YAKUGAKU ZASSHI

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Volume 144 (2024) Issue 5 Pages 553-565

Syntheses and Structure–Activity Relationship Studies of Antitumor Bicyclic Hexapeptide RA-VII Analogues

Yukio Hitotsuyanagi

A series of antitumor bicyclic hexapeptide RA-VII analogues modified at residue 2, 3, or 6 were prepared by the chemical transformation of the hydroxy, methoxy, or carboxy groups or the aromatic rings of natural peptides RA-II, III, V, VII, and X. Analogues with modified side chains or peptide backbones, which cannot be prepared by the chemical transformation of their natural peptides, and newly isolated peptides from Rubia cordifolia roots were synthesized by using protected cycloisodityrosines prepared by the degradation of bis(thioamide) obtained from RA-VII or the diphenyl ether formation of boronodipeptide under the modified Chan–Lam coupling reaction conditions. Studies of the conformational features of the analogues and the newly isolated peptides and their relationships with cytotoxic activities against the HCT-116, HL-60, KATO-III, KB, L1210, MCF-7, and P-388 cell lines revealed the following: the methoxy group at residue 3 is essential for the potent cytotoxic activity; the methyl group at Ala-2 and Ala-4 but not at D-Ala-1 is required to establish the bioactive conformation; the N-methyl group at Tyr-5 is necessary for the peptides to adopt the active conformation preferentially; and the orientation of Tyr-5 and/or Tyr-6 phenyl rings has a significant effect on the cytotoxic activity.

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This review outlines structure-activity relationship (SAR) studies focusing on the plant-derived antitumor bicyclic hexapeptide RA-VII. The SAR data, encompassing conformational properties, were obtained from designed and synthesized analogues that underwent modifications either at the amino acid side-chain or the peptide backbone, along with newly isolated RA-VII congeners from Rubiae Radix. These insights are anticipated to be invaluable for synthesizing analogues of other bioactive natural cyclic peptides incorporating unnatural amino acids.

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2024 Volume 144 Issue 5

Evaluation of Pharmacy Students’ Understanding of Clinical Trials and Research through Questionnaires Before and After the Hospital Practical Training Chihiro Shiraishi, Mayumi Kotera, Yasuyuki Ota, Eiko Takeshige, Chisato Minamide, Rie Kurimoto, Aki Sato, Miho Inamori, Misaki Kataoka, Toru Ogura, Satoshi Tamaru, Takuya Iwamoto
A Questionnaire Survey of Nurses on Pharmacist Services in the Emergency Rooms at Tokushukai Medical Group Hiroki Tateishi, Yasuhiro Saito, Yuichi Miyata, Yuto Sakaguchi, Kojiro Yamamoto, Eiji Takeda, Riku Iwasaki, Yuji Miyazaki, Daisuke Maekawa, Maiki Yoshikawa, Yosuke Takeuchi, Yohei Yano, Takao Goto, Hiroyuki Watanabe

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