1. No category

Commercial Scale Manufacture and Isotopic Labelling of
Cytotoxin/Linker
Jiaxin Yu, Qianlong Deng, Lei Wang, Mingquan Tan, Li Gan*
Dept. of ADCs Research & Technologies, Thode Laboratories, 2 Armando Dr., Markham, Ontario, Canada
Email: [email protected]
Thode Laboratories focuses on the manufacture (semi-/total synthesis) of Cytotoxins, Linkers, and Toxin/Linker Combination in commercial
scale. It also provides isotopic labeled payloads, linkers, or both to facilitate ADC’s ADME/Tox study.
Cytotoxins Highly Demanded
OH
O
O
O
H
N
HN
N
N
OH
H
N
HN
O
O
O
O
O
H
N
O
H
N
N
N
O
O
O
O
O
O
N
H
OH
N
HO
O
H
N
OH
N
O
N
H
N
O
O
H
O
N
N
O
O
O
OH
O
O
OH
N
O
NH2
H
H
O
Features of Total
Synthesis Method
O
O
HN
OH O
OH
Auristatin MMAE
HTI-286
Auristatin MMAF
Tomaymycin DM
pyrrolobenzodiazepine SJG-136
O
O
OH
O
HN
HN
HN
O
OH
O
O
N
O
SH
N
O
Cl
O
O
Cl
SH
N
HO
HO
N
HO
O
I
N
O
O
O
HN
N
H
Duocarmycin DME
O
O
N
O
Dehalogenation
O
O
H
N
Higher Yield and Purity;
O
O
OH
Durocarmycin TM
Durocarmycin DMA
O
N
H HO
O
O
HO
O
O
OH
O
HN
HN
O
O
O
S
O
O
Demethylation
H
Branch modification
O
Cl
O
O
S
S
O
O
O
O
Maytansinoid DM4
Maytansinoid DM1
S
HN
O
O
Maytansine
N
O
N
O
O
H
N
Cl
Cl
O
O
N
O
N
Cl
NC
Cl
HN
O
O
HN
H
N
O
N
O
N
OH
H
HO
O
O
O
O
H
O
O
O
O
O
OH
Epoxide removal
H
Dororubicin
Demethylation
O
Radio labeling
*
Configuration flexible
Ease of Structure Optimizing;
Ease of Frame work Labeling;
Ease of Impurities, metabolites study.
Calicheamicin
Selected Linkers
F
F
O
H2 N
O
H
N
N
H
OH
O
O
N3
N
H
O
O
O
O
F
F
O
N
H
F
O
F
F
O
F
O
N
S
O
O
O
O
O
O
O
O
O
O
O
F
O
O
N
O
O
N
N
O
F
O
O
H
N
N
S
O
O
O
F
O
O
F
F
O
O
N
H
H
O
O
O
N
O
O
O
F
F
NH2
N3-tri-EG-OPFP
Ala-Ala-Asn-PAB
O
H
N
N
H
O
F
O
O
F
N
H
O
O
O
O
O
N3
NH
O
ALD-di-EG-OSu
O
O
O
O
N
H
N
O
O
N
O
O
N
O
S
S
F
F
O
O
O
O
H
N
N
O
F
O
O
O
O
N
O
O
O
H
O
O
F
F
O
F
O
O
N
H
N
O
O
F
F
F
O
F
O
F
O
NH2
O
F
O
O
F
N3-tri-EG-OSu
PHA-di-EG-OSu
MAL-di-EG-OPFP
Py-ds-But-OPFP
COT-di-EG-OSu
ALD-di-EG-OPFP
Fmoc-Val-Cit-PAB-PNP
Linkers for Click Chemistry
Peptide Linkers
Disulfide Linkers
Linkers for Copper Free Click Chemistry
O
O
O
NH
O
H
N
O
H
N
N
O
H
N
N
N
O
N
H
O
O
O
O
O
Thiol Reactive Linkers
OH
OH
N
H
O
H
N
N
O
O
OH
H
N
N
N
O
O
O
O
O
O
OH
O
Boc
OH N
OH
Cl
O
N
H
HO
N
H
N
H
HO
O
O
O
Boc
O
NH 2
Duo-V
O
H
N
N
N
O
O
HN
Boc
O
N
H
HO
Duo-IV
Duo-III
N
H
S
MAY-P2
HN
Tub-III
N
S
O
O
O
S
OH
O
N
N
OMEM
O
OAc
NH2
H
O
MAY-P1
Duo-II
Duo-I
OH
EtO
Dolaphenine
Cl
HO
N
H
HO
O
H
S
NC
HN
Mc-MMAE
O
N
O
Dolaisoleuine
HO
Cl
O
O
O
O
Vc-MMAE
N
OH
N
H
O
O
Dolaproine
O
N
OEt OTBDMS
Cl
O
H2N
O
NH
H2N
Linkers for Aldehyde Chemistry
To Construct Your Own Novel Payloads
For Customers with Their Own MAb
N
Linkers for Oxime Chemistry
O
O
O
O
Tub-I
OH
Boc-Val-Dil-Dap-OH
O
DOXO-EMCH
Stable/Radio Isotope Labeling for ADME/Tox Study
O
D
D
OH
O
H D
N
HN
O
D
D
D
O
H
N
N
N
H
N
HN
O
O
O
O
N
O
13
C
13
C
D
D
13
N
S
O
O
D D
13
O
D
N
HN
O
D
13
H
N
D
D D
D
15
N
O
D D
D
HN
D
D
N3-tri-EG-OPFP D12
O
H
N
13
C
O
O
Cl
O
O
N
SH
O
N
O
O
Cl
O
O
O
*
N
SH
O
O
14
C Radio labeling
F
F
F
OH
O
H
N
F
O
D
O
O
OH
C
O
O
OH H
O
13C
O
F
O
N3
*
HN
C Radio labeling
OH H
N
13
C
14
MMAE 13C515N
D
O
O
C
N
O
D
Py-ds-dmBut-OSu D10
D
O
O
MMAE 13C5
O
D
S
D
D D
O
O
HN
O
C
MMAE D8
D
H
N
N
C
C
O
OH
13
13
O
H
N
N
N
O
O
C
13
13
13
13
C
O
O
H
N
HN
13
C
C
O
O
H
N
N
N
O
O
O
OH
*
O
C
13
C
MMAE 13C5
14
C Labled ADC's Payloads is Under Development
www. post er session. com
Fmoc
PHA-di-EG-OPFP
MAL-di-EG-OSu
Py-ds-dmBut-OSu
COT-di-EG-OPFP
NO2
O
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