| Field | Specification |
|---|---|
| Target | |
| Alternative names | (+)-Largazole |
| CAS no. | |
| Applications | |
| Source | Microbial — Floridian Marine Cyanobacterium Symploca sp. |
| Molecular weight | |
| Molecular formula | C29H42N4O5S3 |
| SMILES | |
| Storage | |
| Shipping | |
| Catalog no. (Mfr.) | |
| Main SKU |
Compound Overview
Largazole, also known as (+)-Largazole, is an orally active, blood-brain barrier-permeable inhibitor of class I histone deacetylases (HDACs), showing anticancer activity and osteogenic efficacy in vivo. Functioning as a prodrug, it is hydrolyzed to Largazole thiol, which inhibits human HDAC2 with a Ki of 0.07 nM. The compound regulates the cell cycle, triggers apoptosis, raises expression of tumor suppressors and osteoblast differentiation markers, suppresses osteoclast formation, and increases expression of neuroprotection-related genes; it can be used in research on various cancers, including colorectal cancer, as well as neurodegenerative diseases[1][2][3][4]. It has the molecular formula C29H42N4O5S3 and a molecular weight of 622.86 g/mol.
Physical & Chemical Properties
| CAS Number | 1009815-87-5 |
|---|---|
| Molecular Formula | C29H42N4O5S3 |
| Molecular Weight | 622.86 g/mol |
| Structure Classification | Others |
| SMILES | CCCCCCCC(SCC/C=C/[C@H](CC(NC1)=O)OC([C@H](C(C)C)NC([C@]2(C)CSC(C3=CSC1=N3)=N2)=O)=O)=O |
| Target | HDAC-2 |
| Signaling Pathway | Cell Cycle/DNA Damage; Epigenetics; TGF-beta/Smad; Stem Cell/Wnt; Apoptosis |
| Initial Source | Microbial — Floridian Marine Cyanobacterium Symploca sp. |
| Storage | Please store the product under the recommended conditions in the Certificate of Analysis. |
| Shipping | Room temperature in continental US; may vary elsewhere. |
Biological Activity
IC50 & Target
|
HDAC-2 0.07 nM (IC50) |
Literature Cited
Sources cited in this description and in the In Vitro & In Vivo Data tab. Peer-reviewed publications that used this product are listed under References.
Safety
For Research Use Only. Not for use in diagnostic or therapeutic procedures, and not for human or veterinary use. Handle in accordance with your institution's chemical hygiene plan.
In Vitro
Largazole is a prodrug. Against HDAC1, its potency is approximately 10-fold lower than the potency of its active metabolite Largazole thiol, and against HDAC6 it is lower by two orders of magnitude. Human class I HDAC subtypes HDAC1, HDAC2, and HDAC3 are potently inhibited by Largazole, with Ki values of 20 nM, 21 nM, and 48 nM, respectively; purified human HDAC2 is potently inhibited by Largazole thiol, with a Ki value of 0.07 nM[1][2][3]. In HCT116 colon cancer cells, Largazole induces acetylation of histone H3 (Lys9/14) at nanomolar low concentrations, yet the acetylation level of α-tubulin (Lys40) is left unaltered, even at concentrations as high as 10 μM; this reflects the selective inhibitory activity of Largazole toward class I HDACs[1]. Largazole upregulates Runx2 and BMPs to induce osteoblast differentiation in a dose-dependent manner and also inhibits osteoclast formation, displaying dual activities of stimulating bone formation and suppressing bone resorption[1]. In SF-268 glioblastoma cells, the expression level of the BDNF gene is increased 1.4-fold by Largazole (0.3 μM; 12 h)[2]. Nanomolar concentrations of Largazole inhibit the growth of various cancer cell lines, whereas inhibitory activity against non-transformed epithelial cells and fibroblasts is significantly lower, which demonstrates selective targeting of transformed cells[1]. Proliferation of SF-268 and SF-295 glioblastoma (GBM) cells is potently inhibited by Largazole (incubated for 48 h), with IC50 values of 62 nM and 68 nM, respectively; proliferation of SH-SY5Y neuroblastoma cells is also potently inhibited, with an IC50 value of 102 nM[2]. Growth of transformed human MDA-MB-231, U2OS, HT29, and IMR-32 cells is potently inhibited by Largazole (GI50 values 7.7 nM, 55 nM, 12 nM, and 16 nM, respectively), and the compound exhibits selective activity relative to untransformed NMuMG and NIH3T3 cells; proliferation of cultured human malignant melanoma cell lines in vitro is also potently inhibited[3][4]. Cell cycle arrest (G1 phase arrest at 3 nM, G2/M phase arrest at concentrations >30 nM) and apoptosis at concentrations >30 nM are induced by Largazole in HCT116 colon cancer cells and NB4 leukemia cells, through regulation of cell cycle inhibitors, as well as CDKs/cyclins and pro-apoptotic BCL2 family proteins[1].
Real Time qPCR[2]
| Cell Line | SF-295 glioblastoma multiforme (GBM) cells |
|---|---|
| Concentration | 0.3 μM |
| Incubation Time | 12 h |
| Result | Increased BDNF gene expression by 1.4-fold. |
In Vivo
In HCT116 colon cancer xenografts, Largazole (i.p.) shows in vivo anticancer activity by downregulating IRS-1 and compromising IGF signaling, with no acute toxicity observed[1]. Delivered locally by collagen sponge implantation, Largazole induces in vivo woven bone formation in a mouse calvarial model of bone formation[1]. In a rabbit calvarial model, local application of Largazole with MBCPs enhances in vivo bone fracture healing and promotes direct contact bone formation[1]. In healthy mice, Largazole (5-200 mg/kg; i.p.; p.o.; single dose; daily for 4 consecutive days) crosses the blood-brain barrier and reaches therapeutically relevant brain concentrations of its active form Largazole thiol. It also upregulates neuroprotective genes including Bdnf, Pax6, and Oprm1, is predicted to benefit nervous system function, and shows low acute and repeated-dose toxicity[2].
| Animal Model | non-tumor bearing[2] |
|---|---|
| Dosage | 5 mg/kg (single i.p.); 10 mg/kg (single i.p.); 50 mg/kg (single i.p.); 50 mg/kg (single p.o.); 60 mg/kg (daily i.p.); 75 mg/kg (daily i.p.); 200 mg/kg (single i.p.) |
| Administration | i.p.; single dose; daily; 4 consecutive days; p.o. |
| Result | Induced slight brain histone hyperacetylation after 4 hours at 5 mg/kg single i.p. Induced pronounced brain histone hyperacetylation after 4 hours at 50 mg/kg single i.p. Resulted in brain largazole thiol concentrations of ~300 nM after 4 hours, decreasing to ~80 nM after 24 hours at 50 mg/kg single i.p. Resulted in brain largazole thiol concentrations near the in vitro GBM IC50 after 4 hours at 10 mg/kg single i.p. or 50 mg/kg single p.o. Resulted in a 3.3-fold increase in brain Bdnf gene expression 12 hours post-administration at 50 mg/kg single i.p. Identified 1220 differentially expressed genes (≥2.5-fold change, p < 0.05), including a 3.0-fold increase in Pax6 and 4.6-fold increase in Oprm1 gene expression after single i.p. dose of 50 mg/kg. Predicted increased activation of nervous system functions (including neurogenesis, neuron development, neurite growth, cognition, and learning) and decreased activation of neurological diseases (including movement disorders, seizure disorders, ataxia, and congenital brain malformations) after single i.p. dose of 50 mg/kg. Was well tolerated at single i.p. doses up to 200 mg/kg. Caused no toxicity with repeated i.p. dosing of 60 mg/kg or 75 mg/kg for 4 consecutive days. |
Data provided by the manufacturer. Numbered citations refer to the Literature Cited list in the product description.
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