MonoMethylauristatin F Chemical Properties

Boiling point:

896.8±65.0 °C(Predicted)

Density 

1.116±0.06 g/cm3(Predicted)

storage temp. 

Sealed in dry,Room Temperature

solubility 

Soluble in DMSO

form 

A solid

pka

3.56±0.10(Predicted)

color 

White to off-white

Stability:

Hygroscopic

InChIKey

MFRNYXJJRJQHNW-UQVYMQKONA-N

MonoMethylauristatin F Usage And Synthesis

in vivo

The maximum tolerated dose in mice of MMAF (Monomethylauristatin F) (>16 mg/kg) is much higher than MMAF (Monomethylauristatin F) (1 mg/kg). cAC10-L1-MMAF4 has an MTD of 50 mg/kg in mice and 15 mg/kg in rats. The corresponding cAC10-L4-MMAF4 ADC was much less toxic, having MTDs in mice and rats of >150 mg/ kg and 90 mg/kg in rats, respectively.

Description

MMAF (Monomethylauristatin F) is an effective tubulin polymerization inhibitor, used as an anti-tumor drug. MMAF (Monomethylauristatin F) is widely used as the cytotoxic component of antibody-conjugated drugs (ADCs), such as Vorsetuzumab mafodotin and SGN-CD19A.

Uses

Monomethyl Auristatin F is an antimicrotubule agent. A potent mitotic inhibitor.

Biological Activity

MMAF (Monomethylauristatin F) is a potent tubulin polymerization inhibitor and is used as a antitumor agent. MMAF (Monomethylauristatin F) is widely used as a cytotoxic component of antibody-drug conjugates (ADCs) such as vorsetuzumab mafodotin and SGN-CD19A.

Biotechnological Applications

MMAF is a new auristatin derivative with a charged C-terminal phenylalanine that attenuates its cytotoxic activity compared to its uncharged counterpart, Monomethyl auristatin E (MMAE). Because of MMAF is highly toxic, it cannot be used as a drug itself. MMAF induces potent antitumor effects when conjugated via protease cleavable linkers to a monoclonal antibody targeting internalizing, tumor-specific cell surface antigens. The linker to the monoclonal antibody is stable in extracellular fluid, but is cleaved by cathepsin once the conjugate has entered a tumor cell, thus activating the anti-mitotic mechanism.

Synthesis

The synthesis of (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylaminopropionamido)butanamido)butanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl) was carried out using the compound (CAS: 1369427-27-9) as starting material. (methylamino)butanamido)butanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid was prepared in the following general steps: (S)-2-((2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-sec-butyl)-6,9-diisopropyl-13-methoxy-2,2,5,11-tetramethyl-4,7,10-trioxo-3- oxa-5,8,11-triazatetradecan-15-yl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid (25 mg, 0.030 mmol) was dissolved in a mixture of 0.3 ml of HCl and 0.9 ml of 1,4-dioxane and stirred at room temperature for 35 min. The reaction mixture was diluted with 1.0 ml of ethanol and 1.0 ml of toluene, subsequently concentrated and evaporated again with ethanol/toluene (2:1) to afford the target product (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butyramido)butanamide (S)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid as a white solid (22 mg, about 400% yield), which can be used in the next reaction without further purification.LC-MS (ESI) m/z calculated value: C39H66N5O8 [M + H]+: 732.48, measured value: 732.60.

in vitro

MMAF inhibits anaplastic large cell lymphoma Karpas 299, breast carcinoma H3396, renal cell carcinoma 786-O and Caki-1 cells with IC50s of 119, 105, 257 and 200 nM in vitro cytotoxicity assay.

References

[1] Patent: WO2015/155753, 2015, A2. Location in patent: Page/Page column 101
[2] Patent: WO2018/86139, 2018, A1. Location in patent: Page/Page column 192; 193
[3] Patent: WO2012/166560, 2012, A1. Location in patent: Page/Page column 165
[4] Patent: WO2013/185117, 2013, A1. Location in patent: Paragraph 00453
[5] Patent: WO2016/59622, 2016, A2. Location in patent: Page/Page column 130

MonoMethylauristatin F(745017-94-1)Related Product Information

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