Stability-indicating LC assay of and impurity identification in homoharringtonine samples

He, Jingyi; Cheung, Andrew P.; Wang, Euphemia; Struble, Elaine; Fang, Kexuan; Nguyen, Namphuong; Liu, Paul

doi:10.1016/s0731-7085(99)00314-3

Cited by 16 publications

(8 citation statements)

References 9 publications

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“…It is an alkyl-substituted succinic acid ester of cephalotaxine [1,2] and possesses antileukemic activity [3][4][5][6]. Several researchers have investigated the antineoplastic mechanism of HHT and related alkaloids; all have concluded that these drugs inhibit protein biosynthesis in a dose-and time-dependent manner by acting on the ribosomes of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Characterization of solvent induced crystalline and amorphous homoharringtonine

Kim

2009

Korean J. Chem. Eng.

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The morphologies of homoharringtonine were conveniently controlled by solvent treatment and the morphologies of homoharringtonine were characterized by XRD and SEM. Crystalline homoharringtonine was simply made by dissolving homoharringtonine in a special polar solvent containing a small amount of water (methanol/water= 98/2, v/v). On the other hand, amorphous homoharringtonine was made by dissolving homoharringtonine in relatively non-polar solvent (methylene chloride/methanol=98/2, v/v). Amorphous homoharringtonine, with a fine particle size, was obtained by dissolving in methylene chloride/methanol (98/2, v/v), following by spray drying. Also, residual solvents, methanol and methylene chloride, were easily removed to less than concentration limit in ICH (International Conference on Harmonisation) guidance by spray drying and successive drying in a vacuum oven. Amorphous homoharringtonine was more soluble in water than crystalline homoharringtonine, and the water content of amorphous homoharringtonine was less changeable than crystalline homoharringtonine at given humidity (95 RH%) during storage. This information is very useful for production and quality control of pharmaceuticals in the commercialization step.

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Section: Introductionmentioning

confidence: 99%

Characterization of solvent induced crystalline and amorphous homoharringtonine

Kim

2009

Korean J. Chem. Eng.

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“…Forced degradation of the active in acid and alkali eluted degradants (Fig. ), as previously reported and identified in the literature (He et al , ). The method is therefore suitable for detection of any degradation of omacetaxine.…”

Section: Resultsmentioning

confidence: 99%

Investigation into omacetaxine solution stability for in vitro study

Marenah

Allan

Mountford

et al. 2011

Biomedical Chromatography

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Omacetaxine is a natural product extract originating from Chinese medicine and finding therapeutic use as a potent myelosuppressive agent in leukemia. When planning in vitro cell biology experiments to assess omacetaxine activity against primary leukemic stem cells, it became apparent that the literature rarely describes the in vitro stability of the molecule, although accessible chromatographic methods have been published. Clearly whole organisms vs their component cells will differ in the way in which they handle xenobiotics, with the latter more dependent on physiochemical parameters such as pH and temperature in the absence of active metabolism or excretion. This could impact on the cells' experience of drug in culture. We therefore report here on examination of a modified, high-performance liquid chromatography (HPLC) method with assessment of degradant production from a 72 h solution stability study, clearly demonstrating that omacetaxine is highly stable in representative cell culture conditions (37 °C, neutral pH) and persists for many days in marked contrast to its short-half life in vivo.

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“…69 CET (1) purification was performed for the first time by reverse phase HPLC. 72 He et al have developed an HPLC analysis method for HHT (2) determination, 73 allowing to reveal three congeners present as impurities in the HHT (2) samples. The acid additive constrained the alkalization of the obtained aqueous phase and its extraction with dichloromethane.…”

Section: Production and Purification Studiesmentioning

confidence: 99%

Cephalotaxus Alkaloids

Pérard-Viret

Quteishat

Alsalim

et al. 2017

The Alkaloids: Chemistry and Biology

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Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. Significant activity against leukemia in mice was demonstrated for extracts of Cephalotaxus. Cephalotaxine (CET) (1), the major alkaloid of this series was isolated from Cephalotaxus drupacea species by Paudler in 1963. The subsequent discovery of promising antitumor activity among new Cephalotaxus derivatives reported by Chinese, Japanese, and American teams triggered extensive structure elucidation and biological studies in this family. The structural feature of this cephalotaxane family relies mainly on its tetracyclic alkaloid backbone, which comprises an azaspiranic 1-azaspiro[4.4]nonane unit (rings C and D) and a benzazepine ring system (rings A and B), which is linked by its C3 alcohol function to a chiral oxygenated side chain by a carboxylic function alpha to a tetrasubstituted carbon center. The botanical distribution of these alkaloids is limited to the Cephalotaxus genus (Cephalotaxaceae). The scope of biological activities of the Cephalotaxus alkaloids is mainly centered on the antileukemic activity of homoharringtonine (HHT) (2), which in particular demonstrated marked benefits in the treatment of orphan myeloid leukemia and was approved as soon as 2009 by European Medicine Agency and by US Food and Drug Administration in 2012. Its exact mechanism of action was partly elucidated and it was early recognized that HHT (2) inhibited protein synthesis at the level of the ribosome machinery. Interestingly, after a latency period of two decades, the topic of Cephalotaxus alkaloids reemerged as a prolific source of new natural structures. To date, more than 70 compounds have been identified and characterized. Synthetic studies also regained attention during the past two decades, and numerous methodologies were developed to access the first semisynthetic HHT (2) of high purity suitable for clinical studies, and then high grade enantiomerically pure CET (1), HHT (2), and analogs.

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Stability-indicating LC assay of and impurity identification in homoharringtonine samples

Cited by 16 publications

References 9 publications

Characterization of solvent induced crystalline and amorphous homoharringtonine

Characterization of solvent induced crystalline and amorphous homoharringtonine

Investigation into omacetaxine solution stability for in vitro study

Cephalotaxus Alkaloids

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