Cephalomannine

The barks of Cephalotaxus sinensis (Rehd. et Wils.) Li

Cephalomannine is a taxol derivative with antitumor, antiproliferative properties. IC50 value: Target: Cephalomannine is an active anti-cancer agent obtained from Taxus yunnanensis and has an antineoplastic effect on tumors found in mice. Cephalomannine is a chemotherapy drug that is given as a treatment for some types of cancer. Cephalomannine is most commonly used to treat non-small cell lung cancer.

References:
[1]. T. Grobosch, B. Schwarze, D. Stoecklein et al. Fatal poisoning with Taxus baccata. Quantification of Paclitaxel (taxol A), 10-Deacetyltaxol, Baccatin III, 10-Deacetylbaccatin III, Cephalomannine (taxol B), and 3,5-Dimethoxyphenol in Body Fluids by Liquid [2]. Jing Zhang et al., Simultaneous Determination of 10-Deacetylbaccatin，Cephalomannine and Taxol in Different Parts of Taxus Media with Different Growth Years by UPLC. Applied Mechanics and Materials. 2011, 108, 326. [3]. Chang Z, Guo N, Liu T, et al. Distribution and variation of paclitaxel and cephalomannine contents in wild Taxus cuspidata. Zhongguo Zhong Yao Za Zhi. 2011 Feb;36(3):294-8. [4]. R Matesanz, J Rodríguez-Salarichs, B Pera, et al. Modulation of Microtubule Interprotofilament Interactions by Modified Taxanes. Biophysical Journal, 2011,101(12): 2970-2980. [5]. Elena Riva, Martin Mattarella, Stella Borrelli, et al. Preparation of Fluorescent Tubulin Binders. ChemPlusChem. Early View (Online Version of Record published before inclusion in an issue)

Cephalomannine and 10-deacetyltaxol cytotoxicity in human glial and neuroblastoma cell-lines.[Pubmed:21573554]

Int J Oncol. 1993 Feb;2(2):297-9.

The cytotoxic effects of taxol, 10-deacetyltaxol, and Cephalomannine at concentrations of 0.1 mug/ml to 10.0 mug/ml for one and 24 hours exposure were determined in two human glioblastoma multiforme and two neuroblastoma cell lines using the MTT method. The neuroblastoma cell lines were established from previously treated patients, while the glioblastomas were from untreated patients. There was a proportionate concentration-toxicity relationship for all four cell lines. The neuroblastoma SK-N-FI was consistently the most resistant to all three drugs. The order of potency after a one hour exposure was taxol, 10-deacetyltaxol and Cephalomannine. Cephalomannine contained 1.5% taxol impurity and 10-deacetyltaxol, 4.5% taxol hence the contribution of taxol to these substances' toxic effects was minimal. We conclude that tumors of the central and peripheral nervous system are sensitive to 10-deacetyltaxol and Cephalomannine and these drugs are less toxic than taxol but remain within a therapeutic range.

Synthesis, isolation, stereostructure and cytotoxicity of paclitaxel analogs from cephalomannine.[Pubmed:23876369]

Fitoterapia. 2013 Oct;90:79-84.

Four paclitaxel derivatives were afforded by preparative HPLC separation of two pairs of diastereoisomers, which were obtained by catalytic hydrogenation and epoxidation of the C-13 side-chain double bond of Cephalomannine, a naturally occurring paclitaxel analog. The four paclitaxel derivatives were analyzed using NMR, CD spectroscopy, and side-chain hydrolysis in order to measure their optical rotations and GC characteristics. In this way, the stereoconfigurations of the products were determined. Evaluation of the compounds' activity indicated that they had differing cytotoxic activities: compound 5 had superior activity in BCG-823 tumor cells compared to paclitaxel, while compound 7 had superior activity in HCT-8 and A549 tumor cells compared to paclitaxel. These results indicate that the stereoconfiguration of the paclitaxel N-acyl side chain has a significant impact on its activity.

Taxane's substituents at C3' affect its regioselective metabolism: different in vitro metabolism of cephalomannine and paclitaxel.[Pubmed:18039807]

Drug Metab Dispos. 2008 Feb;36(2):418-26.

To investigate how taxane's substituents at C3' affect its metabolism, we compared the metabolism of Cephalomannine and paclitaxel, a pair of analogs that differ slightly at the C3' position. After Cephalomannine was incubated with human liver microsomes in an NADPH-generating system, two monohydroxylated metabolites (M1 and M2) were detected by liquid chromatography/tandem mass spectrometry. C4'' (M1) and C6alpha (M2) were proposed as the possible hydroxylation sites, and the structure of M1 was confirmed by (1)H NMR. Chemical inhibition studies and assays with recombinant human cytochromes P450 (P450s) indicated that 4''-hydroxyCephalomannine was generated predominantly by CYP3A4 and 6alpha-hydroxyCephalomannine by CYP2C8. The overall biotransformation rate between paclitaxel and Cephalomannine differed slightly (184 vs. 145 pmol/min/mg), but the average ratio of metabolites hydroxylated at the C13 side chain to C6alpha for paclitaxel and Cephalomannine varied significantly (15:85 vs. 64:36) in five human liver samples. Compared with paclitaxel, the major hydroxylation site transferred from C6alpha to C4'', and the main metabolizing P450 changed from CYP2C8 to CYP3A4 for Cephalomannine. In the incubation system with rat or minipig liver microsomes, only 4''-hydroxyCephalomannine was detected, and its formation was inhibited by CYP3A inhibitors. Molecular docking by AutoDock suggested that Cephalomannine adopted an orientation in favor of 4''-hydroxylation, whereas paclitaxel adopted an orientation favoring 3'-p-hydroxylation. Kinetic studies showed that CYP3A4 catalyzed Cephalomannine more efficiently than paclitaxel due to an increased V(m). Our results demonstrate that relatively minor modification of taxane at C3' has major consequence on the metabolism.

Cephalomannine is an active anti-cancer agent obtained from Taxus yunnanensis and has an antineoplastic effect on tumors found in mice.

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