ZIKV
The primary target of Cephalotaxlen is the protein synthesis machinery in cells. As an alkaloid, it inhibits protein synthesis by interacting with the ribosome. This mechanism is similar to that of homoharringtonine, which binds to the A-site of the 60S ribosomal subunit and prevents the formation of the peptide bond, thereby inhibiting protein elongation. By inhibiting protein synthesis, Cephalotaxlen hinders the growth and proliferation of cancer cells. Its antiviral activity against Zika virus involves impeding viral replication and stability. The compound's ability to target fundamental cellular processes contributes to its broad biological activities.

Cephalotaxine inhibits Zika infection by impeding viral replication and stability.

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In vitro, Cephalotaxlen exhibits cytotoxic activity against various cancer cell lines, including HL-60, NB4, MOLT-4, K562, and Jurkat cells. It inhibits protein synthesis in these cells, leading to reduced cell proliferation and induction of apoptosis. The compound has also been shown to inhibit Zika virus infection by impeding viral replication and stability. Its anticancer activity is related to its ability to inhibit protein synthesis, which is essential for cancer cell growth. Cephalotaxlen's in vitro activity is concentration-dependent, with effects observed at micromolar concentrations. Its cytotoxicity and antiviral activity make it a valuable tool for studying cancer and viral infections.

In vivo, Cephalotaxlen has been studied for its anticancer activity. As the base compound for homoharringtonine, which is used clinically for leukemia treatment, Cephalotaxlen is expected to have similar in vivo effects. Homoharringtonine has been shown to be effective in treating chronic myeloid leukemia and other hematological malignancies. Cephalotaxlen's antiviral activity has also been demonstrated in animal models of viral infection. Its ability to inhibit protein synthesis and viral replication supports its potential as a therapeutic agent. Further studies are needed to fully characterize its in vivo efficacy and safety.

The in vitro activity of Cephalotaxlen can be assessed using cell-free translation assays. A typical protocol involves preparing a cell-free translation system from rabbit reticulocytes or wheat germ extracts. The system is supplemented with a reporter mRNA (e.g., luciferase mRNA) and incubated with Cephalotaxlen at various concentrations. The amount of protein synthesized is measured by assessing the activity of the reporter protein (e.g., luciferase activity). The IC50 value is determined by plotting the percentage of protein synthesis remaining against the compound concentration. The selectivity of the compound for inhibiting protein synthesis can be assessed using different translation systems.

For in vitro cellular experiments, cancer cell lines (e.g., HL-60, K562) are cultured in appropriate media and treated with Cephalotaxlen at various concentrations (typically 0.1-100 microM). Cell viability is measured after 24-72 hours of treatment using MTT, CCK-8, or other cell proliferation assays. Protein synthesis is assessed by measuring the incorporation of radiolabeled amino acids (e.g., [35S]-methionine) into newly synthesized proteins. Apoptosis is assessed by flow cytometry using Annexin V/PI staining or by measuring caspase-3/7 activity. For antiviral studies, virus-permissive cells are infected with Zika virus and treated with Cephalotaxlen, and viral replication is assessed by measuring viral RNA levels or viral titers.

In vivo animal experiments with Cephalotaxlen would typically involve intravenous or intraperitoneal administration in mouse models of leukemia or other cancers. A common dosing regimen would be based on studies with homoharringtonine, which is administered at 1-3 mg/m2/day. For xenograft studies, tumor-bearing mice are treated with Cephalotaxlen, and tumor growth is monitored by caliper measurements. For antiviral studies, animals are infected with Zika virus and treated with the compound, and viral load and survival are assessed. Pharmacokinetic and toxicity studies are also performed to characterize its safety profile.

Cephalotaxlen has a molecular weight of 315.36 g/mol and a molecular formula of C18H21NO4. As the base compound for homoharringtonine, its pharmacokinetic properties are expected to be similar. Homoharringtonine is typically administered intravenously due to poor oral bioavailability. It has a short half-life and is rapidly cleared from the circulation. Cephalotaxlen is metabolized in the liver and excreted in the bile and urine. Its pharmacokinetic profile would need to be characterized in preclinical studies to support its development as a therapeutic agent.

Hepatotoxicity
In controlled trials, 2% to 6% of patients treated with omaxitabine experienced elevated serum transaminases, but most elevations were mild and transient, with only a very small number requiring dose adjustments or discontinuation due to abnormal liver function. No clinically visible liver injury with jaundice was reported in omaxitabine's pre-registration trials, nor is it mentioned in the product information leaflet. Since omaxitabine's approval and widespread use, there has been no literature or description of hepatotoxicity with jaundice related to its use. Therefore, if clinically visible liver injury caused by omaxitabine occurs, it must be extremely rare. Probability Score: E (Unlikely to be the cause of clinically visible liver injury).

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Cephalotaxlen is an alkaloid with a well-established safety profile, as it is the base compound for homoharringtonine, which is used clinically for leukemia treatment. Homoharringtonine has manageable toxicity, with myelosuppression being the most common dose-limiting toxicity. Other adverse effects include gastrointestinal disturbances, hepatotoxicity, and cardiotoxicity. Cephalotaxlen is expected to have similar toxicity. The compound should be handled with standard laboratory precautions and is intended for research use only.

[1]. Studies on the alkaloids of Cephalotaxus. IX. Semi-synthesis of cephalotaxine esters and their anti-leukemic activity Yao Xue Xue Bao. 1992;27(3):178-84.

[2]. Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines. Naunyn Schmiedebergs Arch Pharmacol. 2003 Jan;367(1):56-67.

[3]. Cephalotaxine inhibits Zika infection by impeding viral replication and stability. Biochem Biophys Res Commun. 2020 Feb 19; 522(4): 1052–1058.

Cephalotaxine is a benzodiazepine alkaloid isolated from Cephalotaxus harringtonia. It is a benzodiazepine alkaloid whose basic parent compound is a benzodiazepine, and it also contains organic heteropentane compounds, enol ethers, cyclic acetals, secondary alcohols, and tertiary amine compounds. Omaxistatin is a semi-synthetic cephalotaxine used as a protein translation inhibitor to treat chronic myeloid leukemia resistant to tyrosine kinase receptor antagonists. Elevated serum enzyme levels during omaxistatin treatment are rare, but have not been found to be associated with clinically significant liver damage with jaundice. Cephalotaxine has been reported in Cephalotaxus fortunei, Cephalotaxus hainanensis, and other organisms with relevant data. Omaxistatin is a protein translation inhibitor and cytotoxic plant alkaloid isolated from the evergreen tree Cephalotaxus, possessing potential antitumor activity. Although its exact mechanism of action is not fully elucidated, after administration, omaxistatin targets and binds to the 80S ribosome in eukaryotic cells, inhibiting protein synthesis by interfering with chain elongation. This reduces the levels of certain oncoproteins and anti-apoptotic proteins. Cephalotaxine is a semi-synthetic Harringtonine derivative that acts as a protein synthesis inhibitor and induces apoptosis in tumor cells. It is used to treat chronic myeloid leukemia. See also: Omaxistatin mesylate (active ingredient).

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Cephalotaxlen (Cephalotaxine) is a benzazepine alkaloid isolated from Cephalotaxus harringtonia. It is the base compound for homoharringtonine (HHT), a chemotherapeutic agent used in leukemia treatment. Cephalotaxlen exhibits anticancer and antiviral activities. It inhibits protein synthesis in cancer cells and is cytotoxic to various cancer cell lines, including HL-60, NB4, MOLT-4, K562, and Jurkat cells. It also inhibits Zika virus infection by impeding viral replication and stability. Cephalotaxlen is a valuable research tool for studying protein synthesis inhibition and its therapeutic applications. It is available as a research compound and is not approved for clinical use.

C18H21NO4

315.370

315.147

C, 68.55; H, 6.71; N, 4.44; O, 20.29

24316-19-6

65305

White to light yellow solid powder

1.4±0.1 g/cm3

495.2±45.0 °C at 760 mmHg

253.3±28.7 °C

0.0±1.3 mmHg at 25°C

1.665

2.13

1

5

1

23

523

3

O([H])[C@]1([H])C(=C([H])[C@]23C([H])([H])C([H])([H])C([H])([H])N2C([H])([H])C([H])([H])C2=C([H])C4=C(C([H])=C2[C@@]31[H])OC([H])([H])O4)OC([H])([H])[H]

YMNCVRSYJBNGLD-KURKYZTESA-N

1S/C18H21NO4/c1-21-15-9-18-4-2-5-19(18)6-3-11-7-13-14(23-10-22-13)8-12(11)16(18)17(15)20/h7-9,16-17,20H,2-6,10H2,1H3/t16-,17-,18+/m1/s1

(11bS,12S,14aR)-13-methoxy-2,3,5,6,11b,12-hexahydro-1H-[1,3]dioxolo[4',5'

(-)-Cephalotaxine; Alkaloid A from Cephalotaxus; Cephalotaxine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~79.27 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.93 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)