Omacetaxine mepesuccinate

Base Information

• Chemical Name: Omacetaxine mepesuccinate
• CAS No.: 26833-87-4
• Molecular Formula: C29H39NO9
• Molecular Weight: 545.63
• European Community (EC) Number: 636-662-8
• NSC Number: 141633
• UNII: 6FG8041S5B
• Nikkaji Number: J123.154E
• Wikipedia: Omacetaxine_mepesuccinate
• Wikidata: Q7089373
• NCI Thesaurus Code: C1127
• RXCUI: 27100
• Metabolomics Workbench ID: 65401
• ChEMBL ID: CHEMBL46286
• Mol file: 26833-87-4.mol

Synonyms:Ceflatonin;cephalotaxine;homoharringtonine;Homoharringtonine (3(R))-isomer;Omacetaxine;omacetaxine mepesuccinate;Synribo

Chemical Property of Omacetaxine mepesuccinate

Chemical Property:

• Appearance/Colour: Off-white cryst.
• Vapor Pressure: 2.41E-21mmHg at 25°C
• Melting Point: 144-146 °C
• Refractive Index: 1.604
• Boiling Point: 713.1 °C at 760 mmHg
• PKA: 11.60±0.29(Predicted)
• Flash Point: 385.1 °C
• PSA: 134.99000
• Density: 1.33 g/cm³
• LogP: 2.60430
• Storage Temp.: 2-8°C
• Solubility.: DMSO: soluble20mg/mL, clear
• XLogP3: 0.8
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 10
• Rotatable Bond Count: 11
• Exact Mass: 545.26248182
• Heavy Atom Count: 39
• Complexity: 968

Purity/Quality:

99%, ^*data from raw suppliers

Homoharringtonine ^*data from reagent suppliers

Safty Information:

• Pictogram(s): T+, Xi
• Hazard Codes: T+,Xi
• Statements: 26/27/28-36/37/38-28
• Safety Statements: 36/37/39-45-27-26-36/37-28

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CC(C)(CCCC(CC(=O)OC)(C(=O)OC1C2C3=CC4=C(C=C3CCN5C2(CCC5)C=C1OC)OCO4)O)O
• Isomeric SMILES: CC(C)(CCC[C@@](CC(=O)OC)(C(=O)O[C@H]1[C@H]2C3=CC4=C(C=C3CCN5[C@@]2(CCC5)C=C1OC)OCO4)O)O
• Recent ClinicalTrials: Selinexor and HAAG With/Without HMA in Relapsed/Refractory Acute Leukemia (AML) Patients
• Recent EU Clinical Trials: A Phase II Open-Label Study of the Subcutaneous Administration of Homoharringtonine (Omacetaxine Mepesuccinate, OMA) in the Treatment of Patients with Chronic Myeloid Leukemia (CML) who have failed or are intolerant to Tyrosine Kinase Inhibitor therapy
• uses: Homoharringtonine mainly inhibit leukemia cell DNA and protein synthesis, dissolving the nucleus and causing its necrosis with remarkable nucleolus lesions. It also inhibits the cell in any phases within the proliferation cycle; the most significant effect is the S phase; it can also inhibit and destroy G2 phase cells so that most of the G2 phase cells were inhibited from entering into the M phase, being the cell cycle non-specific drugs. It is used for the treatment of acute monocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia and red blood leukemia, acute myelogenous leukemia and malignant lymphoma. It is also of certain efficacy against the malignant lymphoma and polycythemia Vera as well as some other types of leukemia.
• Description: Omacetaxine mepesuccinate (also known as homoharringtonine) was approved by the US FDA in October 2012 for the treatment of patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance or intolerance to at least two tyrosine kinase inhibitors (TKIs). Omacetaxine is a protein synthesis inhibitor that was studied in the 1970s for the treatment of acute myeloid leukemia (AML) and in the 1990s for CML. Emergence of resistance to first- and second-generation TKIs has lead to renewed interest in omacetaxine due to its differentiated mode of action. Omacetaxine acts on the initial step of protein translation andresults in the rapid loss of a number of short-lived proteins that regulate proliferation and cell survival. Omacetaxine induces apoptosis and shows in vitro activity in anumberof leukemia cell lines andinmurine leukemiamodels. Omacetaxineis a naturally occurring alkaloid isolated from Cephalotaxus coniferous shrubs that are indigenous to Asia. Extracts of the bark have been used by practitioners of traditional Chinese medicine for the treatment of cancer. Although omacetaxine could be isolated directly from bark and roots, a more efficient approach is semi-synthesis by esterification of the abundant biosynthetic precursor cephalotaxine, which can be extracted from leaves rather than nonrenewable sources. Esterification is carried out with an activated ester in which the diol side-chain is protected as a tetrahydropyran; after ester formation, the diol is released in two steps under mild conditions. Homoharringtonine is an alkaloid originally isolated from C. harringtonia and a homolog of harringtonine that has diverse biological activities including protein synthesis inhibitory, antiviral, antiparasitic, and anticancer properties. Homoharringtonine inhibits the chain elongation phase of translation in eukaryotes. It inhibits diphenylalanine formation by rabbit reticulocyte and human placental ribosomes in cell-free assays and binds to human 80S ribosomes (Kd = 39 nM). Homoharringtonine is active against coronaviruses, reducing the viral load in vitro and in vivo and prevents severe symptoms in porcine and chicken models of porcine epidemic diarrhea virus (PEDV) and Newcastle disease virus (NDV), respectively. It reduces the infectious virus yield and viral RNA copy numbers in the culture supernatant of Vero E6 cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (EC50s = 2.55 and 2.14 μM, respectively). It also inhibits the growth of P. falciparum in cultured in human erythrocytes (IC50 = 4 nM). Homoharringtonine is cytotoxic and inhibits the proliferation of Jurkat acute T cell leukemia (IC50 = 9 nM) and K562 chronic myelogenous leukemia (CML) cells (IC50 = 408 μg/ml). In vivo, it decreases the number of peripheral leukemia stem cells and increases survival in CML and B cell acute lymphoblastic leukemia (B-ALL) mouse models when administered at a dose of 0.5 mg/kg. Formulations containing homoharringtonine have been used in the treatment of CML in patients with resistance and/or intolerance to two or more tyrosine kinase inhibitors.
• Physical properties: Appearance: an almost white or pale yellow crystalline powder or an amorphous friable solid. It has the hygroscopic nature. It darkens on exposure to light. Solubility: easily soluble in chloroform, ethanol and methanol, and slightly soluble in ether and water. Melting point: 143–147?°C.
• Uses: Homoharringtonine has been used to check the cytotoxic activity against carfilzomib-resistant derivative of the LP-1 multiple myeloma (MM) cell line (LP-1/Cfz) and is used as a translation-inhibiting drug. Homoharringtonine (HHT) combined with some botanical drugs could induce cancer cells to resemble normal cells. HHT was prepared by a semi-synthetic method from Cephalotaxine, a major alkaloid of Cepahlotaxus species through the formation of a-ketoes
• Indications: This product is recorded in the Pharmacopoeia of the People’s Republic of China (2015).Its main dosage form is homoharringtonine injection, which is mainly used for the treatment of chronic myelocytic leukemia and acute myeloid leukemia.
• Clinical Use: Synribo? (Omacetaxine mepesuccinate) was approved by the FDA for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) exhibiting resistance or intolerance to tyrosine kinase inhibitors (TKI’s). Omacetaxine mepesuccinate inhibits protein synthesis and prevents aminoacyl-tRNA binding during the elongation phase and targets myeloma-promoting molecules Mcl-1, XIAP, and β-catenin, which are particularly important in the survival of myeloma cells. Omacetaxine mepesuccinate is also known as homoharringtonine, an alkaloid originally discovered and structurally identified from Cephalotaxus harringtonia, which occurs naturally in Japan and eastern Asia.

Technology Process of Omacetaxine mepesuccinate

There total 57 articles about Omacetaxine mepesuccinate which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 94.0%

1-((1R,4S,5S)-3-methoxy-9,11,21-trioxa-17-azapentacyclo[15.3.1.01,5.06,14.08,12]henicosa-2,6,8(12),13-tetraen-4-yl) 4-methyl (2R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl)succinate (197569-58-7) → homoharringtonine (26833-87-4)

Guidance literature:

With zinc; In acetic acid; at 47 ℃; for 1h;

DOI:10.1021/jo9711652

Reference yield: 79.0%

1-((1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]cyclopenta[b]pyrrolo[1,2-a]azepin-1-yl) 4-methyl (R)-2-((E)-4-(benzyloxy)-4-methylpent-2-en-1-yl)-2-hydroxysuccinate (1040272-14-7) → homoharringtonine (26833-87-4)

Guidance literature:

With methanol; 10% Pd on charcoal; hydrogen; In acetic acid; at 23 ℃;

DOI:10.1002/chem.200701998

Reference yield: 57.0%

(R)-1-cephalotaxyl 4-methyl 2-(4-benzyloxy-4-methylpent-2-yn-1-yl)-2-hydroxysuccinate → homoharringtonine (26833-87-4)

Guidance literature:

With 5%-palladium/activated carbon; hydrogen; In methanol; acetic acid; at 35 ℃; for 2h; under 760.051 Torr;

upstream raw materials:

methyl magnesium iodide

Methyl 3-carbocephalotaxyl-3-hydroxy-7-oxooctanoate

1-((1R,4S,5S)-3-methoxy-9,11,21-trioxa-17-azapentacyclo[15.3.1.0^1,5.0^6,14.0^8,12]henicosa-2,6,8⁽¹²⁾,13-tetraen-4-yl) 4-methyl (2R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl)succinate

(2'R)-(-)-6'-bromo-6'-deoxyhomoharringtonine

Downstream raw materials:

homoharringtonine acid

Refernces

• 1、 -. "ANALOGUES AND DERIVATIVES OF CEPHALOTAXINE AND METHODS FOR MAKING AND USING THE COMPOUNDS". . . Retrieved 2020/09/30.
• 2、 -. "Synthesis method and intermediate of ester derivative of (-)-cephalotaxine". . . Retrieved 2019/12/29.