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C75 is a novel and potent fatty-acid synthase (FASN) inhibitor used as a tool compound to study fatty acid synthesis in metabolic disorders and cancer.
| Targets |
C75 targets fatty acid synthase (FASN) with an IC50 of 3.8 μM (recombinant FASN) [2]
C75 targets carnitine palmitoyltransferase 1A (CPT1A) [5] |
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| ln Vitro |
PC3 cell growth is inhibited by C75, with an IC50 of 35 μM after 24 hours. With an IC50 of 50 μM, C75 (10-50 μM) still inhibits the development of LNCaP spheroids in a concentration-dependent way [1]. With harmful effects, (-)-C75 suppresses FAS activity in most tumor cell lines without influencing meal intake. The anorexic effects of C75 are dependent on central inhibition of CPT1, as (+)-C75 inhibits CPT1, which causes anorexia. Novel cancer and chemotherapy medications may be developed as a result of the distinct actions of C75 enantiomers [2].
C75 (5 μM–20 μM) dose-dependently inhibited the proliferation of human prostate cancer cells (LNCaP, PC-3): IC50 values were 8.2 μM (LNCaP) and 10.5 μM (PC-3) after 72 hours; it also enhanced radiotherapy sensitivity, reducing the surviving fraction by 45% (LNCaP) and 52% (PC-3) when combined with 4 Gy radiation [1] (-)-C75 (1 μM–10 μM) exhibited stronger antitumor activity than (+)-C75 against human breast cancer MCF-7 cells: (-)-C75 IC50 = 4.1 μM, (+)-C75 IC50 > 20 μM [2] C75 (10 μM) inhibited FASN activity in LNCaP cells by 78%, reducing intracellular fatty acid accumulation by 65% and increasing reactive oxygen species (ROS) levels by 2.3-fold [1] C75 (5 μM–15 μM) inhibited CPT1A activity in human hepatoma HepG2 cells, reducing palmitate oxidation by 58% (10 μM) and promoting mitochondrial permeability transition (MPT) pore opening [5] C75 (10 μM) induced apoptosis in PC-3 cells via the intrinsic pathway: apoptotic rate increased to 42% (Annexin V+/PI+) after 48 hours, accompanied by caspase-9/caspase-3 activation [1] |
| ln Vivo |
The paraventricular nucleus (PVN), hypothalamic lesion area (LHA), and arcuate nucleus (Arc) all showed increased expression of C-Fos 10–24 hours following intraperitoneal injection due to C75-like distention fasting? Over 95% of the mouse body weight can be absorbed in 2 hours by intraperitoneal injection of C75 at a dose of 30 mg/kg body weight [3]. Because of medium oxidation, DIO mice administered with C75 boosted their energy output by 32.9 percent and lost 50% of their body weight. Even in the presence of high malonyl-CoA concentrations, C75 treatment of odontozoan adipocytes, hepatocytes, and human breast cancer cells boosts medium oxidation and ATP levels through boosting CPT-1 activity [4].
In nude mice bearing LNCaP prostate cancer xenografts, intraperitoneal administration of C75 (20 mg/kg, q.o.d.) for 21 days inhibited tumor growth by 63% and enhanced the efficacy of radiotherapy (4 Gy, weekly × 3): combined treatment achieved 87% tumor growth inhibition [1] In diet-induced obese (DIO) C57BL/6 mice, intraperitoneal administration of C75 (5 mg/kg, q.d.) for 14 days reduced body weight by 18%, decreased fat mass by 25%, and increased fatty acid oxidation in skeletal muscle by 3.1-fold [4] (+)-C75 (10 mg/kg, i.p., q.d.) induced anorexia in C57BL/6 mice, reducing food intake by 40% within 7 days without significant weight loss in lean mice [2,3] In a mouse liver transplantation model, C75 (15 mg/kg, i.p.) administered 24 hours before transplantation aggravated fatty liver graft injury: serum ALT/AST levels increased by 2.8-fold, and hepatocyte necrosis rate increased by 55% via inhibiting CPT1A [5] (-)-C75 (25 mg/kg, i.p., q.d.) inhibited MCF-7 breast cancer xenograft growth in nude mice by 58%, while (+)-C75 (25 mg/kg) showed no significant antitumor effect [2] |
| Enzyme Assay |
FASN inhibitory activity assay: Recombinant human FASN enzyme was incubated with C75 (0.1 μM–20 μM) in assay buffer containing acetyl-CoA, malonyl-CoA, and NADPH. The reaction was conducted at 37°C for 60 minutes, and NADPH oxidation was monitored by absorbance at 340 nm. IC50 values were calculated by fitting dose-response curves [2]
CPT1A inhibitory activity assay: Mitochondrial fractions from HepG2 cells were incubated with C75 (1 μM–20 μM) in assay buffer containing palmitoyl-CoA and L-carnitine. The formation of palmitoyl-L-carnitine was quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine CPT1A inhibition rate [5] |
| Cell Assay |
Prostate cancer cell proliferation and radiosensitization assay: LNCaP/PC-3 cells were seeded in 96-well plates (5 × 10³ cells/well) and treated with C75 (5 μM–20 μM) for 24 hours, followed by 0–8 Gy radiation. Cell viability was assessed by CCK-8 assay 72 hours post-radiation; surviving fractions were calculated to evaluate radiosensitization [1]
FASN activity and fatty acid metabolism assay: LNCaP cells were treated with C75 (10 μM) for 48 hours. FASN activity was measured by NADPH oxidation assay; intracellular fatty acids were extracted and quantified by gas chromatography (GC); ROS levels were detected by fluorescent probe and flow cytometry [1] CPT1A inhibition and mitochondrial function assay: HepG2 cells were treated with C75 (5 μM–15 μM) for 24 hours. Palmitate oxidation rate was measured by ¹⁴C-palmitate incorporation; MPT pore opening was detected by calcein-AM/CoCl₂ staining and fluorescence microscopy [5] Breast cancer cell proliferation assay: MCF-7 cells were seeded in 96-well plates (5 × 10³ cells/well) and treated with (-)-C75 or (+)-C75 (1 μM–20 μM) for 72 hours. Cell viability was assessed by MTT assay, and IC50 values were calculated [2] |
| Animal Protocol |
Prostate cancer xenograft and radiosensitization model: Nude mice were subcutaneously inoculated with 5 × 10⁶ LNCaP cells. When tumors reached 100–150 mm³, mice were randomized into control, C75 (20 mg/kg, i.p., q.o.d.), radiation (4 Gy, weekly × 3), and combined groups (n=8/group). C75 was dissolved in 10% DMSO + 90% corn oil. Tumor volume was measured every 3 days; mice were sacrificed on day 21 to measure tumor weight [1]
Diet-induced obesity (DIO) mouse model: C57BL/6 mice were fed a high-fat diet for 12 weeks to induce obesity, then randomized into control and C75 groups (5 mg/kg, i.p., q.d., n=10/group). C75 was dissolved in saline. Body weight and food intake were recorded daily; skeletal muscle and adipose tissue were collected on day 14 for fatty acid oxidation analysis [4] Anorexia model: Lean C57BL/6 mice were treated with (+)-C75 (10 mg/kg, i.p., q.d., n=6/group) for 7 days. Food intake was measured daily; hypothalamus and brainstem tissues were collected to detect neuronal activity by immunohistochemistry [3] Fatty liver transplantation model: C57BL/6 mice were fed a high-fat diet for 8 weeks to induce fatty liver. Donor mice were treated with C75 (15 mg/kg, i.p.) 24 hours before liver transplantation. Recipient mice were sacrificed 24 hours post-transplantation to detect serum ALT/AST levels and hepatocyte necrosis [5] Breast cancer xenograft model: Nude mice were subcutaneously inoculated with 5 × 10⁶ MCF-7 cells. When tumors reached 100–150 mm³, mice were treated with (-)-C75 or (+)-C75 (25 mg/kg, i.p., q.d., n=8/group) for 21 days. Tumor volume and weight were measured to evaluate antitumor efficacy [2] |
| Toxicity/Toxicokinetics |
Anorexia was a dose-dependent side effect of (+)-C75: intraperitoneal injection of ≥10 mg/kg significantly reduced food intake in mice, but no lethal toxicity was observed [2,3]. In a fatty liver transplantation model, C75 (15 mg/kg, intraperitoneal injection) exacerbated hepatocyte necrosis and increased serum liver enzyme (ALT/AST) levels, indicating hepatotoxicity in the context of fatty liver [5]. In a subchronic toxicity study in nude mice (21 days, 20 mg/kg, intraperitoneal injection), C75 did not cause significant changes in body weight, hematological parameters, or histopathological damage to the heart, kidneys, or spleen [1].
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| References | |
| Additional Infomation |
4-Methylene-2-octyl-5-oxo-3-oxacyclopentanecarboxylic acid is a γ-lactone.
C75 is a synthetic small molecule FASN inhibitor, and its two enantiomers exhibit different pharmacological properties: (+)- C75 has anorexia, while (-)- C75 has strong antitumor activity[2] Its antitumor mechanism involves FASN inhibition, leading to intracellular fatty acid depletion, ROS accumulation and activation of intrinsic apoptosis pathways; it can also enhance the sensitivity of cancer cells to radiotherapy by impairing DNA repair[1,2] C75 exerts an anti-obesity effect by increasing peripheral energy utilization and fatty acid oxidation, reducing adipose tissue mass[4] In fatty liver transplantation, C75 hepatotoxicity is mediated by CPT1A inhibition, which disrupts fatty acid oxidation and promotes mitochondrial permeability conversion[5] C75 has potential applications in cancer treatment (as a monotherapy or radiosensitizer) and obesity management, but its anorexia and hepatotoxicity in cases of fatty liver require careful dosage optimization [1,2,4,5]. |
| Molecular Formula |
C14H22O4
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|---|---|
| Molecular Weight |
254.32208
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| Exact Mass |
254.151
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| CAS # |
218137-86-1
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| Related CAS # |
trans-C75;191282-48-1;(−)-C75;1234694-22-4
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| PubChem CID |
4248455
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| Appearance |
White to off-white solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
432.1±45.0 °C at 760 mmHg
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| Flash Point |
159.2±22.2 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.489
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| LogP |
3.65
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
18
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| Complexity |
322
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
VCWLZDVWHQVAJU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H22O4/c1-3-4-5-6-7-8-9-11-12(13(15)16)10(2)14(17)18-11/h11-12H,2-9H2,1H3,(H,15,16)
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| Chemical Name |
4-methylidene-2-octyl-5-oxooxolane-3-carboxylic acid
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 83.3 mg/mL (~327.54 mM)
H2O : < 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.83 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (9.83 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (9.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 1.25 mg/mL (4.92 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 1.25 mg/mL (4.92 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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. Solubility in Formulation 6: ≥ 1.25 mg/mL (4.92 mM) (saturation unknown) in 5% DMSO + 95% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.9321 mL | 19.6603 mL | 39.3205 mL | |
| 5 mM | 0.7864 mL | 3.9321 mL | 7.8641 mL | |
| 10 mM | 0.3932 mL | 1.9660 mL | 3.9321 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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