DNA-intercalating agent (derived from ellipticine). [1]

Datelliptium (100 μM) exhibits marked cytotoxic effects after two hours of treatment in suspension and primary cultures of rat hepatocytes. In vitro and concentration-dependently, Datelliptium mobilizes glycogen in both rat systems. When hepatocytes are isolated, the half-maximum effect is 14.3 μM, while in rat hepatocytes that have been cultured, it is 5.9 μM. The production of gluconeogenesis from lactate in cells is also reduced by Datelliptium in a concentration-dependent manner[1]. Solid tumors over leukemia L1210 are selectively cytotoxic to Datelliptium acetate. Less sensitivity to Datelliptium acetate is shown in human tumors H-125 and HCT-116 [2].

---

Datelliptium showed cytotoxic effects in various hepatic cell models. Cytotoxicity, evaluated by lactate dehydrogenase (LDH) leakage and MTT reduction, gave the following IC50 values (concentration causing 50% maximal inhibitory effect): In rat hepatocyte suspension after 2 hr treatment, LDH leakage IC50 > 100 µM.
In cultured rat hepatocytes, after 2 hr treatment, LDH IC50 = 195 ± 28 µM, MTT IC50 = 40 ± 9 µM. After 23 hr treatment, LDH IC50 = 9 ± 2 µM, MTT IC50 = 9 ± 1 µM.
In cultured human hepatocytes after 23 hr treatment, LDH IC50 = 8 ± 1 µM, MTT IC50 = 7 ± 1 µM.
In rat FaO hepatoma cell line after 23 hr treatment, LDH IC50 = 200 ± 23 µM, MTT IC50 = 320 ± 25 µM.
In human HepG2 hepatoma cell line after 23 hr treatment, LDH IC50 = 200 ± 19 µM, MTT IC50 = 300 ± 26 µM. Primary hepatocytes (rat and human) were much more sensitive than hepatoma cell lines. [1]
Metabolic effects of datelliptium were evaluated in rat hepatocytes (suspension and culture). The following IC50 values (concentration causing 50% inhibitory effect) were obtained for specific metabolic functions in cultured hepatocytes (23 hr exposure) vs. hepatocyte suspension (2 hr exposure): Gluconeogenesis: 7.2 ± 0.8 µM vs. 28.8 µM. Glycogen synthesis: 5.9 ± 0.7 µM vs. 14.3 ± 1.7 µM. Albumin synthesis: 4.1 ± 0.4 µM vs. 15.4 ± 2.1 µM. Cellular protein synthesis: 4.2 ± 0.6 µM vs. 3.0 ± 0.4 µM. Triglyceride secretion: 2.2 ± 0.3 µM vs. 2.3 ± 0.4 µM. Ureogenesis: 8.8 ± 1.1 µM vs. 96.4 µM. Metabolic parameters (especially triglyceride secretion and protein synthesis) were generally more sensitive indicators of toxicity than cytotoxicity endpoints (LDH, MTT). Cultured hepatocytes were more sensitive than suspensions for most parameters. [1]
Metabolic impairment occurred at concentrations below cytotoxic IC10 values. Triglyceride secretion was the most sensitive parameter (lowest IC10). [1]

Datelliptium acetate exhibits strong inhibitory effects in vivo against a range of solid tumors in mice when administered intravenously. Datelliptium acetate exhibits high levels of activity against colon #38 in the early stages, as evidenced by its highest non-toxic dose (HNTD) of 170 mg/kg TD, 10% weight loss, and 0% T/C[2].

---

Datelliptium showed marked antineoplastic activity against experimental tumours in animals (leukemia induced with L1210 and p388 cells, B16 melanoma, M5-M5076 reticulosarcoma and C-38 colon carcinoma). It had a better therapeutic index than elliptinium acetate with no cardiovascular or haemolytic toxicity. [1]
Acute toxicity studies in rats revealed an LD50 ranging between 26 and 27 mg/kg. At doses close to the LD50, an increase in hepatic lobe size, periportal steatosis and some vacuolization were observed in surviving animals. [1]
Chronic toxicity studies in rats and monkeys showed renal disturbances (slight to moderate proximal tubulopathy), and irregular perturbations of lactate dehydrogenase (LDH), aspartate aminotransferase and alanine aminotransferase. [1]
In phase I clinical trials in humans, severe hepatic toxicity was observed as a dose-limiting side-effect at 13 mg/kg/day (500 mg/m2/day), including one fatal case of drug-induced cytolytic hepatitis. This hepatotoxicity was not anticipated from animal studies. [1]

Cytotoxicity Assay (LDH leakage and MTT reduction): Cytotoxicity of datelliptium was evaluated in different cell systems. For rat hepatocyte suspensions, cells were treated with the drug for 2 hours. Cytotoxicity was assessed by measuring the leakage of lactate dehydrogenase (LDH) into the extracellular medium using a colorimetric method.
For cultured cells (rat and human hepatocytes, FaO and HepG2 cell lines), the compound was added to the culture medium. For short-term exposure (2 hr) in cultured rat hepatocytes, cells were treated and then assessed. For longer-term exposure (23 hr), the drug was added 1 hour after cell plating and incubated for 23 hours. Cytotoxicity was evaluated by measuring the intracellular LDH content (for cultured hepatocytes) using a colorimetric method adapted for microwell plates, and by the MTT test. The MTT test measures the reduction of the tetrazolium salt MTT to formazan by mitochondrial succinate dehydrogenase. After incubation with MTT, the formed formazan was quantified. [1]
Metabolic Function Assays: Metabolic effects of datelliptium were studied in rat hepatocyte suspensions (2 hr incubation) and cultured rat hepatocytes (drug added 1 hr after plating, incubated for 23 hr; drug present during the metabolic assay).
Glycogen synthesis was evaluated by incubating hepatocytes with the drug in the presence of 30 mM glucose, followed by measurement of intracellular glycogen content.
Gluconeogenesis was assessed by incubating hepatocytes from fasted rats (or glycogen-depleted cultured cells) with 10 mM lactate. Glucose production was measured using the glucose oxidase method.
Ureogenesis was determined by measuring urea production under specific conditions.
Cellular protein synthesis was determined by measuring the incorporation of radiolabeled leucine (¹⁴C-leucine for suspensions, ³H-leucine for cultures) into acid-insoluble material. Cells were pulsed with the labeled leucine, washed, precipitated with trichloroacetic acid, and the radioactivity in the pellet was counted.
Albumin secretion rate was determined in culture medium aliquots using an enzyme-linked immunosorbent assay (ELISA).
Triglyceride secretion was determined by incubating hepatocytes with ¹⁴C-palmitate and measuring the amount of radiolabeled triglycerides in the extracellular medium. [1]

Datelliptium acetate was dissolved in a diluent consisting of 3% (v/v) ethanol, 1% (v/v) polyoxyethylanesorbitan monopalmitate, and 96% sterile distilled water. [2]
For efficacy trials, mice were implanted bilaterally subcutaneously (SC) with tumor fragments. Treatment with Datelliptium acetate began either at an early stage (within 3 days of implantation, small tumor burden) or at an "upstaged" stage (palpable tumors <200 mg median size). [2]
The primary route of administration was intravenous (IV). Due to acute peak plasma level toxicities (neurotoxicity), the drug was administered by slow IV push twice daily (b.i.d.) with a 4-hour interval between doses (split-dosage schedule) over multiple days (e.g., days 1-10, 3-11, or 7-13 depending on the tumor model). This schedule was used to maximize the total administered dose while mitigating toxicity. Tumor growth was monitored by caliper measurements, and tumor weight was estimated. Endpoints included tumor growth delay (T-C), log cell kill calculation, and T/C value. [2]

The pharmacokinetic characteristics of duteliptin are: rapid and large distribution (Vc = 32 L in 200 g rats), very slow elimination (half-life of 158 hours), and significant tissue accumulation, especially in the liver and kidneys, where concentrations can be about 100 times higher than plasma concentrations and persist for several weeks. The drug accumulates in the mitochondria of the liver, heart, and kidneys. [1] Duteliptin is metabolized by cytochrome P450-dependent monooxygenases to N-deethylated derivatives, which are then oxidized at position 9 to quinone imines. These active quinone imines can covalently bind to proteins, leading to hepatotoxicity. [1]

Acute dose-limiting toxicity manifests as neurotoxicity. A single intravenous bolus dose exceeding 15 mg/kg can cause death in mice. At a dose of 13–15 mg/kg per injection (depending on the strain), mice exhibit tremors approximately 15 seconds after injection, followed by tonic-clonic seizures lasting 30–45 seconds. After the seizure, the mice exhibit rapid breathing, remain still for approximately 10 minutes, then develop ataxia, and recover completely within 30 minutes. Repeated injections of the same dose reduce neurotoxicity (adaptation) and are not cumulative. [2] Extravasation can cause partial tissue necrosis, and subcutaneous injection (SC) can cause pain. [2] Weight loss is observed starting approximately 3–4 days after injection, reaches its lowest point 2–3 days after the end of treatment, and fully recovers within 4–5 days after the end of treatment. At a total dose of 170–200 mg/kg, the average weight loss is 12–16%. [2]
Toxicity showed strain-specific advantages, with Balb/c and CD2F1 mice (especially females) being the most susceptible. [2]
At excessively high total doses (e.g., about 365 mg/kg), mice exhibited hepatosplenomegaly, gastric and colonic distension with bloody fluid, and diarrhea. At lower lethal doses (about 270 mg/kg), the primary manifestation was hepatosplenomegaly with rounded edges, suggesting possible hepatotoxicity. [2]

[1]. Toxicity of the antitumoral drug datelliptium in hepatic cells: Use of models in vitro for the prediction of toxicity in vivo. Toxicol In Vitro. 1992 Jul;6(4):295-302.

[2]. Activity of datelliptium acetate (NSC 311152; SR 95156A) against solid tumors of mice. Invest New Drugs. 1990 Aug;8(3):253-61.

Datelliptium acetate (DHE) is a water-soluble elliptic pyridine analog with a diethylaminoethyl chain at the N-2 position that enhances its solubility. [2]
In vitro cellular studies have shown that DHE is selective for solid tumors. [2]
Based on its preclinical efficacy and toxicity profile, the authors recommend further clinical studies. At the time of this publication, a Phase I clinical trial was underway in Europe, exploring dosing regimens including: 1 hour infusion for 3 consecutive days every 21 days; 24-hour infusion every 21 days; and 1 hour infusion every 21 days. At that time, the maximum total human dose was 400-500 mg/m² per injection. [2]
Although the main mechanism of action of DHE is intercalation into the cell membrane and possible interaction with topoisomerase II, its in vivo toxicity and tumor response patterns are not consistent with those of conventional alkylating agents. [2]

C23H28CLN3O

421.53194

397.192

C, 69.42; H, 7.09; Cl, 8.91; N, 10.56; O, 4.02

105118-14-7

105118-14-7 (chloride); 81531-57-9 (cation); 81531-58-0 (acetate); 157000-76-5 (chloride HCl); 958863-79-1 (mesylate)

72034

Solid powder

5.808

2

3

5

28

496

0

CC1=C2C(NC3=C2C=C(O)C=C3)=C(C)C4=CC=[N+](CCN(CC)CC)C=C41.[Cl-]

UCICRVXYPSKKJK-UHFFFAOYSA-N

InChI=1S/C23H27N3O.ClH/c1-5-25(6-2)11-12-26-10-9-18-16(4)23-22(15(3)20(18)14-26)19-13-17(27)7-8-21(19)24-23;/h7-10,13-14,27H,5-6,11-12H2,1-4H3;1H

2-[2-(diethylamino)ethyl]-5,11-dimethyl-6H-pyrido[4,3-b]carbazol-2-ium-9-ol;chloride

Datelliptium chloride; SR 95156A; SR95156A; SR-95156A; SR 95156; SR95156; SR-95156; NSC 311152; NSC-311152; NSC311152

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

H2O: ~41.7 mg/mL (~104.7 mM)
DMSO: ~5 mg/mL (~12.6 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

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