Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis.

Recent advances in end-to-end continuous-flow synthesis are rapidly expanding the capabilities of automated customized syntheses of small-molecule pharmacophores, resulting in considerable industrial and societal impacts; however, many hurdles persist that limit the number of sequential steps that can be achieved in such systems, including solvent and reagent incompatibility between individual steps, cumulated by-product formation, risk of clogging and mismatch of timescales between steps in a processing chain. To address these limitations, herein we report a strategy that merges solid-phase synthesis and continuous-flow operation, enabling push-button automated multistep syntheses of active pharmaceutical ingredients. We demonstrate our platform with a six-step synthesis of prexasertib in 65% isolated yield after 32 h of continuous execution. As there are no interactions between individual synthetic steps in the sequence, the established chemical recipe file was directly adopted or slightly modified for the synthesis of twenty-three prexasertib derivatives, enabling both automated early and late-stage diversification.

Elevated CTHRC1 expression is an indicator for poor prognosis and lymph node metastasis in cervical squamous cell carcinoma.

Collagen triple helix repeat containing 1 (CTHRC1) is overexpressed in different kinds of cancer tissues and may thus promote tumor formation. Thus, we aimed to explore whether CTHRC1 could be a predictor of clinical significance including survival in cervical squamous cell carcinoma (CSCC). Western blot analysis was conducted in 20 frozen tissue specimens of CSCC and 10 frozen tissue sections of normal cervix. Immunohistochemistry was performed in 130 tissues with CSCC. The relationships of CTHRC1 expression with clinicopathological variables, and prognosis of CSCCs were explored. Statistical analyses were carried out using χ2 test, multivariate Cox proportional-hazard model, Kaplan-Meier method, and univariate and multivariate logistic regression. The expression of the CTHRC1 protein was significantly higher in tumors than in normal tissues (P < .001). CTHRC1 overexpression was strongly associated with the International Federation of Gynecology and Obstetrics stage (P = .038), histologic grade (P < .001), stromal infiltration depth (P < .001), lymphovascular space invasion (P = .023), lymph node metastasis (P = .001), and recurrence (P = .021). The multivariate proportional-hazard model revealed that CTHRC1 overexpression was an independent predictor of overall survival and disease-free survival (P = .034 and P = .025, respectively). Multivariate logistic regression analysis revealed that high CTHRC1 expression was positively correlated with lymph node metastasis (odds ratio: 2.658; 95% confidence interval: 1.120-6.305; P = .020). Therefore, CTHRC1 may be a valuable biomarker for predicting the prognosis and metastasis of CSCC and a potential therapeutic target for treatment of the disease.

Chemoselective Photoredox Synthesis of Unprotected Primary Amines Using Ammonia.

Unprotected α-amino carbon radicals are produced as novel intermediates via a transformation that merges acid-promoted N-H imine generation and chemoselective photocatalytic single-electron reduction. Coupling ammonia and aldehydes/ketones allows the generation of primary amines under mild conditions without the need for protecting groups. The key intermediate can be efficiently transformed into primary (di)amines by a formal dimerization, reductive amination via hydrogen atom transfer, and arylation through radical-radical coupling.

Eosin†Y as a Direct Hydrogen-Atom Transfer Photocatalyst for the Functionalization of C-H Bonds.

Eosin Y, a well-known economical alternative to metal catalysts in visible-light-driven single-electron transfer-based organic transformations, can behave as an effective direct hydrogen-atom transfer catalyst for C-H activation. Using the alkylation of C-H bonds with electron-deficient alkenes as a model study revealed an extremely broad substrate scope, enabling easy access to a variety of important synthons. This eosin Y-based photocatalytic hydrogen-atom transfer strategy is promising for diverse functionalization of a wide range of native C-H bonds in a green and sustainable manner.

MicroRNA-92a promotes cell viability and invasion in cervical cancer via directly targeting Dickkopf-related protein 3.

MicroRNA-92a (miR-92a) was recently reported to have an oncogenic role in cervical cancer; however, the underlying mechanism remains largely unclear. The present study aimed to investigate the expression, clinical significance and regulatory mechanism of miR-92a in cervical cancer. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) data indicated that miR-92a was significantly upregulated in cervical cancer tissues compared with matched adjacent non-tumor tissues (P<0.01). High expression of miR-92a was significantly associated with poor differentiation (P=0.031), advanced clinical stage (P=0.011) and lymph node metastasis (P=0.014), but not associated with age, tumor size and distant metastasis. Knockdown of miR-92a significantly inhibited the viability and invasion of cervical cancer HeLa cells, while overexpression of miR-92a significantly enhanced HeLa cell viability and invasion (P<0.01). Luciferase reporter assay identified Dickkopf-related protein 3 (DKK3) as a target gene of miR-92a, and the protein expression of DKK3 was negatively regulated by miR-92a in HeLa cells. Furthermore, overexpression of DKK3 significantly eliminated the stimulative effects of miR-92a on HeLa cell viability and invasion (P<0.01). Additionally, DKK3 was significantly downregulated in cervical cancer tissues compared with adjacent non-tumor tissues (P<0.01), inversely correlated to the miR-92a levels in cervical cancer tissues (P<0.01). In summary, the present study indicated that miR-92a promotes cell viability and invasion in cervical cancer, partly at least, via inhibiting the protein expression of DKK3. Therefore, the present study highlights the clinical significance of the miR-92a/DKK3 axis in cervical cancer.

Catalytic enantioselective addition of Grignard reagents to aromatic silyl ketimines.

α-Chiral amines are of significant importance in medicinal chemistry, asymmetric synthesis and material science, but methods for their efficient synthesis are scarce. In particular, the synthesis of α-chiral amines with the challenging tetrasubstituted carbon stereocentre is a long-standing problem and catalytic asymmetric additions of organometallic reagents to ketimines that would give direct access to these molecules are underdeveloped. Here we report a highly enantioselective catalytic synthesis of N-sulfonyl protected α-chiral silyl amines via the addition of inexpensive, easy to handle and readily available Grignard reagents to silyl ketimines. The key to this success was our ability to suppress any unselective background addition reactions and side reduction pathway, through the identification of an inexpensive, chiral Cu-complex as the catalytically active structure.

Synthesis of Chiral Tertiary Alcohols by Cu(I) -Catalyzed Enantioselective Addition of Organomagnesium Reagents to Ketones.

Catalytic enantioselective addition of organometallic nucleophiles to ketones is among the most straightforward approaches to the synthesis of chiral tertiary alcohols. The first such catalytic methodologies using the highly reactive organomagnesium reagents, which are the preferred organometallic reagents in terms of cost, availability, atom efficiency, and structural diversity, were developed only during the last five years. This Concept article highlights the fundamental breakthrough that made the development of methodologies for highly enantioselective Cu(I) -catalyzed alkylation of ketones using organomagnesium reagents possible.

Catalytic asymmetric alkylation of acylsilanes.

The highly enantioselective addition of Grignard reagents to acylsilanes is catalyzed by copper diphosphine complexes. This transformation affords α-silylated tertiary alcohols in up to 97% yield and 98:2 enantiomeric ratio. The competing Meerwein-Ponndorf-Verley reduction is suppressed by the use of a mixture of Lewis acid additives. The chiral catalyst can be recovered as a copper complex and used repeatedly without any loss of catalytic activity.

A framework to support automated classification and labeling of brain electromagnetic patterns.

This paper describes a framework for automated classification and labeling of patterns in electroencephalographic (EEG) and magnetoencephalographic (MEG) data. We describe recent progress on four goals: 1) specification of rules and concepts that capture expert knowledge of event-related potentials (ERP) patterns in visual word recognition; 2) implementation of rules in an automated data processing and labeling stream; 3) data mining techniques that lead to refinement of rules; and 4) iterative steps towards system evaluation and optimization. This process combines top-down, or knowledge-driven, methods with bottom-up, or data-driven, methods. As illustrated here, these methods are complementary and can lead to development of tools for pattern classification and labeling that are robust and conceptually transparent to researchers. The present application focuses on patterns in averaged EEG (ERP) data. We also describe efforts to extend our methods to represent patterns in MEG data, as well as EM patterns in source (anatomical) space. The broader aim of this work is to design an ontology-based system to support cross-laboratory, cross-paradigm, and cross-modal integration of brain functional data. Tools developed for this project are implemented in MATLAB and are freely available on request.