Mc-Val-Cit-PABC-PNP Chemical Properties

Boiling point:

1034.5±65.0 °C(Predicted)

Density 

1.338±0.06 g/cm3(Predicted)

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

solubility 

DMF: 25 mg/ml; DMSO: 20 mg/ml; DMSO:PBS(pH 7.2) (1:4): 0.20 mg/ml

form 

A crystalline solid

pka

13.24±0.70(Predicted)

color 

Off-white to light yellow

InChIKey

UQRQGHMQKAXOTE-DHIFEGFHSA-N

SMILES

C(N)(=O)[C@H](CCCNC(N)=O)N(C(=O)[C@H](C(C)C)NC(=O)CCCCCN1C(=O)C=CC1=O)C1=CC=C(COC(OC2=CC=C([N+]([O-])=O)C=C2)=O)C=C1

Mc-Val-Cit-PABC-PNP Usage And Synthesis

Description

Mc-Val-Cit-PABC-PNP is a peptide linker molecule used in the synthesis of antibody-drug conjugates (ADCs). It contains a maleimidocaproyl (Mc) group that can be conjugated to an antibody and a p-nitrophenol (PNP) group that allows the peptide to be linked to anticancer compounds, such as doxorubicin or monomethyl auristatin E (MMAE; ). ADCs target specific cell populations to induce a selective response, such as cell death in cancer cells.

Uses

Mc-Val-Cit-PABC-PNP is a cathepsin cleavable ADC linker used in the synthesis of antibody-drug conjugates.

General Description

Mc-Val-Cit-PABC-PNP is chemically known as L-OrnithinaMide, N-[6-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-1-oxohexyl]-L-valyl-N5-(aMinocarbonyl)-N-[4-[[[(4-nitrophenoxy)carbonyl]oxy]Methyl]phenyl]-, an enzymatically cleavable linker for antibody-drug conjugates (ADCs). Other ADCs linkers include MC-Val-Cit-PAB-PNP, Mc-Val-Ala-PAB-PNP, Mc-Val-Cit-PABOH, and VcMMAE.

Synthesis

GENERAL STEPS: To a mixed solution of compound 11 (500 mg, 0.87 mmol) and bis(4-nitrophenyl) carbonate (bis-PNP, 2.64 g, 8.72 mmol) in DCM:DMF (8:2, 25 mL) was added N,N-diisopropylethylamine (DIPEA, 0.45 mL, 2.61 mmol). The reaction mixture was stirred at 23 °C for 20 h. After purification by silica gel column chromatography (eluent: DCM:CH3OH, 50:1 to 10:1), the target product, maleimidohexanoyl-L-valyl-L-citrulline p-aminobenzyl alcohol p-nitrophenyl carbonate 9 (364 mg, 57% yield) was obtained. Thin layer chromatography (TLC) Rf = 0.40 (unfolding agent: CH2Cl2:CH3OH, 9:1).1H NMR (400 MHz, CDCl3/CD3OD) δ 9.45 (s, 1H), 8.23 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.3 Hz. 2H), 7.34 (d, J = 8.5 Hz, 2H), 6.65 (s, 2H), 5.20 (s, 2H), 4.56 (dt, J = 10.5, 5.4 Hz, 1H), 4.15 (d, J = 7.2 Hz, 1H), 3.46 (dd, J = 8.0, 6.4 Hz, 2H), 3.16-2.89 (m, 2H). 2.21 (dd, J = 8.3, 6.6 Hz, 2H), 2.06-1.97 (m, 1H), 1.90-1.83 (m, 1H), 1.73-1.46 (m, 7H), 1.34-1.20 (m, 2H), 0.91 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H).13C NMR (125 MHz, CDCl3/CD3OD) δ 174.4, 172.4, 171.1, 170.6, 160.5, 155.5, 152.5, 145.3, 138.7, 134.1, 129.9, 129.5, 125.2, 121.8, 120.0, 70.6, 59.0, 53.2, 37.5, 35.8, 30.6, 29.6, 29.3, 28.1, 26.2, 25.1, 19.1, 18.1. ESI-MS m/z: Calculated value C34H42N6O11: 737.3; measured value: 738.3 ([M + H]+).

IC 50

Protease Cleavable Linker; Cleavable Linker

References

[1] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[2] Patent: WO2017/66668, 2017, A1. Location in patent: Paragraph 000199; 000200
[3] Patent: WO2014/191578, 2014, A1. Location in patent: Page/Page column 137-138
[4] Patent: EP2927227, 2015, A1. Location in patent: Paragraph 0051; 0052; 0053; 0054; 0055-0059
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000

Mc-Val-Cit-PABC-PNP(159857-81-5)Related Product Information

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