Evaluation of functional group compatibility and development of reaction-accelerating additives in ammonium salt-accelerated hydrazinolysis of amides.

Functional group compatibility in an amide bond cleavage reaction with hydrazine was evaluated for 26 functional groups in the functional group evaluation (FGE) kit. Accurate and rapid evaluation of the compatibility of functional groups, such as nitrogen-containing heterocycles important in drug discovery research, will enhance the application of this reaction in drug discovery research. These data will be used for predictive studies of organic synthesis methods based on machine learning. In addition, these studies led to discoveries such as the unexpected positive additive effects of carboxylic acids, indicating that the FGE kit can propel serendipitous discoveries.

Risk factors for early recurrence in patients with pancreatic ductal adenocarcinoma who underwent curative resection.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, and surgical resection is the only potentially curative approach. However, the rate of recurrence remains high, particularly within the first 6 months, and is associated with a poor prognosis. The present study evaluated the clinical characteristics and risk factors for early recurrence in pancreatic ductal adenocarcinoma (PDAC) patients who underwent curative resection, regardless of the use of neoadjuvant chemotherapy, to identify predictive factors associated with early recurrence and poor outcomes as well as to determine the optimal treatment strategy for patients at high risk of early recurrence after surgical resection. METHODS: Patients who underwent pancreatic resection for PDAC at our institution from 2013 to 2021 were included in this study. We investigated the clinicopathological features of patients in groups: those with recurrence within 6 months, recurrence between 6 and 12 months, and recurrence beyond 12 months or no recurrence. A logistic regression analysis identified covariates associated with early recurrence at 6 and 12 months. RESULTS: The study included 403 patients with a median follow-up of 25.7 months. Recurrence was observed in 279 patients, with 14.6% recurring within 6 months, 23.3% within 6-12 months, and 62% after 12 months or not at all. The preoperative CA19-9 level, modified Glasgow prognostic score (mGPS), and positive peritoneal cytology were significant risk factors for early recurrence within 6 months, while positive peritoneal cytology, lymph node metastasis, and the absence of adjuvant chemotherapy were significant risk factors for recurrence within 12 months. For patients who received preoperative chemotherapy or chemoradiotherapy, the preoperative CA19-9 level, mGPS, and positive peritoneal cytology were significant independent risk factors for early recurrence within 6 months, while positive peritoneal cytology, lymph node metastasis, and the absence of adjuvant chemotherapy were significant independent risk factors for recurrence within 12 months. The study concluded that the overall survival after surgical resection for potentially resectable PDAC worsened according to the number of risk factors present in the patient. CONCLUSIONS: We clarified that preoperative CA19-9, positive peritoneal cytology, and the lack of adjuvant chemotherapy were consistent predictors for early recurrence within 6 and 12 months. In addition, an increased number of risk factors affecting the patient was associated with a poorer overall survival after potentially curable resection. Calculating the number of risk factors for early recurrence may be an essential predictive factor when considering treatment strategies.

Influence of the Oral Health Assessment Tool Score on Survival of Patients With Esophageal Cancer.

BACKGROUND/AIM: We investigated the influence of the preoperative Oral Health Assessment Tool (OHAT) score on the outcomes of patients with esophageal cancer after curative surgery. PATIENTS AND METHODS: This study included 90 patients with esophageal cancer who underwent curative surgery and who were screened with the OHAT between 2008 and 2021. The OHAT consists of eight categories with three possible scores. The risk factors for 5-year overall survival (OS) and recurrence-free survival (RFS) were identified. RESULTS: Patients were divided into healthy (n=42) and unhealthy (n=48) groups. The OHAT score was identified as a significant risk factor for postoperative pneumonia (11.9% vs. 43.8%, p=0.001) and postoperative hospital stay (20.5 days vs. 50.1 days, p=0.042). The 5-year OS rate after surgery was 71.2% in the healthy group and 43.2% in the unhealthy group, which was a significant difference (p=0.015). A multivariate analysis showed that a high OHAT score was a significant independent factor for 5-year OS (p=0.034). CONCLUSION: The OHAT score was a useful prognostic marker in patients who underwent curative surgery for esophageal cancer. To improve the oncological outcomes of patients with esophageal cancer, it is necessary to carefully plan perioperative oral/dental care using the OHAT score.

Inhibitory Effect of Pyra-Metho-Carnil on Cancer Spheroid Growth Through Decrease in Glycolysis-associated Molecules.

BACKGROUND/AIM: Pyra-Metho-Carnil (PMC) has been identified as a novel candidate compound for treating numerous malignancies; however, its mechanism of action remains unknown. In this study, we conducted RNA-sequencing (RNA-seq) analyses to elucidate the mechanism of PMC against human colorectal cancer cells harboring mutant KRAS (mtKRAS). MATERIALS AND METHODS: RNA-seq analyses of the HKe3-wild-type KRAS and HKe3-mtKRAS spheroids treated with DMSO or PMC for 6 days were performed. RESULTS: RNA-seq data suggested that PMC treatment suppresses the aerobic glycolysis pathway in HKe3-mtKRAS spheroids through the down-regulation of the HIF1 pathway. Indeed, treatment with PMC markedly suppresses the absorption of glucose by spheroids and the secretion of lactate from them. CONCLUSION: PMC suppresses growth of cancer spheroid through down-regulation of cancer-specific glucose metabolism.

Visible-Light-Induced Aminochlorination of Alkenes.

Photoinduced N-internal vicinal aminochlorination of styrene-type terminal alkenes was developed. The reaction proceeded without any catalyst, and the use of N-chloro(fluorenone imine) as both a photoactivatable aminating agent and a chlorinating agent was essential. The imine moiety, introduced at the internal position of the alkenes, could be hydrolyzed under mild conditions to provide versatile ß-chlorinated primary amines, the synthetic utility of which was demonstrated by several transformations.

Multiancestry genomic and transcriptomic analysis of gastric cancer.

Gastric cancer is among the most common malignancies worldwide, characterized by geographical, epidemiological and histological heterogeneity. Here, we report an extensive, multiancestral landscape of driver events in gastric cancer, involving 1,335 cases. Seventy-seven significantly mutated genes (SMGs) were identified, including ARHGAP5 and TRIM49C. We also identified subtype-specific drivers, including PIGR and SOX9, which were enriched in the diffuse subtype of the disease. SMGs also varied according to Epstein-Barr virus infection status and ancestry. Non-protein-truncating CDH1 mutations, which are characterized by in-frame splicing alterations, targeted localized extracellular domains and uniquely occurred in sporadic diffuse-type cases. In patients with gastric cancer with East Asian ancestry, our data suggested a link between alcohol consumption or metabolism and the development of RHOA mutations. Moreover, mutations with potential roles in immune evasion were identified. Overall, these data provide comprehensive insights into the molecular landscape of gastric cancer across various subtypes and ancestries.

O- and N-Selective Electrophilic Activation of Allylic Alcohols and Amines in Pd-Catalyzed Direct Alkylation.

Catalytic control of chemoselectivity is crucial in the synthesis of highly functionalized compounds. Although there are reports of efficient chemoselective reactions of alcohols and amines as nucleophiles, there are no reports of the chemoselective activation of alcohols and amines as electrophiles. In this study, highly O- and N-selective electrophilic activation of allylic alcohols and amines was achieved in Pd-catalyzed direct allylic alkylation. Allylamines were inherently more reactive than allylic alcohols (N-selectivity). On the other hand, the addition of catalytic amounts of 9-phenanthreneboronic acid preferentially activated allylic alcohols over allylamines (O-selectivity). Density functional theory (DFT) calculations suggested that the N-selectivity is due to the selective activation of allylic amines with ammonium cations, and boronate formation accelerates the activation of allylic alcohols.

One-Pot Catalytic Synthesis of α-Tetrasubstituted Amino Acid Derivatives via In Situ Generation of N-Unsubstituted Ketimines.

A one-pot catalytic synthesis of α-tetrasubstituted amino acid derivatives via in situ generation of N-unsubstituted ketimines is reported. Because of the irreversible formation of N-unsubstituted ketimines, the yields were higher than those generated under the conventional one-pot reaction conditions. This process prevents the need to isolate unstable N-unsubstituted ketimines with alkyl substituents and streamlines the synthesis of highly congested α-amino acid derivatives.

Cancer Spheroid Proliferation Is Suppressed by a Novel Low-toxicity Compound, Pyra-Metho-Carnil, in a Context-independent Manner.

BACKGROUND/AIM: In a screen of compounds to selectively suppress the growth of cancer spheroids, which contained mutant (mt) KRAS, NPD10621 was discovered and associated derivatives were investigated. MATERIALS AND METHODS: Spheroid areas from HCT116-derived HKe3 spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were treated with 12 NPD10621 derivatives and measured in three-dimensional floating (3DF) cultures. Several cancers were treated with NPD1018 (pyra-metho-carnil: PMC) in 3DF cultures. In a nude mouse assay, 50% cell growth inhibition (GI50) values were determined. RESULTS: From these 12 derivatives, PMC was the most effective inhibitor of HKe3-mtKRAS spheroid growth with the least toxicity. Furthermore, PMC-mediated growth suppression was observed in all tested cancer cell lines, independent of tissue context, driver gene mutations, and drug resistance, suggesting that the PMC target(s) was crucial for cancer growth in a context-independent manner. The GI50 value of PMC in nude mice assay was 7.7 mg/kg and nude mice that were administered 40 mg/kg PMC for 7 days did not show any abnormal blood cell count values. CONCLUSION: PMC is a low-toxicity compound that inhibits the growth of different tumor cell types.

A TRPC3/6 Channel Inhibitor Promotes Arteriogenesis after Hind-Limb Ischemia.

Retarded revascularization after progressive occlusion of large conductance arteries is a major cause of bad prognosis for peripheral artery disease (PAD). However, pharmacological treatment for PAD is still limited. We previously reported that suppression of transient receptor potential canonical (TRPC) 6 channel activity in vascular smooth muscle cells (VSMCs) facilitates VSMC differentiation without affecting proliferation and migration. In this study, we found that 1-benzilpiperadine derivative (1-BP), a selective inhibitor for TRPC3 and TRPC6 channel activities, induced VSMC differentiation. 1-BP-treated mice showed increased capillary arterialization and improvement of peripheral circulation and skeletal muscle mass after hind-limb ischemia (HLI) in mice. 1-BP had no additive effect on the facilitation of blood flow recovery after HLI in TRPC6-deficient mice, suggesting that suppression of TRPC6 underlies facilitation of the blood flow recovery by 1-BP. 1-BP also improved vascular nitric oxide bioavailability and blood flow recovery after HLI in hypercholesterolemic mice with endothelial dysfunction, suggesting the retrograde interaction from VSMCs to endothelium. These results suggest that 1-BP becomes a potential seed for PAD treatments that target vascular TRPC6 channels.

Impact of Infectious Complications on Survival and Recurrence of Patients With Stage II/III Colorectal Cancer: A Multicenter Retrospective Study.

BACKGROUND/AIM: Postoperative complications are associated with increased recurrence in colorectal cancer (CRC). We investigated the impact of infectious complications on the recurrence of CRC and overall survival after curative surgery in a single study group. PATIENTS AND METHODS: In total, 1,668 patients who underwent radical resection for CRC in Yokohama City University, Yokohama Minami Kyosai Hospital, and Kanagawa Cancer Center between 2011 and 2019 were reviewed. Patients were classified into those with infectious complications (IC group) and those without infectious complications (Non-IC group). The risk factors for recurrence-free survival (RFS) and overall survival (OS) were analyzed. RESULTS: Postoperative complications were found in 560 of the 1,668 patients (33.5%), and IC, which occurred in 312 patients (18.7%), included pneumonia, anastomotic leakage, and intraperitoneal abscess. The 5-year OS rates in the Non-IC and IC groups were 95.5% and 90.4%, respectively, while the 5-year RFS rates were 74.4% and 68.1%, respectively. The multivariate analysis demonstrated that postoperative IC were significant independent risk factors for OS and RFS. CONCLUSION: The presence of postoperative IC after CRC resection is associated with decreased long-term survival. The surgical procedure, surgical strategy, and perioperative care should be carefully planned in order to avoid causing IC.

Postoperative acute pancreatitis after pancreatic resection in patients with pancreatic ductal adenocarcinoma.

INTRODUCTION: Postoperative pancreatic fistula (POPF) is one of the major critical complications after pancreatic resection. Recently, postoperative acute pancreatitis (POAP), a new concept for a pancreatic-specific complication following pancreatic resection, has been advocated, and its association with POPF has been reported. The present study examined the clinical features of POAP and identified the associations of POAP with POPF and other postoperative morbidities in pancreatic ductal adenocarcinoma (PDAC) patients undergoing pancreatic resection. METHODS: A total of 312 consecutive patients who underwent pancreatic resection for PDAC at our institution from 2013 to 2019 were enrolled in this study. POAP was defined as an elevated serum amylase level above the upper limit normal on postoperative day (POD) 0 or 1, based on Connor's definition. The severity of POPF was assessed by the International Study Group on Pancreatic Surgery definition. RESULTS: A total of 184 patients (58.9%) had POAP. POAP occurred in 58.5% of subtotal stomach-preserving pancreatoduodenectomy patients and 60% of distal pancreatectomy combined with splenectomy patients. The presence of POAP was significantly associated with the development of clinically relevant POPF, higher rates of severe morbidity, and a prolonged hospital stay after pancreatic resection. A multivariate analysis showed that the presence of POAP and elevated C-reactive protein levels on POD 3 were independent predictors of clinically relevant POPF after subtotal stomach-preserving pancreatoduodenectomy. CONCLUSIONS: POAP is associated with the development of POPF, higher rates of severe morbidity, and a prolonged hospital stay after pancreatic resection and is an independent risk factor for clinically relevant POPF after pancreatoduodenectomy. POAP represents an important indicator for planning treatment strategies to prevent serious complications, including POPF.

Catalytic Dehydrogenative ß-Alkylation of Amino Acid Schiff Bases with Hydrocarbon.

A synthetic method for the synthesis of a highly congested α,ß-dehydroamino acid through the ß-C-H bond activation of an amino acid Schiff base is described. Abundant hydrocarbon feedstock could be used as an alkylating reagent to afford an α,ß-dehydroamino acid bearing a quaternary carbon at the γ-position with an exclusively (Z)-geometry. Notably, a tetrasubstituted olefin could be constructed from saturated starting materials. The transformation of the synthesized α,ß-dehydroamino acid into unnatural α-amino acid derivatives was also demonstrated.

Impact of Intraoperative Blood Loss on the Survival of Patients With Stage II/III Colorectal Cancer: A Multicenter Retrospective Study.

BACKGROUND: Resection of the primary lesion with radical lymph node dissection is the most promising treatment avenue for patients with cancer. On the other hand, these procedures often induce excessive intraoperative blood loss (IBL) and require perioperative blood transfusion. The influence of IBL on the long-term postoperative outcomes of patients with digestive cancer is controversial. We investigated the impact of IBL on survival and recurrence after curative surgery in patients with colorectal cancer (CRC) in a single study group. PATIENTS AND METHODS: In total, 1,597 patients who underwent radical resection for CRC at three group hospitals between 2000 and 2019 were reviewed. Patients were classified into a group with high IBL (≥200 ml) or low IBL (<200 ml). The risk factors for disease-free (DFS) and overall (OS) survival were analyzed. RESULTS: A total of 489 and 1,108 patients were classified into the high and low IBL groups, respectively. The OS and DFS rates at 5 years after surgery were 89.3% and 63.4%, respectively, for the high IBL group and 96.9% and 77.8% for the low IBL group; these differences were statistically significantly (p<0.001). The multivariate analysis demonstrated that IBL was a significant independent risk factor for OS and DFS. CONCLUSION: The amount of IBL was associated with significant differences in the OS and DFS of patients with stage II/III CRC who received curative resection. The surgical procedure, surgical strategy, and perioperative care should be carefully planned to avoid causing IBL.

Brightness evaluation of pulsed electron gun using negative electron affinity photocathode developed for time-resolved measurement using scanning electron microscope.

Temporal changes in carrier relaxations, magnetic switching, and biological structures are known to be in the order of ns. These phenomena can be typically measured by means of an optical-pump & electron-probe method using an electron microscope combined with a pulsed electron source. A photoemission-type pulsed electron gun makes it possible to obtain a short-pulsed electron beam required for high temporal resolution. On the other hand, spatial resolution is restricted by the brightness of the pulsed electron gun used in electron microscopes when a low brightness electron source is used and an irradiation current larger than a certain value is required. Thus, we constructed a prototype pulsed electron gun using a negative electron affinity (NEA) photocathode for time-resolved measurement using a scanning electron microscope (SEM) with high spatiotemporal resolution. In this study, a high-speed detector containing an avalanche photodiode (APD) was used to directly measure waveforms of the pulsed electron beam excited by a rectangular-shape pulsed light with a variable pulse duration in the range of several ns to several µs. The measured waveforms were the same rectangular shape as incident pulsed excitation light. The maximum peak brightness of the pulsed electron beam was 4.2×107 A/m2/sr/V with a pulse duration of 3 ns. This value was larger than that of the continuous electron beam (1.6 × 107 A/m2/sr/V). Furthermore, an SEM image with image sharpness of 6.2 nm was obtained using an SEM equipped with a prototype pulsed electron gun at an acceleration voltage of 3 kV.

Growth Suppression of Cancer Spheroids With Mutated KRAS by Low-toxicity Compounds from Natural Products.

BACKGROUND/AIM: Among compounds from natural products selectively suppressing the growth of cancer spheroids, which have mutant (mt) KRAS, NP910 was selected and its derivatives explored. MATERIALS AND METHODS: The area of HKe3 spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were measured in three-dimensional floating (3DF) cultures treated with 18 NP910 derivatives. The 50% cell growth inhibition (GI50) was determined by long-term 3DF (LT3DF) culture and nude mice assay. RESULTS: We selected NP882 (named STAR3) as the most effective inhibitor of growth of HKe3-mtKRAS spheroids with the least toxicity among NP910 derivatives. GI50s of STAR3 in LT3DF and nude mice assay were 6 µM and 30.75 mg/kg, respectively. However, growth suppression by STAR3 was observed in 50% of cell lines independent of KRAS mutation, suggesting that the target of STAR3 was not directly associated with KRAS mutation and KRAS-related signals. CONCLUSION: STAR3 is a low-toxicity compound that inhibits growth of certain tumour cells.

Catalytic Enantioselective Strecker Reaction of Isatin-Derived N-Unsubstituted Ketimines.

A catalytic enantioselective Strecker reaction of isatin-derived N-unsubstituted ketimines directly afforded the N-unprotected α-aminonitriles with a tetrasubstituted carbon stereocenter in up to 99% ee without requiring protection/deprotection steps. One-pot Strecker reactions from the parent carbonyl compounds were also realized with comparable yields and enantioselectivities. Direct transformations of the N-unprotected α-aminonitrile products streamlined the synthesis of unnatural amino acid derivatives and achieved the shortest one-pot stereoselective routes to a biologically active compound reported to date.

C-C Bond Cleavage of Unactivated 2-Acylimidazoles.

2-Acylimidazoles are widely used as post-transformable carboxylic acid equivalents in chemoselective and enantioselective reactions. Their transformations, however, require pretreatment with highly reactive, toxic methylating reagents to facilitate C-C bond cleavage. Here, we demonstrate that such pretreatment can be avoided and the C-C bond cleaved under neutral conditions without the use of additional reagents or catalysts. The scope of the reaction, including the use of products reported in the literature as substrates, and some mechanistic insights are described.

Catalytic Aerobic Cross-Dehydrogenative Coupling of Azlactones en Route to α,α-Disubstituted α-Amino Acids.

We developed a catalytic aerobic method to synthesize α,α-disubstituted α-amino acids through cross-dehydrogenative coupling of azlactones. Combining an iron catalyst with a bisoxazolidine ligand resulted in high catalytic performance, and cross-coupling with an indole proceeded smoothly under aerobic conditions. A wide variety of α-aryl and aliphatic amino acid derived azlactones were applied to the present catalysis. In addition, a quaternary carbon could be constructed using oxindole and benzofuranone under aerobic conditions.