Synthesis of the heterocyclic core of the D-series GE2270.

A straightforward enantiomerically pure synthesis of the heterocyclic core of the D-series GE2270 is reported. The synthetic strategy combines the Hantzsch thiazole's building condensation with a cross-coupling reaction including direct C-H hetarylation to build and connect step-by-step thiazolyl moieties to the 5-bromopicolinate as readily available starting material.

Control of vegetable pests in Benin - Farmers' preferences for eco-friendly nets as an alternative to insecticides.

We investigated if eco-friendly nets (EFNs) are a viable and acceptable alternative to extremely high levels of insecticide use in vegetable production. Using a choice experiment, we found that vegetable producing farmers in Benin preferred all of the characteristics of EFNs except the higher labor requirements. The nets had been distributed in a trial phase for free but in the long run farmers would need to purchase the EFNs. The break-even point for investing in nets was found to vary with the lifespan of EFNs, their purchase price and potential health benefits from avoiding large quantities of insecticides. To break even the nets need to be used for at least two production cycles. To overcome risk-averse farmer's reluctance to adopt EFNs we propose a credit and warranty scheme along with the purchase of the nets. The study's findings can guide the implementation of EFNs in other African countries as part of integrated pest management with global benefits for the environment and human health.

Combined inhibition of Wee1 and Chk1 as a therapeutic strategy in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novel agents that have significantly improved clinical outcome, most patients relapse and develop drug resistance. MM is characterized by genomic instability and a high level of replicative stress. In response to replicative and DNA damage stress, MM cells activate various DNA damage signaling pathways. In this study, we reported that high CHK1 and WEE1 expression is associated with poor outcome in independent cohorts of MM patients treated with high dose melphalan chemotherapy or anti-CD38 immunotherapy. Combined targeting of Chk1 and Wee1 demonstrates synergistic toxicities on MM cells and was associated with higher DNA double-strand break induction, as evidenced by an increased percentage of γH2AX positive cells subsequently leading to apoptosis. The therapeutic interest of Chk1/Wee1 inhibitors' combination was validated on primary MM cells of patients. The toxicity was specific of MM cells since normal bone marrow cells were not significantly affected. Using deconvolution approach, MM patients with high CHK1 expression exhibited a significant lower percentage of NK cells whereas patients with high WEE1 expression displayed a significant higher percentage of regulatory T cells in the bone marrow. These data emphasize that MM cell adaptation to replicative stress through Wee1 and Chk1 upregulation may decrease the activation of the cell-intrinsic innate immune response. Our study suggests that association of Chk1 and Wee1 inhibitors may represent a promising therapeutic approach in high-risk MM patients characterized by high CHK1 and WEE1 expression.

Mechanism selection for regiocontrol in base-assisted, palladium-catalysed direct C-H coupling with halides: first approach for oxazole- and thiazole-4-carboxylates.

Both base-assisted non-concerted metallation-deprotonation (nCMD) and concerted metallation-deprotonation (CMD) have been identified as two potent operating mechanisms in palladium-catalysed direct C-H coupling of oxazole and thiazole-4-carboxylate esters with halides through base- and solvent-effect experiments. Novel C2- and C5-selective CMD direct arylation procedures in oxazole- and thiazole-4-carboxylate series were then designed by controlling the balance between electronic and steric factors. Notably, charge interactions between the palladium catalyst and substrate were identified as a parameter for controlling selectivity and reducing the impact of steric factors in the CMD reaction.

Direct C-2 arylation of alkyl 4-thiazolecarboxylates: new insights in synthesis of heterocyclic core of thiopeptide antibiotics.

The Pd(0)-catalyzed regioselective C-2 (hetero)arylation of tert-butyl 4-thiazolecarboxylate with a broad (hetero)aryl halide is reported, including the direct coupling of pyridinyl halides. The process has allowed the preparation of valuable 2-pyridynyl-4-thiazolecarboxylates which are components of the complex heterocyclic core of thiopeptides antibiotics. As a first application, a synthesis of a tert-butyl sulfomycinamate thio-analogue from tert-butyl 4-thiazolecarboxylate is here described through a three-step direct pyridinylation, halogenation, and Stille cross-coupling sequence.

Palladium-catalyzed direct (hetero)arylation of ethyl oxazole-4-carboxylate: an efficient access to (hetero)aryloxazoles.

A straightforward route toward 2-(hetero)arylated and 2,5-di(hetero)arylated oxazoles through regiocontrolled palladium-catalyzed direct (hetero)arylation of ethyl oxazole-4-carboxylate with iodo-, bromo-, and chloro(hetero)aromatics followed by a two-step hydrolysis/decarboxylation sequence was described. The method was applied here to a neat synthesis of two 2,5-di(hetero)aryloxazole natural products, balsoxin and texaline.

Highly efficient borylation Suzuki coupling process for 4-bromo-2-ketothiazoles: straightforward access to micrococcinate and saramycetate esters.

The first palladium-catalyzed borylation of 4-bromo-2-ketothiazoles followed by a Suzuki cross-coupling reaction with haloheteroaromatics using Buchwald's Cy-JohnPhos and XPhos ligands is reported. The methodology has allowed the fast preparation of highly valuable 4-pyridinyl- and 4-thiazolyl-2-ketothiazoles as common subunits of thiopeptide antibiotics. As direct applications, novel concise syntheses of a sulfomycinamate thio-analogue as well as micrococcinate and saramycetate esters are described.