C-3 position. Both series have variable substitution at the C-4' position (i.e., OH, Cl, F, H, OMe). Both kaempferols and carboxymethoxy ethers were evaluated for their ability to inhibit ribosomal s6 kinase (RSK) activity and cancer cell proliferation.
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Fosforilação , Proliferação de CélulasRESUMO
Dynamic photoswitches in proteins that impart spatial and temporal control are important to manipulate and study biotic and abiotic processes. Nonetheless, approaches to install these switches into proteins site-specifically are limited. Herein we describe a novel site-specific method to generate photoremovable protein conjugates. Amine-containing chromophores (e.g., venerable o-nitrobenzyl and less-explored o-nitrophenylethyl groups) were incorporated via transamidation into a glutamine side chain of α-gliadin, LCMV, and TAT peptides, as well as ß-casein and UmuD proteins by transglutaminase (TGase, EC 2.3.2.13). Subsequently, photolysis regenerated the native peptides and proteins. When this modification leads to the reduction or abolishment of certain activities, the process is referred to as caging, as in the case for E. coli polymerase manager protein UmuD. Importantly, this method is simple, robust, and easily adaptable, e.g., all components are commercially available.
Assuntos
Corantes/química , Glutamina/química , Nitrobenzenos/química , Proteínas/química , Transglutaminases/química , Animais , Biocatálise , Humanos , Luz , Modelos Moleculares , Peptídeos/química , FotóliseRESUMO
The de novo asymmetric synthesis of all possible stereoisomers of two polyketide natural products, avocadyne, avocadene, and the saturated variant avocadane, is described. The stereodivergent synthesis of the 12 congeners is accomplished in 4-6 steps from an achiral acylpyruvate derivative, which, in turn, is prepared in five steps from commercially available materials. The approach uses, sequentially, a Noyori asymmetric reduction, a diastereoselective chelate- or directed reduction of a ß-hydroxyketone, and an ester reduction to a primary alcohol.
Assuntos
Técnicas de Química Sintética/métodos , Policetídeos/síntese química , Estrutura Molecular , Persea/química , Policetídeos/química , EstereoisomerismoRESUMO
Tetrahydrolipstatin (THL) is a covalent inhibitor of many serine esterases. In mycobacteria, THL has been found to covalently react with 261 lipid esterases upon treatment of Mycobacterium bovis cell lysate. However, the covalent adduct is considered unstable in some cases because of the hydrolysis of the enzyme-linked THL adduct resulting in catalytic turnover. In this study, a library of THL stereoderivatives was tested against three essential Mycobacterium tuberculosis lipid esterases of interest for drug development to assess how the stereochemistry of THL affects respective enzyme inhibition and allows for cross enzyme inhibition. The mycolyltransferase Antigen 85C (Ag85C) was found to be stereospecific with regard to THL; covalent inhibition occurs within minutes and was previously shown to be irreversible. Conversely, the Rv3802 phospholipase A/thioesterase was more accepting of a variety of THL configurations and uses these compounds as alternative substrates. The reaction of the THL stereoderivatives with the thioesterase domain of polyketide synthase 13 (Pks13-TE) also leads to hydrolytic turnover and is nonstereospecific but occurs on a slower, multihour time scale. Our findings suggest the stereochemistry of the ß-lactone ring of THL is important for cross enzyme reactivity, while the two stereocenters of the peptidyl arm can affect enzyme specificity and the catalytic hydrolysis of the ß-lactone ring. The observed kinetic data for all three target enzymes are supported by recently published X-ray crystal structures of Ag85C, Rv3802, and Pks13-TE. Insights from this study provide a molecular basis for the kinetic modulation of three essential M. tuberculosis lipid esterases by THL and can be applied to increase potency and enzyme residence times and enhance the specificity of the THL scaffold.
Assuntos
Esterases/antagonistas & inibidores , Lactonas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Esterases/química , Humanos , Hidrólise , Cinética , Lactonas/química , Lipase/química , Lipídeos/antagonistas & inibidores , Lipídeos/química , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/patogenicidade , Orlistate , Tuberculose/enzimologia , Tuberculose/microbiologiaRESUMO
While there are targeted treatments for triple positive breast cancers, lack of specific biomarkers for triple-negative breast cancers (TNBC) has hindered the development of therapies for this subset of cancers. In this study, we evaluated the anticancer properties of cardiac glycoside Digitoxin (Dtx) and its synthetic analog MonoD on breast cancer cell lines MCF-7 (estrogen receptor-positive breast cancer) and MDA-MB-468 (triple-negative breast cancer). Both cardiac glycosides, at concentrations within the therapeutic range, increased the fraction of cells in the G0/G1 phase of the cell cycle, decreased viability, and inhibited the migration of MCF-7 and MDA-MB-468 cells. Both cardiac glycosides increased production of superoxide and induced apoptosis in both cell types. Reduced protein levels of nuclear factor kappa B and IkappaB kinase-beta were found in cardiac glycoside-treated cells, indicating that the cellular effects of these compounds are mediated via nuclear factor kappa B pathway. This study demonstrates the cytotoxic potential of digitoxin, and more importantly its synthetic analog MonoD, in the treatment of triple-positive breast cancer and more importantly the aggressive triple-negative breast cancer. Collectively, this study provides a basis for the reevaluation of cardiac glycosides in the treatment of breast cancer and more importantly reveals their potential in the treatment of triple-negative breast cancers.
Assuntos
Digitoxina/administração & dosagem , Receptores de Estrogênio/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Carcinogênese/genética , Glicosídeos Cardíacos/genética , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Digitoxina/análogos & derivados , Feminino , Humanos , Células MCF-7 , Camundongos , NF-kappa B/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Multiple factors including tumor heterogeneity and intrinsic or acquired resistance have been associated with drug resistance in lung cancer. Increased stemness and the plasticity of cancer cells have been identified as important mechanisms of resistance; therefore, treatments targeting cancer cells independent of stemness phenotype would be much more effective in treating lung cancer. In this article, we have characterized the anticancer effects of the antibiotic Nigericin in cells displaying varying degrees of stemness and resistance to anticancer drugs, arising from (1) routine culture conditions, (2) prolonged periods of serum starvation. These cells are highly resistant to conventional anticancer drugs such as Paclitaxel, Hydroxyurea, Colchicine, Obatoclax, Wortmannin, and LY294002, and the multidrug-resistant phenotype of cells growing under prolonged periods of serum starvation is likely the result of extensive rewiring of signaling pathways, and (3) lung tumorspheres that are enriched for cancer stem-like cells. We found that Nigericin potently inhibited the viability of cells growing under routine culture conditions, prolonged periods of serum starvation, and lung tumorspheres. In addition, we found that Nigericin downregulated the expression of key proteins in the Wnt canonical signaling pathway such as LRP6, Wnt5a/b, and ß-catenin, but promotes ß-catenin translocation into the nucleus. The antitumor effects of Nigericin were potentiated by the Wnt activator HLY78 and by therapeutic levels of the US Food and Drug Administration-approved drug Digitoxin and its novel synthetic analog MonoD. We believe that Nigericin may be used in a co-therapy model in combination with other novel chemotherapeutic agents in order to achieve potent inhibition of cancers that display varying degrees of stemness, potentially leading to sustained anticancer effects.
Assuntos
Benzodioxóis/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Nigericina/administração & dosagem , Fenantridinas/administração & dosagem , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Citocinas/química , Citocinas/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Isoindóis/química , Isoindóis/farmacocinética , Isoindóis/farmacologia , Isoindóis/uso terapêutico , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Nicotinamida Fosforribosiltransferase/química , Nicotinamida Fosforribosiltransferase/metabolismo , Relação Estrutura-Atividade , Ureia/farmacocinética , Ureia/uso terapêuticoRESUMO
We have synthesized a novel derivative of Digitoxin, termed "MonoD", which demonstrates cytotoxic effects in lung cancer cells with much higher potency as compared to Digitoxin. Our data show that within 1 h of MonoD treatment, H460 cells showed increased oxidative stress, increased formation of autophagic vacuoles, and increased expression of pro-autophagic markers Beclin-1 and LC3-II. Cells pretreated with MnTBAP, a superoxide scavenger not only lowered superoxide production, but also had lower levels of LC3-II and Beclin-1. Prolonged treatment with MonoD-induced apoptosis in lung cancer cells. We investigated MonoD-dependent regulation of Akt and Bcl2, proteins that are known regulators of both autophagy and apoptosis. Molecular and pharmacologic inhibitors of Bcl2 and Akt, when combined with MonoD, led to higher expression of LC3-II and Beclin-1 as compared to MonoD alone, suggesting a repressive effect for these proteins in MonoD-dependent autophagy. Pretreatment of cells with an autophagy inhibitor repressed the apoptotic potential of MonoD, confirming that early autophagic flux is important to drive apoptosis. Therapeutic entities such as MonoD that target multiple pathways such as autophagy and apoptosis may prove advantageous over current therapies that have unimodal basis for action and may drive sustained tumor regression, which is highly desirable. J. Cell. Physiol. 231: 817-828, 2016. © 2015 Wiley Periodicals, Inc.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Digitoxina/análogos & derivados , Digitoxina/farmacologia , Neoplasias Pulmonares/patologia , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Digoxigenina/análogos & derivados , Digoxigenina/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Modelos Biológicos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Superóxidos/metabolismo , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismoRESUMO
An enantioselective de novo synthesis of a thioglycoside derivative of the 6-O-methyl-D-glycero-L-gluco-heptopyranose residue found in the Campylobacter jejuni NCTC11168 (HS:2) capsular polysaccharide is reported. The compound is obtained from a furfural-derived chiral diol in 11 steps. Notably, compared to the only previous synthesis of this molecule, this approach significantly reduces the number of purification steps required to obtain the target.
Assuntos
Campylobacter jejuni/química , Glicerol/análogos & derivados , Monossacarídeos/síntese química , Polissacarídeos/química , Tioglicosídeos/química , Cápsulas Bacterianas/química , Glicerol/síntese química , Glicerol/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Monossacarídeos/química , Estereoisomerismo , Tioglicosídeos/análiseRESUMO
Flexible acyclic alcohols with one to five hydroxyl groups were bound to a chloride anion and these complexes were interrogated by negative ion photoelectron spectroscopy and companion density functional theory computations. The resulting vertical detachment energies are reproduced on average to 0.10 eV by M06-2X/aug-cc-pVTZ predictions and range from 4.45-5.96 eV. These values are 0.84-2.35 eV larger than the adiabatic detachment energy of Cl(-) as a result of the larger hydrogen bond networks in the bigger polyols. Adiabatic detachment energies of the alcohol-Cl(-) clusters are more difficult to determine both experimentally and computationally. This is due to the large geometry changes that occur upon photodetachment and the large bond dissociation energy of H-Cl which enables the resulting chlorine atom to abstract a hydrogen from any of the methylene (CH2) or methine (CH) positions. Both ionic and nonionic hydrogen bonds (i.e., OH···Cl(-) and OH···OH···Cl(-)) form in the larger polyols complexes and are found to be energetically comparable. Subtle structural differences, consequently can lead to the formation of different types of hydrogen bonds, and maximizing the ionic ones is not always preferred. Solution equilibrium binding constants between the alcohols and tetrabutylammonium chloride (TBACl) in acetonitrile at -24.2, +22.0, and +53.6 °C were also determined. The free energies of association are nearly identical for all of the substrates (i.e., ΔG° = -2.8 ± 0.7 kcal mol(-1)). Compensating enthalpy and entropy values reveal, contrary to expectation and the intrinsic gas-phase preferences, that the bigger systems with more hydroxyl groups are entropically favored and enthalpically disfavored relative to the smaller species. This suggests that more solvent molecules are released upon binding TBACl to alcohols with more hydroxyl groups and is consistent with the measured negative heat capacities. These quantities increase with molecular complexity of the substrate, however, contrary to common interpretation of these values.
RESUMO
The de novo asymmetric total syntheses of daumone 1, daumone 3 along with 5 new analogs are described. The key steps of our approach are: the diastereoselective palladium catalyzed glycosylation reaction; the Noyori reduction of 2-acetylfuran and an ynone, which introduce the absolute stereochemistry of the sugar and aglycon portion of daumone; and an Achmatowicz rearrangement, an epoxidation and a ring opening installing the remaining asymmetry of daumone. The synthetic daumones 1 and 3 as well as related analogs were evaluated for dauer activity in C. elegans and for effects on hatching of the related nematode H. glycines. This data provides additional structure activity relationships (SAR) that further inform the study of nematode signaling.
RESUMO
A concise enantioselective synthesis of tetrahydrolipstatin (THL) and seven stereoisomers has been achieved. The synthesis of THL was accomplished in 10 steps and 31% overall yield from an achiral ynone. Key to the success of the approach is the use of a bimetallic [Lewis acid](+)[Co(CO)4](-) catalyst for a late-stage regioselective carbonylation of an enantiomerically pure cis-epoxide to a trans-ß-lactone. The success of this route to THL and its stereoisomers also demonstrated the practicality of the carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility.
Assuntos
Fármacos Antiobesidade/síntese química , Inibidores Enzimáticos/síntese química , Compostos de Epóxi/química , Lactonas/síntese química , Propanóis/química , Fármacos Antiobesidade/química , Inibidores Enzimáticos/química , Lactonas/química , Orlistate , EstereoisomerismoRESUMO
Rapid and accessible testing was paramount in the management of the COVID-19 pandemic. Our university established KCL TEST: a SARS-CoV-2 asymptomatic testing programme that enabled sensitive and accessible PCR testing of SARS-CoV-2 RNA in saliva. Here, we describe our learnings and provide our blueprint for launching diagnostic laboratories, particularly in low-resource settings. Between December 2020 and July 2022, we performed 158277 PCRs for our staff, students, and their household contacts, free of charge. Our average turnaround time was 16 h and 37 min from user registration to result delivery. KCL TEST combined open-source automation and in-house non-commercial reagents, which allows for rapid implementation and repurposing. Importantly, our data parallel those of the UK Office for National Statistics, though we detected a lower positive rate and virtually no delta wave. Our observations strongly support regular asymptomatic community testing as an important measure for decreasing outbreaks and providing safe working spaces. Universities can therefore provide agile, resilient, and accurate testing that reflects the infection rate and trend of the general population. Our findings call for the early integration of academic institutions in pandemic preparedness, with capabilities to rapidly deploy highly skilled staff, as well as develop, test, and accommodate efficient low-cost pipelines.
RESUMO
The first total syntheses and structural elucidation of cryptocaryol A and cryptocaryol B were achieved in 23 and 25 linear steps, respectively. The synthesis relied on the use of a key pseudo-Cs symmetric pentaol intermediate, which in a stereochemically divergent manner was converted into either enantiomer as well as diastereomers. This synthetic effort enabled the first structure-activity relationships of this class of PDCD4 stabilizing natural products.