Nickel-Catalyzed Asymmetric Reductive Cross-Coupling of a-Chloroesters with (Hetero)Aryl Iodides

An asymmetric reductive cross-coupling of alpha-chloroesters and (hetero)aryl iodides is reported. This nickel-catalyzed reaction proceeds with a chiral BiOX ligand under mild conditions, affording alpha-arylesters in good yields and enantioselectivities. The reaction is tolerant of a variety of functional groups, and the resulting products can be converted to pharmaceutically-relevant chiral building blocks. A multivariate linear regression model was developed to quantitatively relate the influence of the alpha-chloroester substrate and ligand on enantioselectivity

Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata

The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential

Nickel-Catalyzed Asymmetric Reductive Cross-Coupling of a-Chloroesters with (Hetero)Aryl Iodides

An asymmetric reductive cross-coupling of alpha-chloroesters and (hetero)aryl iodides is reported. This nickel-catalyzed reaction proceeds with a chiral BiOX ligand under mild conditions, affording alpha-arylesters in good yields and enantioselectivities. The reaction is tolerant of a variety of functional groups, and the resulting products can be converted to pharmaceutically-relevant chiral building blocks. A multivariate linear regression model was developed to quantitatively relate the influence of the alpha-chloroester substrate and ligand on enantioselectivit

Progress toward the Total Synthesis of <i>N</i>‑Methylwelwitindolinone B Isothiocyanate

Progress toward the welwitindolinone alkaloid <i>N</i>-methylwelwitindolinone B isothiocyanate is reported. A key reaction to synthesize the [4.3.1] bicycle embedded in the core of the molecule is a furan type 2 intramolecular Diels–Alder reaction with a tetrasubstituted dienophile, which sets the two vicinal quaternary centers present in the natural product. The sterically encumbered cycloaddition precursor was synthesized using a Horner–Wadsworth–Emmons reaction followed by a Suzuki cross-coupling reaction. Finally, introduction of the secondary alkyl chloride was achieved by a regio- and diastereoselective opening of a [2.2.1] oxobi­cyclo­heptane functionality

Progress toward the Total Synthesis of <i>N</i>‑Methylwelwitindolinone B Isothiocyanate

Progress toward the welwitindolinone alkaloid <i>N</i>-methylwelwitindolinone B isothiocyanate is reported. A key reaction to synthesize the [4.3.1] bicycle embedded in the core of the molecule is a furan type 2 intramolecular Diels–Alder reaction with a tetrasubstituted dienophile, which sets the two vicinal quaternary centers present in the natural product. The sterically encumbered cycloaddition precursor was synthesized using a Horner–Wadsworth–Emmons reaction followed by a Suzuki cross-coupling reaction. Finally, introduction of the secondary alkyl chloride was achieved by a regio- and diastereoselective opening of a [2.2.1] oxobi­cyclo­heptane functionality

A Randomized Trial of Text Messaging for Smoking Cessation in Pregnant Women.

Introduction There is a need for innovation in both the enrollment of pregnant smokers in smoking cessation treatment programs and in the types of treatments offered. The study tests whether an interactive and intensive text messaging program, Quit4baby, can promote smoking cessation for pregnant women already enrolled in a health text messaging program, Text4baby. Methods Between July 2015 and February 2016, a total of 35,957 recruitment text messages were sent to Text4baby subscribers. Eligible pregnant smokers were enrolled and randomized to receive Text4baby (control) or Text4baby and Quit4baby (intervention; N=497). Participants were surveyed at 1 month, 3 months, and 6 months post-enrollment, and saliva samples were collected at 3 months for biochemical verification of smoking status. Data were collected from 2015 to 2016 and analyzed in 2016. Results Using an intention-to-treat analysis, 28.80% of the intervention group and 15.79% of the control group reported not smoking in the past 7 days at 1 month (p\u3c0.01), and 35.20% of the intervention group and 22.67% of the control group reported not smoking in the past 7 days at 3 months (p\u3c0.01). Biochemical verification of smoking status at 3 months indicated no significant differences between groups (15.60% in the intervention group and 10.93% in the control group [p=0.13]), although significant differences favoring the intervention were found for older smokers (p\u3c0.05) and for those who enrolled in their second or third trimester of pregnancy (p\u3c0.05). Self-report of late pregnancy 7- and 30-day point prevalence abstinence favored the intervention group (p\u3c0.001, p\u3c0.01). No significant differences were observed at the 6-month follow-up or in the postpartum period. Conclusions Results provide limited support of the efficacy of the Quit4baby text messaging program in the short term and late in pregnancy, but not in the postpartum period

Recruiting Pregnant Smokers from Text4baby for a Randomized Controlled Trial of Quit4baby.

Recruiting pregnant smokers into clinical trials is challenging since this population tends to be disadvantaged, the behavior is stigmatized, and the intervention window is limited. The purpose of this study is to test the feasibility and effectiveness of recruiting pregnant smokers into a smoking cessation trial by sending recruitment text messages to an existing subscriber list. Recruitment messages were sent to subscribers flagged as pregnant in Text4baby, a national text messaging program for pregnant women and mothers. Four recruitment messages were rotated to test the effectiveness of different emotional frames and a financial incentive. Study staff called subscribers who expressed interest to screen for eligibility and enroll eligible women. Between October 6, 2015 and February 2, 2016, 10,194 recruitment messages were sent to Text4baby subscribers flagged as pregnant, and 10.18% (1038) responded indicating interest. No significant increase in cancellation was observed compared to subscribers who received other ad hoc messages. Of respondents, 54.05% (561) were reached by phone for follow-up, and 21.97% (228) were found to be eligible. Among the eligible, 87% (199) pregnant smokers enrolled. The recruitment message with a pride emotional appeal had a significantly higher response (p = 0.02) compared to the recruitment message with no emotional appeal, but enrollment did not significantly differ between recruitment messages with different emotional appeals. The recruitment messages with a reference to financial incentive yielded higher response (p \u3c 0.01) and enrollment (p = 0.03) compared to a recruitment message without. This study demonstrates success recruiting pregnant smokers using text message. Future studies should consider building on this approach for recruiting high-risk populations