1-O-[(2R,3S,6R)-4-methoxy-16,18-dioxa-10-azapentacyclo[11.7.0.02,6.06,10.015,19]icosa-1(20),4,13,15(19)-tetraen-3-yl] 4-O-methyl 2-hydroxy-2-(4-hydroxy-4-methylpentyl)butanedioate

DescriptionOmacetaxine 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.

DescriptionHomoharringtonine 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.