Axially chiral biaryls widely exist in natural products and pharmaceuticals and are used as chiral ligands and catalysts in asymmetric synthesis. Compared to the well‐established axially chiral ...6‐membered biaryl skeletons, examples of 5‐membered biaryls have been quite scarce, and mono‐substituted 3‐arylpyrrole atropisomers have not been reported. Here, we disclose a copper‐catalyzed atroposelective diyne cyclization for the construction of a range of axially chiral arylpyrrole biaryls in good to excellent yields with generally excellent enantioselectivities via oxidation and X−H insertion of vinyl cations. Importantly, this protocol not only represents the first synthesis of mono‐substituted 3‐arylpyrrole atropisomers, but also constitutes the first example of atroposelective diyne cyclization and the first atropisomer construction via vinyl cations. Theoretical calculations further support the mechanism of vinyl cation‐involved cyclization and elucidate the origin of enantioselectivity.
A novel copper‐catalyzed atroposelective diyne cyclization enables the efficient synthesis of a range of axially chiral arylpyrrole biaryls in good to excellent yields with generally excellent enantioselectivities via oxidation and X−H insertion of vinyl cations. This method gives the first synthesis of mono‐substituted 3‐arylpyrrole atropisomers and the first atroposelective diyne cyclization.
2,3‐Sigmatropic rearrangement reaction involving sulfonium ylide (Doyle–Kirmse reaction) generated from metal carbenes represents one of the powerful methods for the construction of C(sp3)−S and C−C ...bonds. Although significant advances have been achieved, the asymmetric versions via the generation of sulfonium ylides from metal carbenes have been rarely reported to date, and they have so far been limited to diazo compounds as metal carbene precursors. Here, we describe a copper‐catalyzed enantioselective Doyle–Kirmse reaction via azide‐ynamide cyclization, leading to the practical and divergent assembly of an array of chiral 1,4thiazino3,2‐bindoles bearing a quaternary carbon stereocenter in generally moderate to excellent yields and excellent enantioselectivities. Importantly, this protocol represents a unique catalytic asymmetric Doyle–Kirmse reaction via a non‐diazo approach and an unprecedented asymmetric 2,3‐sigmatropic rearrangement via α‐imino metal carbenes.
A novel copper‐catalyzed asymmetric Doyle‐Kirmse of azide‐ynamides via α‐imino copper carbenes is disclosed, enabling the practical and divergent assembly of chiral 1,4thiazino 3,2‐bindoles in generally moderate to excellent yields and excellent enantioselectivities. This protocol represents the first asymmetric Doyle–Kirmse reaction via a non‐diazo approach and the first asymmetric 2,3‐sigmatropic rearrangement via α‐imino metal carbenes.
Background
The current randomized, controlled, multicenter clinical trial was conducted to investigate the efficacy of concurrent neoadjuvant chemotherapy (NCT) and estrogen deprivation in patients ...with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.
Methods
Eligible patients with AJCC stage IIB to stage IIIC, ER‐positive, HER2‐negative breast cancer were enrolled and randomly assigned to receive NCT with or without estrogen deprivation. The primary endpoint was the objective response rate (ORR).
Results
A total of 249 patients were assigned to either neoadjuvant chemoendocrine therapy (NCET) (125 patients) or the NCT group (124 patients). In the intention‐to‐treat analysis, the ORR was found to be significantly higher in the NCET group compared with the NCT group (84.8% vs 72.6%; odds ratio, 2.11 95% CI, 1.13‐3.95; P = .02). The efficacy of NCET was more prominent in tumors with a higher Ki‐67 index (>20%), with an ORR of 91.2% reported in the NCET group versus 68.7% in the NCT group (P = .001). The pathologic complete response and pathological response rates did not differ significantly between the 2 groups. Although there was no significant difference with regard to progression‐free survival (PFS) between the 2 groups (P = .188), patients with a higher baseline Ki‐67 index appeared to derive a greater PFS benefit from NCET (2‐year PFS rate of 91.5% in the NCET group vs 76.5% in the NCT group; P = .058). Adding endocrine agents to NCT did not result in significant differences in adverse events (grade 3 or 4; graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0) between the 2 groups.
Conclusions
The addition of estrogen deprivation to NCT appears to improve the clinical response in patients with ER‐positive, HER2‐negative breast cancer, especially for those individuals with a higher Ki‐67 index. Patients with a higher Ki‐67 index might derive more PFS benefit from concurrent neoadjuvant treatment.
The findings of the current study indicate that concurrent neoadjuvant chemotherapy and estrogen deprivation could be the preferred neoadjuvant treatment option for patients with estrogen receptor–positive, human epidermal growth factor receptor 2–negative breast cancer, especially for those with higher Ki‐67 levels. These results support concurrent treatment as part of a promising therapeutic strategy for this patient population.
To evaluate the relationship between body mass index (BMI) and response to neoadjuvant chemotherapy (NCT) for breast cancer among Chinese women.
A total of 307 eligible patients were assigned to ...receive four cycles of paclitaxel and carboplatin before standard surgery for breast cancer from 2007 to 2011 at Shanghai Cancer Hospital. The patients were categorized as obese, overweight, normal weight, or underweight based on BMI according to World Health Organization (WHO) criteria. Pathological complete response (pCR) was defined as no invasive cancer in the breast or axillary tissue. A logistic regression and the Chi-squared test were used for detecting the predictors of pCR and determining the relationship between BMI category and pCR rate in the subgroup analysis with respect to other variables.
Categorical BMI, estrogen receptor (ER), and progesterone receptor (PR) status were independent predictors of pCR according to the multivariate analysis. Patients with BMI≥25 were less likely to achieve a pCR to NCT compared with patients with BMI<25 (Odds ratio: 0.454, p = 0.033, multivariate analysis). In the subgroup analysis, the predictive value of BMI for pCR to NCT was significantly shown in post-menopausal patients (p = 0.004) and hormonal receptor status-negative patients (p = 0.038). The incidence of treatment-induced toxicity was similar among the different BMI categories.
Higher BMI was associated with worse pCR to NCT. Further approaches to investigating the mechanism of this influence of BMI on treatment response and a more appropriate schedule for calculating NCT dose for high-BMI-patients should be considered.
An efficient copper-catalyzed formal 4 + 1 annulation of N-propargyl ynamides with diketones is described. This protocol enables practical and atom-economic synthesis of valuable pyrrole-substituted ...dioxoles in generally moderate to excellent yields under mild reaction conditions. Thus, two new five-membered heterocycles can be constructed in one step through this vinyl cation chemistry.
The study was to estimate the likelihood of axillary downstaging and to identify the factors predicting a pathologically node negative status after neoadjuvant chemotherapy (NAC) with or without ...trastuzumab in HER2-positive breast cancer.
Patients with HER2-positive, stage IIa-IIIc breast cancer were enrolled. Axillary status was evaluated by palpation and fine needle aspiration (FNA) before NAC. All patients received 4-6 cycles of PCrb (paclitaxel 80 mg/m2 and carboplatin AUC = 2 d1, 8, and 15 of a 28-day cycle, or paclitaxel 175 mg/m2 and carboplatin AUC = 6 every-3-week) and were non-randomly administered trastuzumab (2 mg/kg weekly or 6 mg/kg every-3-week) or not. After NAC, each patient underwent standard axillary lymph node dissection and breast-conserving surgery or mastectomy. And some patients received sentinel lymph node biopsy (SLNB) before axillary dissection.
Between November-2007 and June-2013, 255 patients were enrolled. Of them, 157 were confirmed as axillary node positive by FNA (group-A) and 98 as axillary node negative either by FNA or impalpable (group-B). After axillary dissection, the overall pathologically node negative rates (pNNR) were 52.9% in group-A and 69.4% in group-B. The ER-poor/HER2-positive subtype acquired the highest pNNR (79.6% in group-A and 87.9% in group-B, respectively) and the lowest rate of residual with ≥4 nodes involvement (1.9% and 3%, respectively) after PCrb plus trastuzumab. In multivariate analysis, trastuzumab added and ER-poor status were independent factors in predicting a higher pNNR in HER2-positive breast cancer. Forty-six tested patients showed that the ER-poor/HER2-positive subtype acquired a considerable high pNNR and axillary status with SLNB was well macthed with the axillary dissection.
ER-poor/HER2-positive subtype of breast cancer is a potential candidate for undergoing sentinel lymph node biopsy instead of regional node dissection for accurate axillary evaluation after effective downstaging by neoadjuvant chemo-trastuzumab therapy.
A numerical study of vortex-induced rotations (VIRs) of an equivalent triangular cylinder, which is free to rotate in the azimuthal direction in a uniform flow, is presented. Based on an immersed ...boundary method, the numerical model is established, and is verified through the benchmark problem of flow past a freely rotating rectangular body. The computation is performed for a fixed reduced mass of
m
*=2.0 and the structural stiffness and damping ratio are set to zero. The effects of Reynolds number (
Re
=25–180) on the characteristics of VIR are studied. It is found that the dynamic response of the triangular cylinder exhibits four distinct modes with increasing
Re
: a rest position, periodic rotational oscillation, random rotation and autorotation. For the rotational oscillation mode, the cylinder undergoes a periodic vibration around an equilibrium position with one side facing the incoming flow. Since the rotation effect, the outset of vortex shedding from cylinder shifts to a much lower Reynolds number. Further increase in
Re
leads to 2P and P+S vortex shedding modes besides the typical 2S pattern. Our simulation results also elucidate that the free rotation significantly changes the drag and lift forces. Inspired by these facts, the effect of free rotation on flow-induced vibration of a triangular cylinder in the in-line and transverse directions is investigated. The results show that when the translational vibration is coupled with rotation, the triangular cylinder presents a galloping response instead of vortex-induced vibration (VIV).
Abstract
One-carbon homologation reactions based on one-carbon insertion into the N−O bond of heterocycles have received tremendous interest over the past decades. However, these protocols have to ...rely on the use of hazardous and not easily accessible diazo compounds as precursors, and examples of the relevant asymmetric catalysis have not been reported. Here we show that a copper-catalyzed intermolecular formal (5 + 1) annulation of 1,5-diynes with 1,2,5-oxadiazoles involving one-carbon insertion into the heterocyclic N−O bond via non-diazo approach. This method enables practical and atom-economic synthesis of valuable pyrrole-substituted oxadiazines in generally moderate to good yields under mild reaction conditions. In addition, the possibility of such an asymmetric formal (5 + 1) annulation also emerges.
Background.
The efficacy and tolerability of two different schedules of paclitaxel, carboplatin, and trastuzumab (PCarH) for HER2‐positive, locally aggressive (stage IIB–IIIC) breast cancers were ...evaluated in this phase II trial.
Methods.
Patients were randomly assigned to receive either weekly (12 doses over 16 weeks) or once‐every‐3‐weeks (4 doses over 12 weeks) treatment. The primary endpoint was pathologic complete remission (pCR) in the breast and axilla. To detect an assumed 35% pCR absolute difference between the two schedules, a minimum of 26 assessable patients in each group was required (two‐sided α = 0.05, β = 0.2).
Results.
A total of 56 patients were enrolled (weekly group, n = 29; every‐3‐weeks group, n = 27). In the intent‐to‐treat analysis, pCR in the breast/axilla were found in 31 patients (55%; 95% confidence interval CI: 41%–69%). Compared with the every‐3‐weeks schedule, the weekly administration achieved higher pCR (41% vs. 69%; p = .03). After adjustment for clinical and pathological factors, the weekly administration was more effective than the every‐3‐weeks schedule, with hazard ratio of 0.3 (95% CI: 0.1–0.9; p = .03). Interestingly, weekly administration resulted in high pCR rates in both luminal‐B (HER2‐positive) and ERBB2+ tumors (67% vs. 71%; p = .78), whereas luminal‐B (HER2‐positive) tumors benefited less from the every‐3‐weeks schedule compared with the ERBB2+ tumors (21% vs. 62%, p = .03). These results remain after multivariate adjustment, showing weekly administration was more effective in the luminal‐B (HER2‐positive) subgroup (p = .02) but not in the ERBB2+ subgroup (p = .50).
Conclusion.
A more frequent administration might improve the possibility of eradicating invasive cancer in the breast and axilla, especially in the luminal‐B (HER2‐positive) subtype. Further studies to validate our findings are warranted.
The efficacy and tolerability of two different schedules of paclitaxel, carboplatin, and trastuzumab for HER2‐positive, locally aggressive (stage IIB–IIIC) breast cancers were evaluated in this phase II trial. The results indicate that more frequent administration might improve the possibility of eradicating invasive cancer in the breast and axilla, especially in the luminal‐B (HER2‐positive) subtype.
PDF
