Copper-Catalyzed Decarboxylative Trifluoromethylation of Propargyl Bromodifluoroacetates

The development of efficient methods for accessing fluorinated functional groups is desirable. Herein, we report a two-step method that utilizes catalytic Cu for the decarboxylative trifluoromethylation of propargyl bromodifluoroacetates. This protocol affords a mixture of propargyl trifluoromethanes and trifluoromethyl allenes

Neisseria gonorrhoeae Penicillin-Binding Protein 3 Demonstrates a Pronounced Preference for N ε -Acylated Substrates

Penicillin-binding proteins (PBPs) are bacterial enzymes involved in the final stages of cell wall biosynthesis, and are the lethal targets of β-lactam antibiotics. Despite their importance, their roles in cell wall biosynthesis remain enigmatic. A series of eight substrates, based on variation of the pentapeptide Boc-L-Ala-γ-D-Glu-L-Lys-D-Ala-D-Ala, were synthesized to test specificity for three features of PBP substrates: 1) the presence or absence of an Nε-acyl group, 2) the presence of D-IsoGln in place of γ-D-Glu, and 3) the presence or absence of the N-terminal L-Ala residue. The capacity of these peptides to serve as substrates for Neisseria gonorrhoeae (NG) PBP3 was assessed. NG PBP3 demonstrated good catalytic efficiency (2.5 × 105 M−1sec−1) with the best of these substrates, with a pronounced preference (50-fold) for Nε-acylated substrates over Nε-nonacylated substrates. This observation suggests that NG PBP3 is specific for the ∼D-Ala-D-Ala moiety of pentapeptides engaged in cross-links in the bacterial cell wall, such that NG PBP3 would act after transpeptidase-catalyzed reactions generate the acylated amino group required for its specificity. NG PBP3 demonstrated low selectivity for γ-D-Glu vs D-IsoGln, and for the presence or absence of the terminal L-Ala residue. The implications of this substrate specificity of NG PBP3 with respect to its possible role in cell wall biosynthesis, and for understanding the substrate specificity of the LMM PBPs in general, are discussed

Multi-Institutional experience with FOLFIRINOX in pancreatic adenocarcinoma

Combination chemotherapy with FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) was shown to be effective in a large phase III trial. The purpose of this study was to examine the tolerance and effectiveness of FOLFIRINOX as practiced outside of the confines of a clinical trial and to document any dose modifications used by practicing oncologists. Data on patients with all stages of pancreatic adenocarcinoma treated with FOLFIRINOX at three institutions was analyzed for efficacy, tolerance, and use of any dose modifications. Total of 61 patients was included in this review. Median age was 58 years (range: 37 to 72 years), 33 were male (54.1%) and majority had ECOG performance of 0 or 1 (86.9%, 53 patients). Thirty-eight (62.3%) had metastatic disease, while 23 (37.7%) were treated for locally advanced or borderline resectable disease. Patients were treated with a median number of four cycles of FOLFIRINOX, with dose modifications in 58.3% (176/302) of all cycles. Ten patients had stable disease (16.4%), four had a partial response (6.6%) while eight had progressive disease (13.1%) on best imaging following therapy. Median progression-free survival and overall survival were 7.5 months and 13.5 months, respectively. The most common grade 3-4 adverse event was neutropenia at 19.7% (12 cases), with 4.9% (3 cases) rate of febrile neutropenia. Twenty-one patients (34.4%) were hospitalized as a result of therapy but there were no therapy-related deaths. Twenty-three (37.7%) had therapy eventually discontinued as a result of adverse events. Despite substantial rates of adverse events and use of dose modifications, FOLFIRINOX was found to be clinically effective in both metastatic and non-metastatic patients. Regimen toxicity did not detract from overall response and survival

Ligand-controlled Regioselective Cu-Catalyzed Trifluoromethylation to Generate Trifluoromethylallenes

“Cu–CF3” species have been used historically for a broad spectrum of nucleophilic trifluoromethylation reactions. Although recent advancements have employed ligands to stabilize and harness the reactivity of this key organometallic intermediate, the ability of a ligand to differentiate a regiochemical outcome of a Cu–CF3-mediated or -catalyzed reaction has not been previously reported. Herein, we report the first example of a Cu-catalyzed trifluoromethylation reaction in which a ligand controls the regiochemical outcome. More specifically, we demonstrate the ability of bipyridyl-derived ligands to control the regioselectivity of the Cu-catalyzed nucleophilic trifluoromethylation reactions of propargyl electrophiles to generate trifluoromethylallenes. This method provides a variety of di-, tri- and tetra-substituted trifluoromethylallenes, which can be further modified to generate complex fluorinated substructures

PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer

The incidence of breast cancer brain metastases has increased in recent years, largely due to improved control of systemic disease with human epidermal growth factor receptor 2 (HER2)-targeted agents and the inability of most of these agents to efficiently cross the blood-blood barrier (BBB) and control central nervous system disease. There is, therefore, an urgent unmet need for treatments to prevent and treat HER2+ breast cancer brain metastases (BCBMs). Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is frequently observed in many cancers, including primary breast tumors and BCBMs. Agents targeting key components of this pathway have demonstrated antitumor activity in diverse cancers, and may represent a new treatment strategy for BCBMs. In preclinical studies, several inhibitors of PI3K and mTOR have demonstrated an ability to penetrate the BBB and down-regulate PI3K signaling, indicating that these agents may be potential therapies for brain metastatic disease. The PI3K inhibitor buparlisib (BKM120) and the mTOR inhibitor everolimus (RAD001) are currently under evaluation in combination with trastuzumab in patients with HER2+ BCBMs

Ado-trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: latest evidence and clinical potential

In February 2013, ado-trastuzumab emtansine (T-DM1, Kadcyla®) received regulatory approval in the United States for treatment-refractory human epidermal growth factor receptor 2 (HER2) positive metastatic or locally advanced breast cancer based on results from EMILIA, a large phase III trial that compared standard of care lapatinib plus capecitabine to T-DM1. Several other studies have been reported in the metastatic setting and multiple trials are ongoing or planned in the neoadjuvant, adjuvant and advanced disease settings. Here we provide an updated and comprehensive review of clinical trials evaluating T-DM1, discuss management of toxicity associated with this drug, propose potential mechanisms of resistance and offer practical considerations for the treating oncologist