Emad El Sayed, senior manager- PR & D at Carbogen Amcis, presents the challenges involved in synthesising and manufacturing a complex structure derived from a natural product *
HIGH POTENCY APIS
Scaling complexity: Industrial synthesis of highly potent amanitin derivatives
Emad El Sayed, senior manager- PR & D at Carbogen Amcis, presents the challenges involved in synthesising and manufacturing a complex structure derived from a natural product *
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OH
AA 6
OH O
1) Macrolactamization H H AA
N 5
AA 4
HN NH
AA 7
O
O O
HO NH
N
O H
S N
N O
H H OH N H
2) Savige-Fontana
HN cyclization O O
AA 2 O
AA
AA 1 O 8
NH 2
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AA 3 |
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HO |
OH HO
H N
O
O
HO
OH
N
O O
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HS
HN
N H
NH 2
OH
H
O
N H
NH
O
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O
HN
HN
HN O
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O |
Figure 1- Retrosynthesis of α-amanitin |
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The evolution of cancer treatment has long demonstrated the value of chemical synthesis, not only in replicating natural products but also in modifying them to create new, therapeutically active compounds. A notable early example is methotrexate, derived from folic acid, which became a key treatment for childhood acute leukaemia.
By the 1970s, the advent of combination chemotherapy significantly improved outcomes for many cancer types. 1 Alongside these chemical advances, biologics began to re-emerge as promising therapeutic agents, leading to the development of cancer immunotherapies, antibody-drug conjugates( ADCs) and peptide-drug conjugates( PDCs). 2
Carbogen Amcis began its work in the ADC field in 2006, with its first conjugation activities at the Bubendorf site in Switzerland. With over 40 years of experience in pharmaceutical and biologics development, the company has since built robust capabilities for cGMP synthesis of ADC warheads and linkers, including compounds with occupational exposure limits( OEL) below 0.01 µ g / m 3. 3
These activities are supported by purpose-designed containment laboratories for highly potent materials, from early development to small-scale production. Since 2014, cleanroom suites at the site have been qualified for the manufacture of bioconjugate bulk drug substances. Based on these capabilities, Carbogen Amcis entered a direct collaboration with Heidelberg Pharma of Germany to manufacture amanitin derivatives intended for Phase I and II clinical trials.
α-Amanitin: Potential payload
α-Amanitin is a toxic bicyclic octapeptide that was first isolated in 1941 from Amanita phalloides( death-cap mushroom). 4 It is currently under investigation as a payload for ADCs. Its extremely high cytotoxicity, combined with the potential for tumour-specific targeting, offers a promising approach to increasing
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