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Tesirine
| Molecular Formula: | C75H101N9O23 |
|---|---|
| Molecular Weight: | 1496.673 g/mol |
UNII-8DVQ435K46;
CAS 1595275-62-9
(11S,11aS)-4-((2S,5S)-37-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5-isopropyl-2-methyl-4,7,35-trioxo-10,13,16,19,22,25,28,31-octaoxa-3,6,34-triazaheptatriacontanamido)benzyl 11-hydroxy-7-methoxy-8-((5-(((S)-7-methoxy-2-methyl-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-2-methyl-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate
SG3249, Tesirine
[4-[[(2S)-2-[[(2S)-2-[3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (6S,6aS)-3-[5-[[(6aS)-2-methoxy-8-methyl-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]pentoxy]-6-hydroxy-2-methoxy-8-methyl-11-oxo-6a,7-dihydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate
PATENT
WO 2014057074
In 2012, tesirine (SG3249) was developed by Spirogen, as a drug linker combining a set of desired properties: fast and straightforward conjugation to antibody cysteines by maleimide Michael addition, good solubility in aqueous/DMSO (90/10) systems, and a traceless cleavable linker system delivering the highly potent pyrrolobenzodiazepine (PBD) DNA cross-linker SG3199
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CLIP
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CLIP
Scale-up Synthesis of Tesirine
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, Christina von Bulow†, Conor Barry†, Huajun Ge§, Christian Noti∥, Florence Collet Leiris#, Marc McCormick‡, Philip W. Howard†, and Jeremy S. Parker‡ Image may be NSFW.Clik here to view.
This work describes the enabling synthesis of tesirine, a pyrrolobenzodiazepine antibody–drug conjugate drug-linker. Over the course of four synthetic campaigns, the discovery route was developed and scaled up to provide a robust manufacturing process. Early intermediates were produced on a kilogram scale and at high purity, without chromatography. Midstage reactions were optimized to minimize impurity formation. Late stage material was produced and purified using a small number of key high-pressure chromatography steps, ultimately resulting in a 169 g batch after 34 steps. At the time of writing, tesirine is the drug-linker component of eight antibody–drug conjugates in multiple clinical trials, four of them pivotal
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Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody–drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy. Tesirine was evaluated in vitro both in stochastic and engineered ADC constructs and was confirmed as a potent and versatile payload. The conjugation of tesirine to anti-DLL3 rovalpituzumab has resulted in rovalpituzumab-tesirine (Rova-T), currently under evaluation for the treatment of small cell lung cancer.
https://cdn-pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00062/suppl_file/ml6b00062_si_001.pdf
SG3249 (tesirine) (860 mg, 73% over 2 steps). LC/MS, method 2, 2.65 min (ES+) m/z (relative intensity) 1496.78 ([M+H] +. , 20). [] 24 D = +262 (c = 0.056, CHCl3).
1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.20 (d, J = 7.0 Hz, 1H), 8.03 (t, J = 5.6 Hz, 1H), 7.97 – 7.84 (m, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.32 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 – 6.96 (m, 3H), 6.84 (s, 1H), 6.79 – 6.57 (m, 4H), 5.59 (d, J = 9.4 Hz, 1H), 5.16 (d, J = 12.7 Hz, 1H), 4.81 (d, J = 12.4 Hz, 1H), 4.38 (t, J = 7.1 Hz, 1H), 4.32 – 4.17 (m, 2H), 4.17 – 4.07 (m, 1H), 4.07 – 3.87 (m, 3H), 3.80 (d, J = 14.2 Hz, 6H), 3.74 – 3.62 (m, 1H), 3.59 (t, J = 7.2 Hz, 4H), 3.55 – 3.42 (m, 28H), 3.35 (d, J = 5.2 Hz, 2H), 3.21 – 3.11 (m, 2H), 3.11 – 2.98 (m, 2H), 2.98 – 2.83 (m, 1H), 2.49 – 2.28 (m, 5H), 2.03 – 1.88 (m, 1H), 1.87 – 1.65 (m, 10H), 1.64 – 1.47 (m, 2H), 1.29 (t, J = 5.9 Hz, 3H), 0.85 (dd, J = 17.1, 6.7 Hz, 6H).
13C NMR (126 MHz, DMSO-d6) δ 171.55, 171.29, 171.16, 170.78, 169.91, 164.80, 162.52, 155.03, 150.25, 139.27, 134.99, 128.84, 123.13, 122.67, 121.76, 119.28, 111.93, 110.93, 86.05, 70.21, 70.16, 70.02, 69.95, 69.46, 68.93, 68.79, 67.39, 57.94, 56.16, 54.03, 49.49, 38.97, 38.89, 36.39, 34.53, 34.40, 31.04, 28.69, 28.65, 22.72, 19.60, 18.55, 18.37, 13.88, 13.82. HRMS (ESI) m/z Calc. C75H101N9O23 1495.70831 found 1495.70444.
FT-IR (ATR, cm‐1 ) 3311, 2911, 2871, 1706, 1643, 1623, 1601, 1512, 1435, 1411, 1243, 1213, 1094, 1075, 946, 827, 747, 695, 664.
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| Patent ID | Title | Submitted Date | Granted Date |
|---|---|---|---|
| US2015297746 | PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES |
2013-10-11
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| US2015283258 | PYRROLOBENZODIAZEPINE – ANTI-PSMA ANTIBODY CONJUGATES |
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2015-10-08
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2016-04-21
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| US2014127239 | PYRROLOBENZODIAZEPINES AND CONJUGATES THEREOF |
2013-10-11
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.//////////Tesirine, SG3249, SG 3249
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