Synthesis of Cycloaliphatic Polyamides via Palladium-Catalyzed Hydroaminocarbonylative Polymerization.

Polyamides represent one class of materials that is important in modern society. Because of the numerous potential applications of polyamides in various fields, there is a high demand for new polyamide structures, which necessitates the development of new polymerization methods. Herein, we report a novel and efficient palladium-catalyzed hydroaminocarbonylative polymerization of dienes and diamines for the synthesis of cycloaliphatic polyamides. The method employs readily available starting materials, proceeds in an atom-economic manner, and creates a series of new functional polyamides in high yields and high molecular weights. In contrast with the traditional polyamides based on adipic acid, the cycloaliphatic polyamides have superior thermal resistance, higher glass-transition temperature, and better solubility in common organic solvents, thus probably featuring the merits of high-performance and good processability.

Palladium-Catalyzed Inward Isomerization Hydroaminocarbonylation of Alkenes.

In contrast to the kinetically favored outward isomerization-hydrocarbonylation of alkenes, the disfavored inward isomerization-hydrocarbonylation of alkenes remains an important challenge. Herein, we have developed a novel and effective palladium-catalyzed inward isomerization-hydroaminocarbonylation of unactivated alkenes and aniline hydrochlorides for the formation of synthetically valuable α-aryl carboxylic amides in high yields and high site-selectivities. The high efficiency of the reaction is attributed to a relay catalysis strategy, in which the Markovnikov-favored [PdH]-PtBu3 catalyst is responsible for inward isomerization, while the [PdH]-Ruphos catalyst is responsible for hydroaminocarbonylation of the resulting conjugated aryl alkenes. The reaction exhibits highly functional group tolerance and provides a new method for formal carbonylation of remote C(sp3)-H bond.

Design, Synthesis, and Evaluation of Glucose Transporter Inhibitor-SN38 Conjugates for Targeting Colorectal Cancer.

Irinotecan (1), a prodrug of SN38 (2) approved by the US Food and Drug Administration for treating colorectal cancer, lacks specificity and causes many side effects. To increase the selectivity and therapeutic efficacy of this drug, we designed and synthesized conjugates of SN38 and glucose transporter inhibitors (phlorizin (5) or phloretin (6)), which could be hydrolyzed by glutathione or cathepsin to release SN38 in the tumor microenvironment, as a proof of concept. These conjugates (8, 9, and 10) displayed better antitumor efficacy with lower systemic exposure to SN38 in an orthotopic colorectal cancer mouse model compared with irinotecan at the same dosage. Further, no major adverse effects of the conjugates were observed during treatment. Biodistribution studies showed that conjugate 10 could induce higher concentrations of free SN38 in tumor tissues than irinotecan at the same dosage. Thus, the developed conjugates exhibit potential for treating colorectal cancer.

Palladium-catalyzed regiodivergent hydrochlorocarbonylation of alkenes for formation of acid chlorides.

Novel strategy for acid chlorides formation that do not use carboxylic acids is particularly attractive in chemical synthesis but remains challenging. Herein, we reported the development of a highly effective Pd-catalyzed hydrochlorocarbonylation of alkenes with CO for the formation of alkyl acid chlorides. Chlorosilane and AcOH were found as a mild HCl source for the reaction. The reaction shows broad substrate scope and produces both branched and linear alkyl acid chlorides in good to high yields upon different ligands and solvents. Cooperating with follow-up acylation reactions, the Pd-catalyzed hydrochlorocarbonylation offers a complementary platform for the synthesis of diverse carbonyl compounds from alkenes. Mechanistic investigations suggested that the reaction proceeded though a palladium hydride pathway, and CO prompted reductive elimination of the acyl-Pd-Cl intermediate.

Ophthalmic artery flow direction change predicts recurrence of ischemic stroke after carotid stenting: a longitudinal observational study.

BACKGROUND AND PURPOSE: The implantation of carotid artery stents prevents recurrent ischemic stroke in patients with carotid stenosis. This study aimed to investigate associations between change of ophthalmic artery flow (COAF) post carotid stenting and recurrent ischemic stroke, as well as the link toward the anterior and posterior circulations and patients' prognosis after carotid stenting. METHODS: This retrospective, longitudinal cohort study recruited 87 left side carotid stenosed ischemic stroke patients undergoing left side carotid stenting between year of 2009 and 2013, and patients were followed up to 9 years after carotid procedures. Clinical data were derived from medical records. The primary outcome was stroke recurrence. Predictive factors were stenosis > 50% in one intracranial artery and ROAF. Kaplan-Meier and Cox regression analyses were used to identify risk factors associated with stroke recurrence. RESULTS: Among 87 included patients undergone left side carotid stent treatment, 44 had stroke recurrence within 3 years after carotid stenting. The recurrence group had significantly greater proportions of COAF after stenting (p = 0.001), and middle cerebral artery (MCA) and basilar artery or vertebral artery (BA/VA) stenosis > 50% (all p < 0.001) than the no-recurrence group. Survival was significantly shorter in patients with COAF than in those without (p < 0.01). Regression analysis showed that COAF was associated with stroke recurrence (HR: 3.638, 95% CI 1.54-8.62, p = 0.003). The recurrence rate was highest in patients with bilateral MCA stenosis > 50% (100%), followed by left MCA stenosis > 50% plus BA/VA stenosis > 50% (83.33%) or COAF (82.14%). Patients with bilateral MCA stenosis < 50% had no recurrence within 3-year follow-up. CONCLUSIONS: Prognosis after carotid stenting is poorer for patients with MCA stenosis > 50%, BA/VA stenosis > 50% and/or COAF. Carotid duplex and magnetic resonance angiography provide definitive information for prognosis prediction.

Palladium-Catalyzed Asymmetric Markovnikov Hydroxycarbonylation and Hydroalkoxycarbonylation of Vinyl Arenes: Synthesis of 2-Arylpropanoic Acids.

Asymmetric hydroxycarbonylation is one of the most fundamental yet challenging methods for the synthesis of carboxylic acids. Herein, we reported the development of a palladium-catalyzed highly enantioselective Markovnikov hydroxycarbonylation of vinyl arenes with CO and water. A monodentate phosphoramidite ligand L6 plays vital role in the reaction. The reaction tolerates a range of functional groups, and provides a facile and atom-economical approach to an array of 2-arylpropanoic acids including several commonly used non-steroidal anti-inflammatory drugs. The catalytic system has also enabled an asymmetric Markovnikov hydroalkoxycarbonylation of vinyl arenes with alcohols to afford 2-arylpropanates. Mechanistic investigations suggested that the hydropalladation is irreversible and is the regio- and enantiodetermining step, while hydrolysis/alcoholysis is probably the rate-limiting step.

Palladium-Catalyzed Markovnikov Hydroaminocarbonylation of 1,1-Disubstituted and 1,1,2-Trisubstituted Alkenes for Formation of Amides with Quaternary Carbon.

Hydroaminocarbonylation of alkenes is one of the most promising yet challenging methods for the synthesis of amides. Herein, we reported the development of a novel and effective Pd-catalyzed Markovnikov hydroaminocarbonylation of 1,1-disubstituted or 1,1,2-trisubstituted alkenes with aniline hydrochloride salts to afford amides bearing an α quaternary carbon. The reaction makes use of readily available starting materials, tolerates a wide range of functional groups, and provides a facile and straightforward approach to a diverse array of amides bearing an α quaternary carbon. Mechanistic investigations suggested that the reaction proceeded through a palladium hydride pathway. The hydropalladation and CO insertion are reversible, and the aminolysis is probably the rate-limiting step.

Targeting Colorectal Cancer with Conjugates of a Glucose Transporter Inhibitor and 5-Fluorouracil.

Overexpression of glucose transporters (GLUTs) in colorectal cancer cells is associated with 5-fluorouracil (1, 5-FU) resistance and poor clinical outcomes. We designed and synthesized a novel GLUT-targeting drug conjugate, triggered by glutathione in the tumor microenvironment, that releases 5-FU and GLUTs inhibitor (phlorizin (2) and phloretin (3)). Using an orthotopic colorectal cancer mice model, we showed that the conjugate exhibited better antitumor efficacy than 5-FU, with much lower exposure of 5-FU during treatment and without significant side effects. Our study establishes a GLUT-targeting theranostic incorporating a disulfide linker between the targeting module and cytotoxic payload as a potential antitumor therapy.

Asymmetric Markovnikov Hydroaminocarbonylation of Alkenes Enabled by Palladium-Monodentate Phosphoramidite Catalysis.

A palladium-catalyzed asymmetric Markovnikov hydroaminocarbonylation of alkenes with anilines has been developed for the atom-economical synthesis of 2-substituted propanamides bearing an α-stereocenter. A novel phosphoramidite ligand L16 was discovered which exhibited very high reactivity and selectivity in the reaction. This asymmetric Markovnikov hydroaminocarbonylation employs readily available starting materials and tolerates a wide range of functional groups, thus providing a facile and straightforward method for the regio- and enantioselective synthesis of 2-substituted propanamides under ambient conditions. Mechanistic studies revealed that the reaction proceeds through a palladium hydride pathway.

Identifying EGFR mutations from SCLC patient plasma by mutant-enriched liquidchip technology.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) such as erlotinib and gefitinib are targeted drugs for the kinase domain of EGFR. They are widely used for the treatment of non-small cell lung cancer (NSCLC). The EGFR exon 19 deletion mutation and the L858R mutation in exon 21 comprise approximately 90% of the somatic mutations in NSCLC patients that respond to EGFR TKI. Several recent studies have also reported that small cell lung cancer (SCLC) patients with EGFR mutations responded to gefitinib. Further study, however, has been limited due to the difficulty obtaining tumor specimens from SCLC patients. OBJECTIVES: The aim of this study was to explore the EGFR mutation status in SCLC patients by plasma analysis. MATERIAL AND METHODS: Plasma samples from SCLC patients were collected for mutant-enriched liquidchip (MEL) analysis to identify the EGFR mutations in exon 19 and 21. RESULTS: The exon 19 deletion mutation was detected in one out of 35 patients (a female non-smoker). No exon 21 mutations were found. CONCLUSIONS: A prevalence of EGFR mutations in SCLC is rare, and occurs most frequently in females and nonsmokers.

Personalized medicine of esophageal cancer.

The fatality rate of esophageal carcinomas is high in developing countries, making effective treatment desirable. Traditional treatment has now entered into the platform, and treatments based on the detection of biomarkers increasingly become a trend. This review presents several biomarkers of esophageal cancer, including chemotherapy-related biomarkers and targeted drug-related biomarkers, and the correlation of these biomarkers with drug response.