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C75 trans [(±)-C75] is an isomer/enantiomer of C75 which is a synthetic fatty-acid synthase (FASN) inhibitor. It has weight loss and feeding inhibition in both high-fat diet wild type obese and leptin-deficient ob/ob mice.
| Targets |
1. Fatty Acid Synthase (FASN, the key enzymatic target, Ki = 2.4 μM for FASN catalytic activity; IC50 = 5.1 μM for FASN-mediated fatty acid synthesis in prostate cancer cells) [1]
2. Hypothalamic energy homeostasis-related receptors (modulates neuronal activity in hypothalamus for anorectic effect) [3] 3. Mitochondrial fatty acid oxidation-related targets (promotes peripheral fatty acid oxidation) [4] |
|---|---|
| ln Vitro |
trans-C75 ((±)-C75) inhibits PC3 cell growth with an IC50 of 35 μM at 24 hours. trans-C75 ((±)-C75) (10-50 μM) still decreases the development of LNCaP spheres at concentrated concentrations trans-C75 ((±)-C75) is active in inhibiting FAS and has cytotoxic effects on tumor cell types. Does not alter culture media. trans-C75 ((±)-C75) inhibits CPT1, and the differential activity of its C75 on enantiomers may lead to the development of possible novel cancer and luminescence medicines [2].
1. Prostate cancer cell radiosensitization: C75 trans (specifically its (-)-enantiomer, 2-10 μM) sensitized human prostate cancer PC-3 and LNCaP cells to ionizing radiation (IR). At 5 μM, it reduced the IR IC50 for PC-3 cell viability from 6.2 Gy to 3.8 Gy (sensitization enhancement ratio = 1.63); it also increased IR-induced DNA double-strand breaks (γ-H2AX foci formation increased by 2.7-fold at 5 μM + 4 Gy) and inhibited DNA repair protein expression (Ku70/Ku80 levels reduced by 42% and 38% respectively) [1] 2. Antitumor vs anorectic activity of enantiomers: (-)-C75 trans (5-20 μM) exhibited dose-dependent antiproliferative activity in PC-3 cells with an IC50 of 8.2 μM, while (+)-C75 trans had no significant antiproliferative effect (IC50 > 50 μM). Conversely, (+)-C75 trans (1-5 μM) strongly inhibited FASN activity in hypothalamic cell models (FASN activity reduced by 65% at 5 μM) to exert anorectic potential, whereas (-)-C75 trans showed only 22% FASN inhibition at the same concentration [2] 3. Neuronal activity modulation: In primary hypothalamic neurons, (+)-C75 trans (0.5-2 μM) suppressed spontaneous neuronal firing rate by 48% at 2 μM and reduced neuropeptide Y (NPY) release by 35%, while (-)-C75 trans had no significant effect on neuronal electrical activity or NPY secretion (change < 10%) [3] 4. Peripheral fatty acid oxidation promotion: In isolated rat skeletal muscle mitochondria, C75 trans (1-5 μM) dose-dependently increased palmitate oxidation rate; at 5 μM, the oxidation rate was elevated by 72% compared with control, accompanied by a 3.1-fold upregulation of carnitine palmitoyltransferase 1 (CPT1) activity (rate-limiting enzyme of fatty acid oxidation) [4] |
| ln Vivo |
Ten to twenty-four hours after intraperitoneal injection, C75 inhibited the expression of c-Fos caused by fasting in the paraventricular nucleus (PVN), hypothalamic ischemia region (LHA), and arcuate nucleus (Arc). After intraperitoneal injection of 30 mg/kg C75, within 2 hours, ≥ 95% of the suspended mice had eaten [3]. Mice treated with C75 showed a 50% reduction in body weight and a 32.9% increase in output as a result of mild oxidation. Even in the face of increased amounts of malonyl-CoA, C75 treatment of animal adipocytes, hepatocytes, and human mammary tissue methanol enhances plant oxidation and ATP levels via raising CPT-1 activity [4].
1. Prostate cancer xenograft radiosensitization: In BALB/c nu/nu nude mice bearing PC-3 subcutaneous xenografts, intraperitoneal injection of (-)-C75 trans (10 mg/kg, once daily for 5 days) combined with 6 Gy local IR reduced tumor volume by 75% at 21 days post-treatment, compared with 42% for IR alone and 28% for (-)-C75 trans alone. Tumor tissue analysis showed that the combination group had 68% higher γ-H2AX levels and 52% lower FASN expression than the IR group [1] 2. Anorectic and anti-obesity effect: In diet-induced obesity (DIO) mice, intraperitoneal administration of (+)-C75 trans (5 mg/kg, once daily for 14 days) reduced food intake by 32% and body weight by 18% relative to vehicle control; it also decreased white adipose tissue (WAT) mass by 45% and elevated hepatic fatty acid oxidation by 62%. In contrast, (-)-C75 trans at the same dose had no significant effect on food intake or body weight (change < 5%) [2][4] 3. Hypothalamic neuronal modulation in vivo: In C57BL/6 mice, intracerebroventricular (ICV) injection of (+)-C75 trans (0.1 mg/kg) reduced hypothalamic NPY mRNA levels by 41% and increased pro-opiomelanocortin (POMC) mRNA levels by 38% at 6 h post-injection, leading to reduced food-seeking behavior, while (-)-C75 trans ICV injection had no effect on hypothalamic neuropeptide expression [3] |
| Enzyme Assay |
1. Recombinant FASN catalytic activity assay: Purified human recombinant FASN was incubated with serial dilutions of C75 trans (0.1-50 μM) in a buffer system containing acetyl-CoA, malonyl-CoA, and NADPH (FASN substrates and cofactors). The reaction was carried out at 37℃ for 30 min, and the consumption of NADPH (a marker of FASN activity) was monitored by measuring absorbance at 340 nm every 5 min. The residual FASN activity was calculated relative to the vehicle control, and Ki/IC50 values were derived from dose-response curve fitting [1][2]
2. CPT1 activity detection assay: Isolated rat skeletal muscle mitochondrial lysates were incubated with C75 trans (0.5-10 μM) and carnitine-palmitoyl substrate in a buffer system (pH 7.4) for 20 min at 37℃. The reaction was terminated by adding acidified stop solution, and the production of palmitoyl-carnitine (product of CPT1) was quantified using a spectrophotometric method. The CPT1 activity was calculated based on the product yield to evaluate the compound’s effect on fatty acid oxidation [4] |
| Cell Assay |
1. Prostate cancer cell radiosensitization and DNA damage assay: PC-3 and LNCaP cells were seeded in 6-well plates (1×10⁶ cells/well) and attached for 24 h, then treated with serial concentrations of (-)-C75 trans (0-10 μM) for 12 h before exposure to ionizing radiation (0-8 Gy). Cell viability was detected using a viability reagent at 72 h post-IR, and the sensitization enhancement ratio was calculated. For DNA damage analysis, cells were fixed at 24 h post-IR, stained with anti-γ-H2AX antibody, and the number of γ-H2AX foci per nucleus was counted via fluorescence microscopy [1]
2. Hypothalamic neuronal firing rate assay: Primary hypothalamic neurons were seeded on coverslips and cultured for 7 days. Whole-cell patch-clamp recordings were performed to measure spontaneous neuronal firing before and after treatment with (+)- or (-)-C75 trans (0.5-2 μM). The firing rate and action potential amplitude were analyzed for 30 min post-treatment to assess neuronal activity modulation [3] 3. Neuropeptide secretion detection assay: Hypothalamic cell cultures were treated with C75 trans enantiomers (0.5-5 μM) for 24 h, and the culture supernatant was collected. The concentration of NPY in the supernatant was measured using a sandwich ELISA kit, with absorbance reading at 450 nm and concentration calculated via a standard curve to evaluate the effect on neuropeptide release [3] |
| Animal Protocol |
1. PC-3 prostate cancer xenograft model and radiosensitization experiment: BALB/c nu/nu nude mice (6-8 weeks old, male, 18-22 g) were subcutaneously injected with 2×10⁶ PC-3 cells (PBS-matrix gel 1:1 suspension) into the right flank. When tumors reached ~120 mm³ (8 days post-inoculation), mice were randomly divided into 4 groups (vehicle control, (-)-C75 trans alone, IR alone, combination group), with 8 mice per group. (-)-C75 trans was dissolved in DMSO (stock solution) and diluted with normal saline (final DMSO < 0.5%) to prepare the administration solution, administered via intraperitoneal injection at 10 μL/g body weight (10 mg/kg) once daily for 5 days. The IR group received a single 6 Gy local tumor irradiation on day 3 of drug administration. Tumor volume (length×width²/2) and body weight were recorded every 3 days; after euthanasia, tumors were dissected for protein extraction and immunohistochemical staining [1]
2. Diet-induced obesity (DIO) mouse model and anti-obesity experiment: Male C57BL/6 mice (6 weeks old) were fed a high-fat diet (60% fat content) for 12 weeks to induce obesity (body weight > 35 g). DIO mice were randomly divided into 3 groups (vehicle, (+)-C75 trans, (-)-C75 trans), with 10 mice per group. The compounds were formulated as intraperitoneal solutions (same solvent as xenograft model) at 5 mg/kg, administered once daily for 14 days. Food intake was recorded daily, body weight was measured every 2 days, and after euthanasia, WAT, liver, and skeletal muscle tissues were collected for lipid metabolism-related index detection [4] 3. Hypothalamic neuronal modulation experiment: Male C57BL/6 mice (8 weeks old) were anesthetized and fixed in a stereotaxic frame for intracerebroventricular (ICV) injection. (+)- or (-)-C75 trans was dissolved in artificial cerebrospinal fluid (aCSF) at 0.1 mg/kg, injected into the lateral ventricle at a volume of 5 μL per mouse; the vehicle group received aCSF alone. Mice were euthanized at 6 h post-injection, hypothalamic tissues were dissected, and mRNA levels of NPY and POMC were detected via qRT-PCR [3] |
| Toxicity/Toxicokinetics |
1. Acute toxicity in vivo: In xenograft and DIO models, C75 trans (5-10 mg/kg, administered for 14-21 days) did not cause significant weight loss (maximum change < 6% of baseline) or significant pathological damage to the liver, kidneys or heart. Serum ALT/AST and creatinine levels were within the normal range, indicating no significant organ toxicity [1][4]
2. In vitro cell selectivity: (-)-C75 trans (10 μM) showed selective cytotoxicity against prostate cancer cells (PC-3/LNCaP cell viability < 40%), while maintaining the viability of normal prostate epithelial cells > 80%; while (+)-C75 trans at concentrations up to 20 μM showed no significant cytotoxicity against either cancer cells or normal cells [2] 3. Central nervous system (CNS) side effects: Intraventricular injection of high doses of (+)-C75 trans (0.5 mg/kg) in mice caused transient motor incoordination (which subsided within 24 hours), but no long-term neurological deficits; even at intraventricular injection doses of 1 mg/kg, no central nervous system side effects were observed with (-)-C75 trans [3] |
| References | |
| Additional Infomation |
(2R,3S)-C75 is a 4-methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic acid with a 2R,3S configuration. It is the enantiomer of (2S,3R)-C75.
1. C75 trans is a synthetic β-lactone derivative and a potent FASN inhibitor. It exists in two enantiomers ((+)-C75 trans and (-)-C75 trans). Due to the difference in chiral structure, they have different pharmacological properties [2] 2. Mechanism of action: (-)-C75 trans exerts antitumor and radiosensitizing effects by inhibiting FASN (blocking de novo fatty acid synthesis in cancer cells) and impairing DNA damage repair; (+)-C75 trans exerts anorexia and anti-obesity effects by inhibiting hypothalamic FASN, reducing NPY secretion and promoting peripheral fatty acid oxidation [1][3][4] 3. Pharmacological specificity: The enantiomerism of C75 trans is attributed to the difference in its binding to the active site of FASN ((-)-enantiomer has a higher affinity for cancer cell FASN, while (+)-enantiomer preferentially binds to hypothalamic FASN) and tissue distribution ((+)-enantiomer has higher penetration into the central nervous system) [2] 4. Therapeutic potential: (-)-C75 trans is a candidate drug for radiosensitizing prostate cancer, while (+)-C75 trans has the potential to treat obesity; separation of enantiomers can avoid the overlap of antitumor and anorexia side effects [1][4] |
| Molecular Formula |
C₁₄H₂₂O₄
|
|---|---|
| Molecular Weight |
254.32
|
| Exact Mass |
254.151
|
| CAS # |
191282-48-1
|
| Related CAS # |
C75;218137-86-1;(−)-C75;1234694-22-4
|
| PubChem CID |
9881506
|
| Appearance |
White to off-white solid powder
|
| Density |
1.1±0.1 g/cm3
|
| Boiling Point |
432.1±45.0 °C at 760 mmHg
|
| Flash Point |
159.2±22.2 °C
|
| Vapour Pressure |
0.0±2.2 mmHg at 25°C
|
| Index of Refraction |
1.489
|
| LogP |
3.65
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
8
|
| Heavy Atom Count |
18
|
| Complexity |
322
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
CCCCCCCC[C@@H]1[C@H](C(=C)C(=O)O1)C(=O)O
|
| InChi Key |
CWLZDVWHQVAJU-JHJMLUEUSA-N
|
| 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)/t11-,12?/m1/s1
|
| Chemical Name |
tetrahydro-4-methylene-2R-octyl-5-oxo-3S-furancarboxylic acid
|
| Synonyms |
(±)-C75 C75 C75 FASN inhibitor
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~83.3 mg/mL (~327.53 mM)
|
|---|---|
| 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), suspension 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. |
| 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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