N2'-Deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine
[CAS# 796073-69-3]

Identification

• Classification: API >> Antineoplastic agents
• Name: N2'-Deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine
• Synonyms: Maytansine DM 4; DM 4; Ravtansine;[(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] (2S)-2-[methyl-(4-methyl-4-sulfanylpentanoyl)amino]propanoate
• Molecular Formula: C₃₈H₅₄ClN₃O₁₀S
• Molecular Weight: 780.37
• CAS Registry Number: 796073-69-3
• EC Number: 641-067-1
• SMILES: C[C@@H]1[C@@H]2C[C@]([C@@H](/C=C/C=C(/CC3=CC(=C(C(=C3)OC)Cl)N(C(=O)C[C@@H]([C@]4([C@H]1O4)C)OC(=O)[C@H](C)N(C)C(=O)CCC(C)(C)S)C)C)OC)(NC(=O)O2)O

Properties

• Solubility: Insoluble (3.7E^-4 g/L) (25 °C), Calc.^*
• Density: 1.29±0.1 g/cm³ (20 °C 760 Torr), Calc.^*
• Melting point: 185-187 °C (decomp)^**

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2015 ACD/Labs)

^** Widdison, Wayne C.

Safety Data

• Hazard Symbols: GHS05;GHS06;GHS07;GHS08 Danger
• Risk Statements: H300-H301-H310-H311-H314-H315-H319-H331-H340-H360-H361-H371
• Safety Statements: P203-P260-P261-P262-P264-P264+P265-P270-P271-P280-P301+P316-P301+P330+P331-P302+P352-P302+P361+P354-P304+P340-P305+P351+P338-P305+P354+P338-P308+P316-P316-P318-P321-P330-P332+P317-P337+P317-P361+P364-P362+P364-P363-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Germ cell mutagenicity	Muta.	1B	H340
Skin corrosion	Skin Corr.	1B	H314
Reproductive toxicity	Repr.	1B	H360
Specific target organ toxicity - single exposure	STOT SE	1	H370
Acute toxicity	Acute Tox.	1	H310
Acute toxicity	Acute Tox.	2	H300
Acute toxicity	Acute Tox.	1	H300
Acute toxicity	Acute Tox.	3	H311
Skin irritation	Skin Irrit.	2	H315
Acute toxicity	Acute Tox.	3	H301
Acute toxicity	Acute Tox.	3	H331
Eye irritation	Eye Irrit.	2	H319
Reproductive toxicity	Repr.	2	H361

Discovery and Applications

N2'-Deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine, commonly referred to as DM4, emerged from research efforts in the late 1970s by scientists at Takeda Chemical Industries in Japan. It is a potent cytotoxic agent derived from maytansine, a compound initially isolated from the plant Maytenus serrata. Through chemical modifications of maytansine's structure, DM4 was synthesized with the aim of enhancing its anticancer properties while reducing systemic toxicity.

DM4 serves as the cytotoxic payload in ADCs, a class of targeted cancer therapies. In ADCs, DM4 is conjugated to monoclonal antibodies specific to antigens expressed on the surface of cancer cells. Upon binding to the target antigen, the ADC is internalized into the cancer cell, where DM4 is released and exerts its cytotoxic effects. This targeted delivery minimizes systemic toxicity and enhances the therapeutic index of DM4, making it an attractive option for cancer treatment.DM4-based ADCs have demonstrated efficacy in the treatment of solid tumors, including breast cancer, gastric cancer, and bladder cancer. ADCs such as trastuzumab deruxtecan (DS-8201) utilize DM4 as the cytotoxic payload and have shown promising results in clinical trials. DM4-based ADCs have also shown promise in the treatment of hematological malignancies. Several ADCs targeting different antigens expressed on hematological cancer cells, such as CD30 and CD22, incorporate DM4 as the cytotoxic payload. These ADCs have demonstrated efficacy in the treatment of Hodgkin lymphoma, non-Hodgkin lymphoma, and acute lymphoblastic leukemia, among others.

References

2024. Synthesis and evaluation of antibody-drug conjugates with high drug-to-antibody ratio using dimaleimide-DM1 as a linker-payload. Bioorganic Chemistry, 149(1).
DOI: 10.1016/j.bioorg.2024.107504

2024. eSOMA-DM1, a Maytansinoid-Based Theranostic Small-Molecule Drug Conjugate for Neuroendocrine Tumors. Bioconjugate Chemistry, 35(10).
DOI: 10.1021/acs.bioconjchem.4c00413

1977. Tumor inhibitors. 122. The maytansinoids. Isolation, structural elucidation, and chemical interrelation of novel ansa macrolides. The Journal of Organic Chemistry, 42(14).
DOI: 10.1021/jo00434a001