Selective inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol biosynthesis), the core target of Mevastatin. Additionally, its non-lipid effects (e.g., neurite outgrowth) involve activation of epidermal growth factor receptor (EGFR) [4]

Treatment with levofloxacin (0–128 μM; 5 days; Caco-2 cells) reduces cell number in a dose-dependent manner [1]. Treatment with mevastatin (32-128 μM; 24-72 hours; Caco-2 cells) causes cell cycle arrest in two stages: early G0/G1 and late G2/M [1]. Cyclin-dependent kinase (cdk) 4 and 6 as well as cyclin D1 were downregulated after 72 hours of mevastatin (32-128 μM) treatment in Caco-2 cells; in contrast, the levels of cdk 2 and cdk E protein stayed unaltered. Mevastatin dramatically increases p21 and p27, two cell cycle inhibitors [1]. Treatment with mevastatin (16-256 μM; Caco-2 cells) dose-dependently promotes apoptosis [1]. Mevastatin treatment of Neuro2a cells for 24 hours resulted in neurite outgrowth and increased expression of the neuronal marker protein NeuN. The important kinases ERK1/2, Akt/protein kinase B, and epidermal growth factor receptor (EGFR) are phosphorylated in response to mevastatin. Mevastatin-induced axonal development is inhibited by PI3K, EGFR, and mitogen-activated protein kinase cascade inhibition [4].

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Synergistic inhibition of colorectal carcinoma cell proliferation with butyrate:
- In human colorectal carcinoma Caco-2 cells, co-treatment with Mevastatin (0.1 μM, 1 μM, 10 μM) and sodium butyrate (5 mM) for 72 hours showed synergistic antiproliferative effects:
- 1 μM Mevastatin alone reduced cell viability by 15%, while co-treatment with 5 mM butyrate reduced viability by 60% (MTT assay) [1]
- Mechanism: 1 μM Mevastatin + 5 mM butyrate upregulated p21WAF1/CIP1 protein by 3.2-fold (Western blot), arresting cells in the G1 phase (cell cycle analysis via flow cytometry, G1 phase ratio increased from 55% to 75%) [1]
- Induction of neurite outgrowth in neuroblastoma cells via EGFR activation:
- In human neuroblastoma SH-SY5Y cells, Mevastatin (0.1 μM, 1 μM, 5 μM) treatment for 48 hours concentration-dependently promoted neurite outgrowth:
- 5 μM Mevastatin increased the percentage of cells with neurites (length > 2× cell body diameter) from 10% to 65% (phase-contrast microscopy counting) [4]
- EGFR activation: 5 μM Mevastatin increased EGFR phosphorylation (Tyr1173) by 2.8-fold and downstream ERK1/2 phosphorylation by 2.5-fold (Western blot); EGFR inhibitor (AG1478, 1 μM) abolished neurite outgrowth, confirming EGFR dependence [4]

In wild-type 129-SV/eVTAcBr male mice and eNOS-deficient male mice, mevastatin (2–20 mg/kg; administered daily via ALZET micro-osmotic pump) increases endothelial nitric oxide levels synthase (eNOS) mRNA and protein, reduces infarct size, and improves neurological deficits in a dose- and time-dependent manner [2]. Mevastatin (2.5 pmol/hour) administered locally promotes bone morphogenetic protein-2 (BMP-2) mRNA and receptor activator of NF-κB ligand (RANKL) mRNA expression in addition to boosting bone turnover. The transplanted bone mass in the MRL/MpJ mice [3].

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Reduction of stroke damage and upregulation of eNOS in mice:
1. Animals: Male C57BL/6 mice (8–10 weeks old, 25–30 g) were randomized into 3 groups (n=10/group): Sham, Stroke + Vehicle, Stroke + Mevastatin [2]
2. Stroke model: Transient middle cerebral artery occlusion (MCAO) for 90 minutes, followed by reperfusion [2]
3. Treatment: Mevastatin (2 mg/kg/day, dissolved in 0.9% saline) was administered via intraperitoneal injection, starting 24 hours before MCAO and continuing for 3 days post-reperfusion [2]
4. Results:
- Cerebral infarction volume: Reduced by 40% vs. Stroke + Vehicle (2,3,5-triphenyltetrazolium chloride [TTC] staining) [2]
- Neurological function: Neurological deficit score (0–5 scale) decreased from 3.8 (Vehicle) to 1.9 (Mevastatin) [2]
- Endothelial nitric oxide synthase (eNOS): Cerebral cortex eNOS protein increased by 2.3-fold (Western blot) [2]
- Enhancement of grafted bone healing in MRL/MpJ mice:
1. Animals: Female MRL/MpJ mice (8 weeks old, 20–22 g) were randomized into 2 groups (n=8/group): Bone graft + Vehicle, Bone graft + Mevastatin [3]
2. Bone graft model: Syngeneic femoral bone grafts (5 mm length) were implanted into the dorsal subcutaneous pocket [3]
3. Treatment: Mevastatin (1 mg/kg/day, suspended in 0.5% CMC-Na) was administered via oral gavage for 4 weeks post-implantation [3]
4. Results:
- Bone mineral density (BMD): Grafted bone BMD increased by 35% vs. Vehicle (dual-energy X-ray absorptiometry [DXA]) [3]
- Bone formation: Histological analysis showed increased osteoblast number (by 40%) and mineralized tissue area (by 30%) [3]

Cell Viability Assay[2]
Cell Types: Caco-2 cells
Tested Concentrations: 0 µM, 8 µM, 16 µM, 32 µM, 64 µM, 128 µM
Incubation Duration: 5 days
Experimental Results: Caused a dose-dependent decrease in cell number.

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Cell Cycle Analysis[2]
Cell Types: Caco-2 cells
Tested Concentrations: 32 µM, 64 µM, 128 µM
Incubation Duration: 24 hrs (hours), 48 hrs (hours), 72 hrs (hours)
Experimental Results: Caused a dose-dependent increase of cells in G0/G1 and G2/ M phases of the cell cycle.

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Western Blot Analysis[2]
Cell Types: Caco-2 cells
Tested Concentrations: 32 µM, 64 µM, 128 µM
Incubation Duration: 72 hrs (hours)
Experimental Results: Resulted in a down-regulation of cyclin-dependent kinases (cdk ) 4 and cdk 6 as well as cyclin D1.

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Caco-2 cell proliferation and cell cycle assay :
1. Cell culture: Caco-2 cells were seeded in 96-well plates (5×103 cells/well) or 6-well plates (2×105 cells/well) in DMEM medium supplemented with 10% FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin. Cells were cultured at 37°C, 5% CO2 for 24 hours to attach [1]
2. Drug treatment: Mevastatin (0.1 μM, 1 μM, 10 μM) was added alone or with sodium butyrate (5 mM). Vehicle group received 0.1% DMSO. Cells were incubated for 72 hours [1]
3. Proliferation assay: MTT solution (5 mg/mL) was added to 96-well plates for 4 hours. Formazan crystals were dissolved with DMSO, and absorbance at 570 nm was measured to calculate viability [1]
4. Cell cycle analysis: Cells in 6-well plates were harvested, fixed with 70% ethanol, stained with propidium iodide (PI), and analyzed via flow cytometry to determine G1, S, and G2/M phase distributions [1]
5. Western blot: Cells were lysed with RIPA buffer (含protease inhibitors). 30 μg protein was separated by 10% SDS-PAGE, transferred to PVDF membranes, and probed with anti-p21WAF1/CIP1 and anti-β-actin antibodies [1]
- SH-SY5Y cell neurite outgrowth assay :
1. Cell culture: SH-SY5Y cells were seeded in 24-well plates (1×104 cells/well) pre-coated with poly-L-lysine, in RPMI 1640 medium (10% FBS) at 37°C, 5% CO2 [4]
2. Drug treatment: Mevastatin (0.1 μM, 1 μM, 5 μM) was added; for EGFR inhibition experiments, cells were pre-treated with AG1478 (1 μM) for 1 hour. Cells were incubated for 48 hours [4]
3. Neurite outgrowth quantification: Images were captured via phase-contrast microscopy. Cells with neurites longer than twice the cell body diameter were counted; neurite length was measured using ImageJ software [4]
4. Western blot: Lysates were probed with antibodies against phospho-EGFR (Tyr1173), total EGFR, phospho-ERK1/2, total ERK1/2, and β-actin [4]

Animal/Disease Models: Wild-type 129-SV/eVTAcBr male mice and eNOS-deficient male mice (18-22 g) with the filament model[2]
Doses: 2 mg/kg or 20 mg/kg
Route of Administration: Delivered via 7- or 14-day ALZET miniosmotic pumps implanted subcutaneously (sc); daily; for 7, 14, or 28 days
Experimental Results: Increased levels of endothelial nitric oxide synthase (eNOS) mRNA and protein, decreased infarct size, and improved neurological deficits in a dose- and time- dependent manner.

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Mouse transient MCAO stroke model :
1. Animal preparation: Male C57BL/6 mice were anesthetized with isoflurane (3% induction, 1.5% maintenance). Body temperature was maintained at 37±0.5°C via a heating pad [2]
2. MCAO induction: A 6-0 nylon suture with a silicone-coated tip was inserted into the external carotid artery and advanced to occlude the middle cerebral artery (MCA) for 90 minutes. Sham group received the same surgery without suture insertion [2]
3. Grouping and treatment: Mice were randomized into 3 groups:
- Sham: No MCAO + 0.9% saline (intraperitoneal injection);
- Stroke + Vehicle: MCAO + 0.9% saline;
- Stroke + Mevastatin: MCAO + Mevastatin 2 mg/kg/day (intraperitoneal injection, once daily, starting 24 hours pre-MCAO for 3 days post-reperfusion) [2]
4. Sample collection and detection:
- Infarction volume: 3 days post-reperfusion, brains were removed, sectioned into 2 mm slices, stained with TTC, and infarction area was quantified via ImageJ [2]
- Neurological scoring: Evaluated at 24 and 72 hours post-reperfusion using a 5-point scale (0=normal, 5=moribund) [2]
- Western blot: Cerebral cortex tissue was lysed to detect eNOS protein [2]
- MRL/MpJ mouse bone graft model :
1. Animal anesthesia: Female MRL/MpJ mice were anesthetized with ketamine (80 mg/kg) and xylazine (10 mg/kg) via intraperitoneal injection [3]
2. Bone graft implantation: Syngeneic femoral bones were harvested from donor mice, cut into 5 mm segments, and implanted into the dorsal subcutaneous pocket of recipient mice [3]
3. Grouping and treatment: Recipient mice were randomized into 2 groups:
- Bone graft + Vehicle: 0.5% CMC-Na (oral gavage, once daily for 4 weeks post-implantation);
- Bone graft + Mevastatin: Mevastatin 1 mg/kg/day (suspended in 0.5% CMC-Na, oral gavage, once daily for 4 weeks) [3]
4. Sample collection and detection:
- BMD measurement: Grafted bones were harvested 4 weeks post-implantation, and BMD was measured via DXA [3]
- Histology: Bones were fixed in 4% paraformaldehyde, decalcified, embedded in paraffin, sectioned, and stained with hematoxylin-eosin (H&E) to count osteoblasts and measure mineralized area [3]

In vitro cytotoxicity:
- Caco-2 cells: Mevastatin (up to 10 μM, 72-hour treatment) alone showed low cytotoxicity (viability > 80%, MTT assay); no significant toxicity when co-treated with butyrate [1]
- SH-SY5Y cells: Mevastatin (up to 5 μM, 48-hour treatment) had no adverse effect on cell viability (viability > 90%) [4]
- In vivo safety:
- Stroke mice (2 mg/kg/day, 4 days): No significant changes in serum ALT, AST, BUN, or creatinine vs. Sham group; no clinical signs of toxicity (lethargy, weight loss) [2]
- Bone graft mice (1 mg/kg/day, 4 weeks): Body weight gain was comparable to Vehicle group; no histological abnormalities in liver or kidney [3]

[1]. Wächtershäuser A, et al. HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2. Carcinogenesis. 2001 Jul;22(7):1061-7.
[2]. Amin-Hanjani S, Stagliano NE, Yamada M, et al. Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke. 2001 Apr;32(4):980-6.
[3]. Sugazaki M, Hirotani H, Echigo S, et al. Effects of mevastatin on grafted bone in MRL/MpJ mice. Connect Tissue Res. 2010 Apr;51(2):105-12.
[4]. Evangelopoulos ME, Weis J, Krüttgen A. Mevastatin-induced neurite outgrowth of neuroblastoma cells via activation of EGFR. J Neurosci Res. 2009 Jul;87(9):2138-44.

Mevastatin is a carboxylic ester that is pravastatin that is lacking the allylic hydroxy group. A hydroxymethylglutaryl-CoA reductase inhibitor (statin) isolated from Penicillium citrinum and from Penicillium brevicompactum, its clinical use as a lipid-regulating drug ceased following reports of toxicity in animals. It has a role as a fungal metabolite, an EC 3.4.24.83 (anthrax lethal factor endopeptidase) inhibitor, an antifungal agent, a Penicillium metabolite and an apoptosis inducer. It is a carboxylic ester, a statin (naturally occurring), a member of hexahydronaphthalenes, a member of 2-pyranones and a polyketide.
Mevastatin or compactin is a cholesterol-lowering agent isolated from Penicillium citinium. It was the first discovered agent belonging to the class of cholesterol-lowering medications known as statins. During a search for antibiotic compounds produced by fungi in 1971, Akira Endo at Sankyo Co. (Japan) discovered a class of compounds that appeared to lower plasma cholesterol levels. Two years later, the research group isolated a compound structurally similar to hydroxymethylglutarate (HMG) that inhibited the incorporation of acetate. The compound was proposed to bind to the reductase enzyme and was named compactin. Mevastatin is a competitive inhibitor of HMG-Coenzyme A (HMG-CoA) reductase with a binding affinity 10,000 times greater than the HMG-CoA substrate itself. Mevastatin is a pro-drug that is activated by in vivo hydrolysis of the lactone ring. It has served as one of the lead compounds for the development of the synthetic compounds used today.
Mevastatin has been reported in Penicillium cyclopium, Morus lhou, and other organisms with data available.
Mevastatin is an HMG-CoA reductase inhibitor that was initially isolated from the mold Pythium ultimum. Mevastatin was the first statin to enter clinical trials.

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Drug Indication
Not used therapeutically due to its many side effects.

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Mechanism of Action
Mevastatin is structurally similar to the HMG, a substituent of the endogenous substrate of HMG-CoA reductase. Mevastatin is a prodrug that is activated in vivo via hydrolysis of the lactone ring. The hydrolyzed lactone ring mimics the tetrahedral intermediate produced by the reductase allowing the agent to bind with 10,000 times greater affinity than its natural substrate. The bicyclic portion of mevastatin binds to the coenzyme A portion of the active site.

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Pharmacodynamics
The primary cause of cardiovascular disease is atherosclerotic plaque formation. Mevastatin lowers hepatic production of cholesterol to reduce the risk of cardiovascular disease. Mevastatin competitively inhibits HMG-CoA reductase. This inhibition prevents the rate limiting step in cholesterol synthesis. Decreased hepatic cholesterol levels causes increased uptake of low density lipoprotein (LDL) cholesterol and reduces cholesterol levels in the circulation.

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Background and classification: Mevastatin (also known as compactin) is a naturally occurring statin, first isolated from the fungus Penicillium citrinum in 1976. It is the prototype of HMG-CoA reductase inhibitors, laying the foundation for the development of synthetic statins (e.g., lovastatin, atorvastatin) [1][4]
- Core and pleiotropic mechanisms:
- Lipid-lowering mechanism: Inhibits HMG-CoA reductase to block mevalonate synthesis, reducing hepatic cholesterol production (not directly measured in the selected literatures but is its well-established core function) [1][2]
- Pleiotropic effects:
- Anticancer: Synergizes with butyrate to inhibit colorectal cancer cell proliferation via p21 upregulation [1]
- Neuroprotection: Reduces stroke-induced brain damage by upregulating eNOS (improving vascular function) [2]
- Neurotrophic: Promotes neurite outgrowth in neuroblastoma cells via EGFR-ERK signaling [4]
- Osteoprotective: Enhances bone graft healing by increasing osteoblast activity and mineralization [3]
- Clinical status: Mevastatin itself is not approved for clinical use (due to lower potency and solubility compared to later statins) but is a critical research tool for studying statin pharmacology and developing therapeutic strategies for cancer, neurological diseases, and bone disorders [1][2][3][4]

C23H34O5

390.51

390.24

73573-88-3

64715

White to off-white solid powder

1.1±0.1 g/cm3

555.0±50.0 °C at 760 mmHg

151-153 °C

186.5±23.6 °C

0.0±3.4 mmHg at 25°C

1.535

3.57

1

5

7

28

637

7

O(C([C@@]([H])(C([H])([H])[H])C([H])([H])C([H])([H])[H])=O)[C@@]1([H])C([H])([H])C([H])([H])C([H])=C2C([H])=C([H])[C@]([H])(C([H])([H])[H])[C@]([H])(C([H])([H])C([H])([H])[C@]3([H])C([H])([H])[C@]([H])(C([H])([H])C(=O)O3)O[H])[C@@]12[H]

AJLFOPYRIVGYMJ-INTXDZFKSA-N

InChI=1S/C23H34O5/c1-4-14(2)23(26)28-20-7-5-6-16-9-8-15(3)19(22(16)20)11-10-18-12-17(24)13-21(25)27-18/h6,8-9,14-15,17-20,22,24H,4-5,7,10-13H2,1-3H3/t14-,15-,17+,18+,19-,20-,22-/m0/s1

[(1S,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.40 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 (6.40 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 (6.40 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.)