MMAF Hydrochloride
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| Category | Mycotoxins |
| Catalog number | BBF-05830 |
| CAS | 1415246-68-2 |
| Molecular Weight | 768.42 |
| Molecular Formula | C39H66ClN5O8 |
| Purity | >98% |
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Description
MMAF Hydrochloride, a synthetic antineoplastic agent, is a tubulin polymerization inhibitor that inhibits cell division by blocking the polymerization of tubulin. It is part of some experimental anti-cancer antibody-drug conjugates such as vorsetuzumab mafodotin and SGN-CD19A.
Specification
| Related CAS | 745017-94-1 (free base) |
| Synonyms | Monomethylauristatin F Hydrochloride; Monomethyl Auristatin F Hydrochloride; N-Methyl-L-valyl-L-valyl-(3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoyl-(αR,βR,2S)-β-methoxy-α-methyl-2-pyrrolidinepropanoyl-L-phenylalanine Hydrochloride; Monomethylauristatin Phenylalanine Hydrochloride; L-Valinamide, N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1S)-1-carboxy-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-, Hydrochloride (1:1); ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoyl)-L-phenylalanine Hydrochloride |
| Shelf Life | ≥12 months if stored properly |
| Storage | Store at 2-8°C under inert atmosphere |
| IUPAC Name | (2S)-2-[[(2R,3R)-3-methoxy-3-[(2S)-1-[(3R,4S,5S)-3-methoxy-5-methyl-4-[methyl-[(2S)-3-methyl-2-[[(2S)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid; hydrochloride |
| Canonical SMILES | CCC(C)C(C(CC(=O)N1CCCC1C(C(C)C(=O)NC(CC2=CC=CC=C2)C(=O)O)OC)OC)N(C)C(=O)C(C(C)C)NC(=O)C(C(C)C)NC.Cl |
| InChI | InChI=1S/C39H65N5O8.ClH/c1-12-25(6)34(43(9)38(48)33(24(4)5)42-37(47)32(40-8)23(2)3)30(51-10)22-31(45)44-20-16-19-29(44)35(52-11)26(7)36(46)41-28(39(49)50)21-27-17-14-13-15-18-27;/h13-15,17-18,23-26,28-30,32-35,40H,12,16,19-22H2,1-11H3,(H,41,46)(H,42,47)(H,49,50);1H/t25-,26+,28-,29-,30+,32-,33-,34-,35+;/m0./s1 |
| InChI Key | BUPKFQQDMNUXOY-KMYLZLQDSA-N |
Properties
| Appearance | Solid Power |
| Application | ADCs Cytotoxin |
| Antibiotic Activity Spectrum | Neoplastics (Tumor) |
| Solubility | Soluble in DMF (Slightly), DMSO (Slightly), Methanol (Slightly), Water (Slightly) |
| LogP | 5.01620 |
Reference Reading
1. Emerging classes of armed antibody therapeutics against cancer
Christian Hess, Dario Venetz, Dario Neri*. Med. Chem. Commun.,2014, 5,408–431
Calicheamicins bind to the DNA minor groove where they induce double-strand breaks leading to chromosomal disruption, ultimately resulting in programmed cell death, while the other two drugs interfere with microtubule restructuring. Auristatins were originally derived from the naturally occurring pentapeptide dolastatin-10. Mono-methyl auristatin E (MMAE) and F (MMAF) are the most prominent dolastatin-10 derivatives, which are implemented in many current clinical-stage ADCs. These fully synthetic analogues differ from natural dolastatin-10 in terms of an N-terminal methyl group, which results in superior proteolytic stability. Additionally, MMAF features a C-terminal charged phenylalanine residue, which attenuates its cytotoxic activity compared to the uncharged MMAE. Maytansinoids such as DM1 and DM4 are derivatives of the natural product maytansine and represent two of the most widely used ADC payloads to date. Upon lysosomal degradation of the antibody, the mechanism of action of these two agents is considered to be identical. However, the linker region of the drug can have a profound impact on ADC performance. It has been reported for disulfide-linked maytansinoids that two additional methyl groups at positions directly adjacent to the disulfide bond (corresponding to DM4) can increase plasma stability of the conjugate.
2. The antibody-drug conjugate: an enabling modality for natural product-based cancer therapeutics
Hans-Peter Gerber, Frank E. Koehnb, Robert T. Abraham*. Nat. Prod. Rep., 2013, 30, 625–639
An additional clinically-relevant auristatin, MMAF, bears a C-terminated phenylalanine residue with a free carboxyl group. MMAF proved effective in preclinical models of Hodgkin's lymphoma and anaplastic large cell lymphoma (ALCL) when conjugated to anti-CD30 antibodies and has now been conjugated to additional antibodies with non-cleavable linkers. Themaleimidocaproyl (MalC) linker is used in SGN-75 of Seattle Genetics to conjugate MMAF to an anti-CD70 antibody. Once in the lysosome, the antibody is degraded to yield the MMAF-caproylmaleido-cysteine adduct as the active cyto-Toxin. Due to its free carboxyl group, MMAF itself has limited cell permeability, and its in vitro potency is roughly 10–200-fold lower than that of the MMAE. However, these shortcomings are effectively overcome by transfer to the ADC format, which effectively delivers the payload intracellularly, leading to a potency increase of 2200-fold as well as reduced toxicity against non-antigen-expressing cells.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
