Development of a traceable linker containing a thiol-responsive amino acid for the enrichment and selective labelling of target proteins

A traceable linker that is potentially applicable to identification of a target protein of bioactive compounds was developed. It enabled not only thiol-induced cleavage of the linker for enrichment of the target protein but also selective labelling to pick out the target from contaminated non-target proteins for facile identification

Development of a fluoride-responsive amide bond cleavage device that is potentially applicable to a traceable linker

A fluoride-responsive (FR) amino acid that induces amide bond cleavage upon the addition of a fluoride was developed, and it was applied to a FR traceable linker. By the use of an alkyne-containing peptide as a model of an alkynylatd target protein of a bioactive compound, introduction of the FR traceable linker onto the peptide was achieved. Subsequent fluoride induced cleavage of the linker followed by labeling of the released peptide derivative was also conducted to examine the potential applicability of the FR traceable linker to the enrichment and labeling of alkynylated target molecules

Proton beam therapy for intrahepatic cholangiocarcinoma: A multicenter prospective registry study in Japan

Introduction: Intrahepatic cholangiocarcinoma (ICC) can be treated with chemotherapy in unresectable cases, but outcomes are poor. Proton beam therapy (PBT) may provide an alternative treatment and has good dose concentration that may improve local control. Methods: Fifty-nine patients who received initial PBT for ICC from May 2016 to June 2018 at nine centers were included in the study. The treatment protocol was based on the policy of the Japanese Society for Radiation Oncology. Forty patients received 72.6-76 Gy (RBE) in 20-22 fr, 13 received 74.0-76.0 Gy (RBE) in 37-38 fr, and 6 received 60-70.2 Gy (RBE) in 20-30 fr. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results: The 59 patients (35 men, 24 women; median age 71 years; range 41-91 years) had PS of 0 (n=47), 1 (n=10) and 2 (n=2). Nine patients had hepatitis and all 59 cases were considered inoperable. The Child-Pugh class was A (n=46), B (n=7), and unknown (n=6); the median maximum tumor diameter was 5.0 cm (range 2.0-15.2 cm); and the clinical stage was I (n=12), II (n=19), III (n=10), and IV (n=18). At the last follow-up, 17 patients were alive (median follow-up 36.7 months; range 24.1-49.9 months) and 42 had died. The median OS was 21.7 months (95% CI 14.8-34.4 months). At the last follow-up, 37 cases had recurrence, including 10 with local recurrence. The median PFS was 7.5 months (95% CI 6.1-11.3 months). In multivariable analyses, Child-Pugh class was significantly associated with OS and PFS, and Child-Pugh class and hepatitis were significantly associated with local recurrence. Four patients (6.8%) had late adverse events of Grade 3 or higher. Discussion/Conclusion. PBT gives favorable treatment outcomes for unresectable ICC without distant metastasis and may be particularly effective in cases with large tumors

Remote Stereoinduction in the Organocuprate-Mediated Allylic Alkylation of Allylic <i>gem</i>-Dichlorides: Highly Diastereoselective Synthesis of (<i>Z</i>)‑Chloroalkene Dipeptide Isosteres

Highly diastereoselective synthesis of (<i>Z</i>)-chloroalkene dipeptide isosteres has been achieved by 1,4-asymmetric induction in the organocuprate-mediated allylic alkylation adjacent to the chiral center of allylic <i>gem</i>-dichlorides. The reaction proceeds with a variety of heterocuprates prepared from CuCN and various organometallic reagents. It allows rapid construction of valuable architectures of l,d-type and l,l-type (<i>Z</i>)-chloroalkene dipeptide isosteres from the corresponding (<i>E</i>)- and (<i>Z</i>)-allylic <i>gem</i>-dichlorides in high yields, with excellent (<i>Z</i>)-selectivity and diastereoselectivity