121st General Meeting of the KCS

Type Poster Presentation
Area Organic Chemistry
Room No. Event Hall
Time 4월 19일 (목요일) 11:00~12:30
Code ORGN.P-519
Subject Total Synthesis of S-deoxo-[aTrp4]-α-Amanitin: A Synthetic Analogue of Cytotoxic α-Amanitin
Authors Gangadhar Rao Mathi, Raghavendra Achary, Jong Yeon Hwang, jae du ha1, Chang-Soo Yun, Sung Yun Cho1, Hyoung Rae Kim1, PILHO KIM*
Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Korea
1WCI, Korea Research Institute of Chemical Technology, Korea
Abstract Amanita phalloides and Amanita verna are mushrooms with lethal toxicity. α-Amanitin has tremendous attention to the Antibody Drug Conjugate (ADC) communities as a DNA damaging agent in ADC studies. Amatoxins are bicyclic octapeptides, characterized by a thioether bridge between cysteine and tryptophan side chains and by the presence of uncommon hydroxylated amino acids. The toxin shows a remarkable binding affinity for eukaryotic RNA polymerase II. Inhibition of RNA polymerase II compromises cellular homeostasis and leads to apoptosis. α-Amanitin is an extremely toxic natural product, consisting of eight amino acids (Asn-hPro-DHIle-hTrp-Gly-Ile-Gly-Cys) (Bridge: 4-8). α-Amanitin is usually isolated from Amanita phalloides mushrooms or from pure cultures with very low yields and the flexibility for further modifications are limited. The use of complete synthetic routes to amatoxins may offer the supply of large quantities required for therapeutic use. No entire solution phase synthetic approach to the relevant amatoxins has been reported so far. Hence there is a high necessity for convenient synthesis of a bicyclic octapeptide which can provide access to bioactive amanitin analogues. Herein, we describe the total chemical synthesis of a S-deoxo-[aTrp4]-α-Amanitin, a synthetic analogue of α-Amanitin comprising unnatural amino acids, such as enantiomerically pure dihydroxyisoleucine, 6-aminotryptophan, and trans-4-hydroxyproline. Cyclisation and cross-linking strategies that are unprecedented for the synthesis of cyclic and bicyclic peptides will be presented.
E-mail gangadhar.mathi@gmail.com