796073-69-3 Usage
Description
N2'-Deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine, also known as DM4, is a maytansinoid, a chemical derivative of maytansine. It is an antitubulin agent that inhibits cell division and is used as an intermediate in the preparation of semisynthetic maytansine analogs.
Used in Pharmaceutical Industry:
N2'-Deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine is used as a cytotoxic payload for the targeted treatment of cancer in the form of antibody-drug conjugates (ADCs). It is conjugated with antibodies to specifically target and deliver the cytotoxic payload to cancer cells, minimizing damage to healthy cells and reducing side effects.
Additionally, N2'-Deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine can be used in the development of novel drug delivery systems to enhance the efficacy and bioavailability of the payload in cancer treatment.
Biological Activity
The anticancer properties of maytansinoids have been attributed to their ability to disrupt microtubule function. The maytansinoid emtansine (DM1), for example, binds at the ends of microtubules and thereby suppress their dynamic instability. Other maytansinoids include: Ansamitocin; Mertansine/emtansine (DM1); Ravtansine/soravtansine (DM4).
Synthesis
A solution of N-methyl-N-(4-methyldithio-4-methyl-1-oxopropyl)-L-alanine (36.6 mg, 0.313 mmol) and 1,3-dicyclohexylcarbodiimide (13.51 mg, 0.065 mmol) was prepared in CH2Cl2 (0.5 mL) in a round bottom flask equipped with a stir bar and maintained under an argon atmosphere. The solution stirred vigorously at room temperature for 30 minutes as the symmetrical anhydride formed. The reaction mixture was filtered through glass wool and added to a reaction flask containing maytansinol (12.3 mg, 0.022 mmol) and zinc bis[bis(trimethylsilyl)amide] (42.5 mg, 0.109 mmol) prepared in CH2Cl2 (1 mL). The reaction proceeded at room temperature under an argon atmosphere with stirring. After 3 hours, an additional 5 equivalents of zinc bis[bis(trimethylsilyl)amide] (42.5 mg, 0.109 mmol) were added to the reaction vessel and the reaction proceeded overnight. Analytical thin layer chromatography (Analtech Uniplate, 2.5×10 cm, 250 micron), eluting in a mixture of methylene chloride and methanol (95:5, v/v) indicated the formation of the desired N-methyl-L-alanyl ester of maytansinol at C3. The degree of conversion of the reaction was determined by analytical HPLC analysis using a Vydac protein & peptide C18 column (4.6×250 mm) at a flow rate of 1.50 mL/min, eluting with a gradient of water and acetonitrile, as follows: Time (min) % A (water) % B (acetonitrile) 0 95 5 2.5 95 5 32 5 95 35 5 95 Under these conditions the thiol containing product eluted at 20.75 min with no detected D-isomer. MS: m/z found 780.8 (M+Na+) calculated 781.4.
in vitro
DM4, a structural analogue of maytansine, is a new thiol-containing and potent maytansinoid. DM4 is a cytotoxic maytansinoid drug. It is synthesized in order to link maytansinoids to antibodies via disulfide bonds. Maytansinoids inhibit tubulin polymerization and microtubule assembly and enhance microtubule destabilization, so there is potent suppression of microtubule dynamics resulting in a mitotic block and subsequent apoptotic cell death.
Check Digit Verification of cas no
The CAS Registry Mumber 796073-69-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 7,9,6,0,7 and 3 respectively; the second part has 2 digits, 6 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 796073-69:
(8*7)+(7*9)+(6*6)+(5*0)+(4*7)+(3*3)+(2*6)+(1*9)=213
213 % 10 = 3
So 796073-69-3 is a valid CAS Registry Number.
796073-69-3Relevant articles and documents
Uses of immunoconjugates targeting CD138
-
, (2018/11/23)
Disclosed is a method and composition for treating a disease associated with target cells expressing CD138 in a multiple dose regimen. An immunoconjugate comprising an engineered targeting antibody targeting CD138 expressing cells and an effector molecule is administered in a multiple dose regimen. The multiple dose regimen comprises at least two doses and the aggregate dose administered within an active treatment cycle is an aggregate maximum tolerable dose (AMTD) or a fraction of the AMTD. The AMTD and/or said fraction exceeds the dose resulting in dose limiting toxicity (DLT) and/or exceeds the maximum tolerable dose (MTD) when the immunoconjugate is administered as a single dose, including as part of a multiple single dose regimen within said active treatment cycle.
Ado-trastuzumab emtansine (T-DM1): An antibody-drug conjugate (ADC) for HER2-positive breast cancer
Lambert, John M.,Chari, Ravi V. J.
, p. 6949 - 6964 (2014/10/16)
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the antitumor properties of the humanized anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, with the maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker. Upon binding to HER2, the conjugate is internalized via receptor-mediated endocytosis, and an active derivative of DM1 is subsequently released by proteolytic degradation of the antibody moiety within the lysosome. Initial clinical evaluation led to a phase III trial in advanced HER2-positive breast cancer patients who had relapsed after prior treatment with trastuzumab and a taxane, which showed that T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine. In 2013, T-DM1 received FDA approval for the treatment of patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination, the first ADC to receive full approval based on a randomized study.
Semisynthetic Maytansine analogues for the targeted treatment of cancer
Widdison, Wayne C.,Wilhelm, Sharon D.,Cavanagh, Emily E.,Whiteman, Kathleen R.,Leece, Barbara A.,Kovtun, Yelena,Goldmacher, Victor S.,Xie, Hongsheng,Steeves, Rita M.,Lutz, Robert J.,Zhao, Robert,Wang, Lintao,Bl?ttler, Walter A.,Chari, Ravi V. J.
, p. 4392 - 4408 (2007/10/03)
Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clinical trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent were varied. Several of these maytansinoids were found to be even more potent in vitro than maytansine. The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo.
