Speciality Chemicals Magazine JUL / AUG 2025 | Page 21

HIGH POTENCY APIS
O
HO
O
O O
O
AcO
N
O O
O
O
OH
NH H 2 N
H N
N H
O
O
N H
HN
O
S O O
NH
N H
HO
O
O
N
O
O
O
O O
O O
O
NH
H N
O
H N
N H
O
O
N H
HN
O
S O O
NH
N H
1. Reaction 2. Prep. HPLC purification
HO
O
HO
HO
N HO
O O
NH
NH 2
H N
O
H N
N H
O
O
N H
HN
O
S O O
NH
N H
Compound 4 CGAM Cat. 2
CGAM Cat. 4 + CGAM Cat. 4 +
HO
HO
O
H
O
N 5
O H
Br
O
H
O
HO
N 5
O H
O
N
HO
O O
O
NH
NH 2
H N
O
H N
N H
O
O
N H
HN
O
S O O
NH
N H
1. Reaction 2. Prep. HPLC purification
O
HO
N 5
O
O
N
HO
O O
O
NH
NH 2
H N
O
H N
N H
O
O
N H
HN
O
S O O
NH
N H
Compound 5 CGAM Cat. 2
CGAM Cat. 4 +
Compound 6 CGAM Cat. 4 +
Figure 3- Manufacturing of amanitin derivative with linker( compound 6)
phase, intramolecular peptide bond formation and macrolactam ring closure generated the bicyclic octapeptide.
A subsequent reaction involved deprotection of the phenolic group and conversion of the aspartic acid moiety into the corresponding asparagine— a noteworthy transformation at such an advanced stage of synthesis.
Following purification by preparative HPLC, a linker was introduced at the phenolic position. This was followed by a chemistry reaction step and a preparative HPLC purification, yielding the maleimide functionality present in compound 6.9
Combining cytotoxic agents with monoclonal antibodies enhances tumour specificity while retaining high potency. 10 This approach broadens the therapeutic window by reducing systemic toxicity and lowering the minimum effective dose through targeted delivery via antibody binding.
The final step in Carbogen- Amcis’ contribution to the amanitin programme was the conjugation of compound 6 to a monoclonal antibody, yielding the ADC candidate.
Summary
This article has presented an overview of the first total industrial synthesis of amanitin derivatives entering Phase I and II clinical trials. It has also examined the structural complexity of the molecule and outlined the retrosynthetic and operational strategies used to overcome its synthetic challenges.
Central to the project’ s success was the strong collaboration between Heidelberg Pharma and Carbogen Amcis, combining customer-driven innovation with coordinated internal execution across multiple sites and functions. The programme exemplifies the potential of strategic CDMO partnerships in advancing highly potent, targeted therapies, and this collaboration continues to progress. ●
* The author would like to acknowledge the contributions of the following: Andreas Krotz, Erik Lauterbach, Janos Kovacs, Kathryn Williams, Issa Sulaiman, Lucy Shapely, Peter Brown, Marco Rudolf von Rohr, Simon Ruppenthal, Martin Doll, Bick Vivant, Luca Mannocci, Giulia Marafon, Artem Osypenko, Julian Wolf, Thomas Schlatterer, Thorsten Fritz and Emmanuel Bourcet, all of Carbogen Amcis; and Christian Lutz, and Christoph Müller of Heidelberg Pharma
References: 1: V. T. DeVita Jr & E. Chu, Cancer Res., 2008, 68, 8643 – 8653. 2: K. Huang et al., Curr. Med. Chem., 2017, 24, 1 – 24. 3: P. Dobosz & T. Dzieciątkowski, Front. Immunol., 2019, 10, 2965.
4: H. Wieland, R. Hallermayer & J. Liebigs, Ann. Chem., 1941, 548, 1 – 18. 5: D. M. Perrin et al., J. Am. Chem. Soc., 2018, 140, 6513 – 6517. 6: C. Lutz, W. Simon, A. Pahl & C. Müller, Angew. Chem. Int. Ed. Engl., 2020, 59, 11390 – 11393; A. Pahl, C. Lutz & T. Hechler, Drug Discov. Today Technol., 2018, 30, 85 – 89.
7: W. E. Savige & A. J. Fontana, Chem. Soc. Chem. Commun., 1976, 600. 8: A. Pryyma, K. Matinkoo, A. A. W. L. Wong & D. M. Perrin, Chem. Sci., 2020, 11, 11927 – 11935. 9: S. Kotha & S. Banerjee, RSC Adv., 2013, 3, 7642 – 7666. 10: R. Singh, P. Chandley & S. Rohatgi, Immunohorizons, 2023, 7, 886 – 897.
Emad El Sayed
SENIOR MANAGER PR & D
CARBOGEN AMCIS AG
k + 41 58 909 08 54 J emad. el-sayed @ carbogen-amcis. com j www. carbogen-amcis. com
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