120th General Meeting of the KCS

Type Oral Presentation
Area Oral Presentations of Young Scholars in Organic Division
Room No. Room 304+305+306
Time THU 10:45-:
Code ORGN.O-8
Subject Total Synthesis of α-Amanitin Derivative: A Novel Cytotoxic Agent for Antibody Drug Conjugate Payload
Authors Gangadhar Rao Mathi, 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 α-Amanitin belongs to a large group of protoplasmic mushroom toxins known as amatoxin family isolated from the green death cap mushroom Amanita phalloides. α-Amanitin is characterized by a defined rigid structure consisting of a bicyclic octapeptide, with an intraannular linkage known as a tryptathionine bridge between tryptophan and cysteine. The toxin shows remarkable binding affinity for eukaryotic RNA polymerase II. Inhibition of RNA polymerase II compromises cellular homeostasis and leads to apoptosis. Amatoxins are usually isolated from collected amanita phalloides mushrooms or from pure cultures. However the amounts that can be obtained are rather low and the flexibility for further modifications are limited. The use of entirely synthetic routes to amatoxins may offer the supply of large quantities required for therapeutic use. No fully solution phase synthetic approach to the relevant amatoxins has been reported so far. Hence there is high need in the prior art to identify alternate method for synthesizing α-Amanitin and its derivatives. α-Amanitin seems to be a suitable toxic payload for use in an Antibody-Drug Conjugate (ADC) because of the unique mode of action and the molecular characteristics of the toxin. A new α-Amanitin derivative applicable for diverse linker chemistry was designed to improve stability with prolonged cytotoxicity. Retrosynthesis and the utilization of orthogonal protecting groups during the course of total chemical synthesis of α-Amanitin derivative will be presented.
E-mail gangadhar.mathi@gmail.com