Cat. No.: HY-187723

CT-2584 mesylate

CT-2584 mesylate is an inhibitor targeting CTP:phosphocholine cytidylyltransferase and MDR1, with antitumor activity. CT-2584 mesylate inhibits de novo synthesis of phosphatidylcholine, induces accumulation of phosphatidic acid and phosphatidylinositol in tumor cells, disrupts and dilates the endoplasmic reticulum and mitochondria, induces apoptosis, and inhibits tumor growth. CT-2584 mesylate induces intravascular hemolysis, has mild hypotensive and antiarrhythmic effects, is an intravenous irritant, and may trigger hypersensitivity reactions when combined with Cremophor EL. CT-2584 mesylate can be used in research on neoplastic diseases, hepatocellular carcinoma, solid tumors, malignant pleural mesothelioma, and cancer.

For research use only. We do not sell to patients.

CAS No.: 353525-62-9
Formula: C₃₁H₅₉N₅O₆S
Molecular Weight:629.90

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Please store the product under the recommended conditions in the Certificate of Analysis.

CT-2584 mesylate Chemical Structure

CAS No.: 353525-62-9

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Biological Activity
- Description
- Cellular Effect
- In Vitro
- In Vivo
Chemical Information
Purity & Documentation
References
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Biological Activity

Description

Cellular Effect

Cell Line	Type	Value	Description	References
NCI-H460	LC₅₀	3.3 μM	Cytotoxicity against human NCI-H460 cells assessed by viability assays using Alamar Blue after 24 h treatment with CT-2584 followed by 24 h drug-free incubation. Cytotoxicity against human NCI-H460 cells assessed by viability assays using Alamar Blue after 24 h treatment with CT-2584 followed by 24 h drug-free incubation.	11016649
MCF7	LC₅₀	4.5 μM	Cytotoxicity against human MCF-7 cells assessed by viability assays using Alamar Blue after 24 h treatment with CT-2584 followed by 24 h drug-free incubation. Cytotoxicity against human MCF-7 cells assessed by viability assays using Alamar Blue after 24 h treatment with CT-2584 followed by 24 h drug-free incubation.	11016649
ECV-304	LC₅₀	4.5 μM	Cytotoxicity against human endothelial ECV304 control cells assessed as reduction in cell viability incubated for 3 days by alamarBlue indicator dye assay. Cytotoxicity against human endothelial ECV304 control cells assessed as reduction in cell viability incubated for 3 days by alamarBlue indicator dye assay.	8981042

In Vitro

Anti-cancerLipid MetabolismOthers

Anti-cancer

CT-2584 mesylate (1-50 μM; 24 h) potently induced cytotoxicity in a cell panel composed of 35 human tumor cell lines, with a mean LC₅₀ of 4.0 μM; whereas non-tumorigenic HBMS cells were 3-4 times less sensitive, with an LC₅₀ of 15.7 μM^[1].
CT-2584 mesylate (2-5 μM; 4-48 h) can potently kill human hepatocellular carcinoma Alex 0 cells in vitro, with an LC₅₀ of 2.73 μM after 24 hours; at 5 μM for 48 hours, it can eliminate all surviving cells and inhibit HBsAg secretion^[2].
CT-2584 mesylate (2-5 μM; 4-48 h) can potently kill MDR1-overexpressing multidrug-resistant human hepatoma Alex 0.5 cells in vitro, with an LC₅₀ of 2.63 μM after 24 hours; after treatment with 5 μM for 48 hours, it can eliminate all surviving cells and inhibit HBsAg secretion^[2].

Lipid Metabolism

CT-2584 mesylate (1-15 μM; 0.5-10 h) decreased phosphatidylcholine (PC) levels and increased phosphatidylinositol (PI) levels in NCI-H460, MCF-7, NCI-H23, and DU-145 human tumor cell lines in a concentration- and time-dependent manner, and PI accumulation occurred prior to cell death^[1].
CT-2584 mesylate (10 μM; 2 h) specifically inhibits the activity of CTP:phosphocholine cytidylyltransferase (CT) in MCF-7 cell lysates, while having no effect on the activity of choline kinase (CK) or CDP-choline:1,2-diacylglycerol cholinephosphotransferase (CPT)^[1].
CT-2584 mesylate (10 μM; 2 h) increases CDP-diacylglycerol (CDP-DAG) production by 3-4 fold in MCF-7 cells, thereby promoting enhanced phosphatidylinositol (PI) biosynthesis^[1].

Others

CT-2584 mesylate (10 μM; 1-10 h) can induce swelling and disruption of mitochondria and rough endoplasmic reticulum in NCI-H460 cells, but does not disrupt the plasma membrane and nuclear membrane^[1].
CT-2584 mesylate (5-20 μM; 24 h) showed significantly lower toxicity to primary rat hepatocytes in vitro, with an LC₅₀ of 12.6 μM after 24 hours and a cell viability of 78.7% at 5 μM^[2].
CT-2584 mesylate (5-20 μM; 24 h) exhibited significantly lower toxicity to primary human hepatocytes in vitro, with an LC₅₀ of 17.3 μM after 24 hours and a cell viability of 85.6% at a concentration of 5 μM^[2].
CT-2584 mesylate (4.5-14 μM; 3 days) resistance is mediated by overexpression of NKEF-B in ECV304 human endothelial cells and 293-EBNA human embryonic kidney cells; compared with an LC₅₀ of 4.5 μM in control ECV304 cells, the LC₅₀ in ECV304/B/1 cells is 6.5 μM^[4].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Cytotoxicity Assay^[1]

Cell Line:

35 human tumor cell lines (including breast, lung, prostate, sarcoma, colon, melanoma, brain, ovarian, and leukemia cells) and nontumorigenic human bone marrow stromal (HBMS) cells
Concentration:

1-50 μM; 10 μM
Incubation Time:

24 h (followed by 24 h drug-free incubation); up to 50 h (time-course assays)
Result:

Exhibited cytotoxicity to the panel of human tumor cell lines with a mean LC₅₀ of 4.0 μM.
Nontumorigenic HBMS cells showed 3-4-fold less sensitivity, with an LC₅₀ of 15.7 μM.
Kept NCI-H460 cells (LC₅₀ 3.3 μM) and MCF-7 cells (LC₅₀ 4.5 μM) viable for more than 4 h, with detectable cell death starting at 6 h and complete cell death by 24 h.

Cell Cytotoxicity Assay^[2]

Cell Line:

human hepatocellular carcinoma PRF/PLC/5 (Alex 0) cells
Concentration:

2-5 μM
Incubation Time:

4-48 h
Result:

Caused significant cytotoxicity at 3.5 μM after 4 hours of incubation.
Reduced HBsAg secretion to 6.5% of control levels and cell viability to 2.6% of control levels after 24 hours of incubation; the LC₅₀ was 2.73 μM.
Eliminated all viable Alex 0 cells and rendered HBsAg levels undetectable after 48 hours of incubation with 5 μM.

Cell Cytotoxicity Assay^[2]

Cell Line:

multidrug-resistant human hepatocellular carcinoma Alex 0.5 cells (MDR1-overexpressing clone of Alex 0)
Concentration:

2-5 μM
Incubation Time:

4-48 h
Result:

Caused significant cytotoxicity at 2.0 μM after 4 hours of incubation.
Reduced HBsAg secretion to 20.5% of control levels and cell viability to 24.4% of control levels after 24 hours of incubation; the LC₅₀ was 2.63 μM.
Eliminated all viable Alex 0.5 cells and rendered HBsAg levels undetectable after 48 hours of incubation with 5 μM.

Cell Cytotoxicity Assay^[2]

Cell Line:

freshly isolated primary rat hepatocytes
Concentration:

5-20 μM
Incubation Time:

24 h
Result:

Left 78.7% of rat hepatocytes viable after 24 hours of incubation with 5 μM.
Exhibited an LC₅₀ of 12.6 μM for rat hepatocytes.

Cell Cytotoxicity Assay^[2]

Cell Line:

freshly isolated primary human hepatocytes
Concentration:

5-20 μM
Incubation Time:

24 h
Result:

Left 85.6% of human hepatocytes viable after 24 hours of incubation with 5 μM.
Exhibited an LC₅₀ of 17.3 μM for human hepatocytes.

Cell Cytotoxicity Assay^[4]

Cell Line:

ECV304, ECV304/pCE2, ECV304/B/1, 293-EBNA (empty vector-transfected), 293-EBNA (NKEF-B-overexpressing)
Concentration:

4.5-7 μM; 14 μM
Incubation Time:

3 d
Result:

Exhibited an LC₅₀ of 6.5 μM for NKEF-B-overexpressing ECV304/B/1 cells, compared to an LC₅₀ of 4.5 μM for control ECV304 or ECV304/pCE2 cells.
Retained spindle-shaped morphology in viable ECV304/B/1 cells after exposure to 7 μM, while control ECV304 and pCE2 cells became rounded and detached.
Showed much lower toxicity towards ECV304/B/1 cells at 14 μM, despite being toxic to ECV304 and pCE2 cells.
Conferred a slight increase in resistance to NKEF-B-overexpressing 293-EBNA cells compared to control 293-EBNA cells.

In Vivo

Anti-cancerApoptosisOthers

Anti-cancer

CT-2584 mesylate can cause delayed tumor growth in human liver cancer xenografts in severe combined immunodeficient mice, including multidrug-resistant tumor cells overexpressing mdr1^[1].

Anti-cancer

Apoptosis

CT-2584 (25-35 mg/kg; intraperitoneal injection; once daily; for 3 consecutive days) mesylate significantly inhibited the growth of Alex 0 hepatocellular carcinoma xenografts in SCID mice, as measured by a day 7/day 1 HBsAg ratio of 1.93 (a lower ratio indicates a higher degree of tumor growth inhibition), and its mechanism of action is the induction of tumor cell apoptosis and cytolysis without damaging normal liver parenchyma^[2].
CT-2584 (25 mg/kg; intraperitoneal injection; once daily; for 3 consecutive days) mesylate significantly reduced the growth of MDR1-overexpressing Alex 0.5 hepatocellular carcinoma xenografts in SCID mice, as evidenced by a day 7/day 1 HBsAg ratio of 2.2 (a lower ratio indicates tumor growth inhibition); its mechanism of action involves the induction of tumor cell apoptosis and cytolysis without damaging normal liver parenchyma^[2].

Others

CT-2584 (150-1000 mg/m²; intravenous injection; single 6-hour infusion) mesylate causes intravascular hemolysis in Sprague Dawley rats at doses ≥150 mg/m², with an LD₁₀ of 650 mg/m² and an LC₅₀ between 650 and 1000 mg/m²^[3].
CT-2584 (200-1500 mg/m²; intravenous injection; various infusion regimens) mesylate induced dose-dependent toxicity in cynomolgus monkeys, with a no-effect dose of 200 mg/m², and severe toxicity occurred at a dose of 1500 mg/m²; target plasma levels were achieved with different infusion regimens at doses of 350 mg/m² and 490 mg/m², respectively^[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:

CB-17 (SCID) (4- to 6-week-old male, intrahepatic xenografts induced by subcapsular splenic injection of 2 × 10⁶ Alex 0 cells followed by splenectomy)^[2]
Dosage:

25 mg/kg; 35 mg/kg
Administration:

i.p.; daily; 3 days
Result:

Produced an HBsAg ratio (day 7 titer / day 1 titer) of 1.93, where a lower ratio indicates reduced tumor growth.
Induced condensed cytoplasm, compact nuclear chromatin, numerous apoptotic bodies, and extensive cell lysis in Alex 0 xenografts, with normal adjacent liver parenchyma.
Eliminated xenografts in some treated mice, though serum HBsAg remained detectable.
Caused HBsAg titers to rise to pretreatment levels and tumor morphology to return to match untreated tumors when treatment was stopped for 1 week.
Failed to show efficacy when retreatment with 35 mg/kg was given after a 1-week break.

Animal Model:

CB-17 (SCID) (4- to 6-week-old male, intrahepatic xenografts induced by subcapsular splenic injection of 2 × 10⁶ Alex 0.5 cells followed by splenectomy)^[2]
Dosage:

25 mg/kg
Administration:

i.p.; daily; 3 days
Result:

Produced an HBsAg ratio (day 7 titer / day 1 titer) of 2.2, where a lower ratio indicates reduced tumor growth.
Induced condensed cytoplasm, compact nuclear chromatin, numerous apoptotic bodies, and extensive cell lysis in Alex 0.5 xenografts, with normal adjacent liver parenchyma.
Eliminated xenografts in some treated mice, though serum HBsAg remained detectable.
Caused HBsAg titers to increase to a lesser extent than in mice bearing Alex 0 xenografts when treatment was stopped for 1 week.

Animal Model:

Sprague Dawley rats^[3]
Dosage:

150 mg/m²; 650 mg/m²; 1000 mg/m²
Administration:

i.v.; single 6-hour infusion
Result:

Caused red urine associated with a fall in haemoglobin and a rise in bilirubin, consistent with intravascular haemolysis at doses of 150 mg/m² and above.
Reached an LD₁₀ of 650 mg/m².
Had an LC₅₀ between 650 and 1000 mg/m².

Animal Model:

Beagles^[3]
Dosage:

200 mg/m²; 400 mg/m²; 800 mg/m²
Administration:

i.v.; daily 6-hour infusion; 5 consecutive days
Result:

Exhibited intravascular haemolysis-related effects.
Showed a robust hypersensitivity reaction to Cremophor®EL, which was prevented with Benadryl® pre-medication.

Animal Model:

Macaca fascicularis^[3]
Dosage:

200 mg/m² (5-day 6-hour infusion); 490 mg/m² (single 24-hour infusion); 350 mg/m² (3-day 3-hour infusion); 1500 mg/m² (5-day 6-hour infusion)
Administration:

i.v.; daily 6-hour infusion; 5 consecutive days; i.v.; single 24-hour continuous infusion; i.v.; 3-hour infusion daily; 3 consecutive days
Result:

Caused hypotension, lethargy, haematuria, and emesis at 1500 mg/m², with recovery several hours after treatment discontinuation.
Showed no biologically significant clinical observations at 200 mg/m².
Achieved stable plasma levels of 0.50 µM with a 24-hour infusion of 490 mg/m².
Achieved plasma levels of 2.27 µM with a 3-hour infusion of 350 mg/m² for 3 consecutive days.

Related Protocols :

Chemical Information

CAS No. 353525-62-9
Molecular Weight 629.90
Formula C₃₁H₅₉N₅O₆S
SMILES

O=C1C2=C(N(C)C(N1CCCCCCCCCC(CNCCCCCCCCCCCC)O)=O)N=CN2C.O=S(O)(C)=O
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Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Purity & Documentation

Handling Instructions (2659 KB)

References

[1]. Finney RE, et al. Pharmacological inhibition of phosphatidylcholine biosynthesis is associated with induction of phosphatidylinositol accumulation and cytolysis of neoplastic cell lines. Cancer research. 2000 Sep 15;60(18):5204-13.

[2]. Marucci L, et al. Effect of a xanthine analog on human hepatocellular carcinoma cells (Alexander) in culture and in xenografts in SCID mice. Hepatology (Baltimore, Md.). 1997 Nov;26(5):1195-202.

[3]. Cheeseman SL, et al. Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours. British journal of cancer. 2000 Dec;83(12):1599-606.

[4]. Shau H, et al. Endogenous natural killer enhancing factor-B increases cellular resistance to oxidative stresses. Free radical biology & medicine. 1997;22(3):497-507. [Content Brief]

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CT-2584 mesylate