Direct C À H bond transformations have received much attention as ideal and highly efficient methods for the synthesis of useful organic compounds. However, several difficulties remain, in particular the issue of regioselectivity. To solve this problem, directing groups bearing the unshared electron pair of a heteroatom have been used, resulting in dramatic development of the chemistry of C À H bond transformations over the last few decades. [1] The directing group usually acts as a Lewis base to coordinate a transition metal, and thus, the metal center comes close to an appropriate site (a CÀH bond) for the reaction, and subsequent CÀH activation occurs (Scheme 1 a). Herein, we report the orthoselective borylation of aromatic C À H bonds with a palladium catalyst using the interaction between a Lewis basic nitrogen and Lewis acidic boron atoms. [2,3] This is a new concept for the directing group; the group also has an electron pair, but coordinates to a Lewis acidic main-group metal, and a boron atom that also bears a hydrogen atom, which is then converted into a reactive species for C À H activation upon treatment with a transition metal (Scheme 1 b). Until recently, it was difficult to promote transition-metal-catalyzed orthoselective CÀH borylation, but several examples of such transformations have appeared in the last one or two years. [4,5] In C À H borylation, pinacolborane and bis(pinacolate)diboron are usually employed as substrates.[6] Therefore, we initially investigated the reactions between 2-phenylpyridine (1 a) and various borane reagents in the presence of a catalytic amount of several transition metal compounds. However, the desired reaction did not occur at all. [7][8][9] The reason for the low reactivity was thought to be that the Lewis acidity of the borane reagents was not enough to promote the Lewis acidbase interaction between the pyridyl group of 1 a and the boron atom of pinacolborane or bis(pinacolate)diboron. Consequently, 9-borabicyclo[3.3.1]nonane (9-BBN, 2 a) was selected as a promising substrate, because 9-BBN has higher Lewis acidity than pinacolborane and bis(pinacolate)diboron. Treatment of 2-phenylpyridine (1 a) with 9-BBN (2 a) in the presence of a catalytic amount of a palladium salt, Pd(OAc) 2 , in 1,2-dichloroethane at 25 8C for 24 h gave ortho-borylated 2-phenylpyridine 3 a in 87 % yield [Eq. (1)]. [10][11][12][13][14] To verify the existence of the Lewis acid-base interaction, the following experiment was carried out: a mixture of 2-phenylpyridine (1 a) and 9-BBN (2 a) in CD 2 Cl 2 was stirred at 25 8C for 24 h, and 11 B NMR analysis of the reaction mixture was then conducted. As a result, a new signal was observed at 0.3 ppm (vs. 27.7 ppm for 2 a), which is consistent with signals observed for boranes coordinated to pyridine derivatives. [15] This result indicates that the borylation reaction proceeded, supported by Lewis acid-base interaction. Moreover, the reaction proceeded even in the absence of the palladium catalyst at higher temperature (135 8C, 73 %). In this reac...
Graphene and graphitic nanoribbons possess different types of carbon hybridizations exhibiting different chemical activity. In particular, the basal plane of the honeycomb lattice of nanoribbons consisting of sp(2)-hybridized carbon atoms is chemically inert. Interestingly, their bare edges could be more reactive as a result of the presence of extra unpaired electrons, and for multilayer graphene nanoribbons, the presence of terraces and ripples could introduce additional chemical activity. In this study, a remarkable irreversibility in adsorption of CO(2) and H(2)O on graphitic nanoribbons was observed at ambient temperature, which is distinctly different from the behavior of nanoporous carbon and carbon blacks. We also noted that N(2) molecules strongly interact with the basal planes at 77 K in comparison with edges. The irreversible adsorptions of both CO(2) and H(2)O are due to the large number of sp(3)-hybridized carbon atoms located at the edges. The observed irreversible adsorptivity of the edge surfaces of graphitic nanoribbons for CO(2) and H(2)O indicates a high potential in the fabrication of novel types of catalysts and highly selective gas sensors.
<b><i>Background and Aims:</i></b> The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. <b><i>Approach and Results:</i></b> We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009–2012, <i>n</i> = 267; period 2: 2013–2016, <i>n</i> = 352; period 3: 2017–2019, <i>n</i> = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, <i>p</i> < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (<i>p</i> = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; <i>p</i> < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. <b><i>Conclusions:</i></b> The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.
<b><i>Background:</i></b> There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy. <b><i>Methods:</i></b> We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions. <b><i>Results:</i></b> Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5–15.2) and 6.7 months (95% CI, 5.6–7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6–3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5–4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1–6.5 months), 17.6%, and 41.2%, respectively. <b><i>Conclusion:</i></b> Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.
Background Although the efficacy of atezolizumab has been demonstrated in randomized controlled trials, its long‐term efficacy and association with adverse events in real‐world practice are unknown. This study was designed to shed light on these issues. Methods In this multicenter retrospective study, data were collected from patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab in seven institutions in Japan. The authors focused on the efficacy and adverse events related to vascular endothelial growth factor (VEGF) inhibition. Results A total of 123 patients were enrolled in this study. The median progression‐free survival (PFS) for the first‐line treatment group was 8.0 months (95% confidence interval [CI], 6.1–9.9), whereas the median PFS for the second‐ or later‐line treatment group was 4.1 months (95% CI, 2.6–5.7), which was significantly worse than that of the first‐line treatment group (p = .005). Twenty‐seven patients had interrupted bevacizumab treatment. Proteinuria accounted for the largest proportion of bevacizumab treatment interruptions. The cumulative incidence rate of bevacizumab interruption due to anti‐VEGF–related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus than in those without (p = .026). The landmark analysis showed that patients experienced bevacizumab interruption by 24 weeks from treatment initiation had poorer PFS than those who did not (p = .013). Conclusions The PFS of atezolizumab plus bevacizumab as first‐line treatment mostly replicates that of a global phase 3 trial. Interrupted bevacizumab treatment was more common in patients with hypertension and/or diabetes mellitus, which may be associated with worsening long‐term PFS. Plain language summary Atezolizumab plus bevacizumab has been the standard front line systemic therapy for advanced hepatocellular carcinoma. With the growing incidence of fatty liver due to metabolic syndrome as a background liver disease for hepatocellular carcinoma, the rate of comorbid hypertension and diabetes mellitus has been increasing accordingly. The present study demonstrated the cumulative incidence rate of bevacizumab interruption due to anti‐VEGF–related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus. The landmark analysis clarified that interruption of bevacizumab might be a risk of impaired efficacy of atezolizumab plus bevacizumab over the long term in patients with advanced hepatocellular carcinoma.
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