Ferroptosis-IN-1

Ferroptosis-IN-1, a diterpene derived from A. campylantha, functions as a ferroptosis inhibitor with an EC50 of 10 μM and is utilized in the study of neuroinflammatory diseases [1].

Ferroptosis-IN-12 (Cpd-A1) is an inhibitor of ferroptosis. It effectively suppresses ferroptosis in mouse renal tubular epithelial cells (mTECs) treated with Erastin and improves renal function in dose-dependent manners in mouse models of acute kidney injury (AKI) induced by ischemia reperfusion (I R) or cecal ligation and puncture (CLP). This compound also reduces renal tubular damage and eliminates inflammation. Exhibiting good plasma stability and high distribution in renal tissues during pharmacokinetic studies in mice, Ferroptosis-IN-12 shows promising potential for research in the field of AKI.

Ferroptosis-IN-14 (compund 36) exhibits the most potent anti-ferroptotic activity with an EC50 value of 0.58 ± 0.02 μM, demonstrating excellent anti-ferroptotic efficacy, as well as stability in microsomes and plasma.

Ferroptosis-IN-15 (compound 12) serves as an effective inhibitor of ferroptosis, exhibiting EC50 values of 0.76 μM and 0.67 μM in A375 cells and 786-O cells, respectively. It acts as a potential iron chelator and radical-scavenging antioxidant.

Ferroptosis-IN-16 (Compound 13l) acts as a specific inhibitor of ferroptosis, demonstrating EC50 values of 0.7 nM in ES-2 cells and 0.9 nM in LX-2 cells. It effectively alleviates acute liver injury induced by Acetaminophen in mouse models and shows excellent metabolic stability in mouse liver microsomes.

Ferroptosis-IN-17 (Compound 18) is an inhibitor of ferroptosis with an EC50 value of 0.57 μM. It effectively reduces the accumulation of intracellular ferrous ions and lipid peroxidation while restoring levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4). In rat plasma, Ferroptosis-IN-17 demonstrates good solubility and notable metabolic stability. This compound holds potential for research in tumor suppression, neurodegenerative diseases, and cardiovascular disorders.

Ferroptosis-IN-11 (compound 43) is an inhibitor of ferroptosis, effectively suppressing Erastin-induced ferroptosis in HT-1080 human fibrosarcoma cells (EC50=36 nM). This compound is applicable in research related to cardiovascular diseases and neurodegeneration.

Ferroptosis-IN-10 (compound D1) is an inhibitor of ferroptosis, demonstrating a potent IC50 value of 22 nM. It exhibits neuroprotective activity in the oxygen-glucose deprivation reoxygenation (OGD R) model.

Arvanil (N-Vanillylarachidonamide) is a synthetic capsaicin-amphetamine hybrid and a ligand for vanilloid receptor 1 (VR1) and cannabinoid receptor 1 (CB1), exhibiting neuroprotective activity, inhibiting spasm, and enhancing cisplatin chemotherapy sensitivity by inducing ferroptosis in HCC cells in vivo. It induces ferroptosis in liver cancer cells via binding to MICU1.

iFSP1, a potent, selective, and glutathione-independent ferroptosis suppressor protein 1 (FSP1) (AIFM2) inhibitor with an EC50 of 103 nM, sensitizes diverse human cancer cell lines to ferroptosis inducers like (1S,3R)-RSL3. It uniquely triggers ferroptosis in GPX4-knockout cells overexpressing FSP1.

CIL56 (CA3) is a small molecule that induces cellular ferroptosis through the production of iron-dependent reactive oxygen species (ROS). It also induces accumulation of long-chain saturated, monounsaturated, and polyunsaturated fatty acids in HT-1080 cells in vitro.HT-1080 cells lacking acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in fatty acid synthesis, exhibit 5-fold resistance to CIL56 treatment, indicating ACC1 activity sensitizes cells to CIL56-induced cell death.

HDAC-IN-77 (HL-5s), an HDAC inhibitor, has the capability to induce ferroptosis and suppress the Nrf2 HO-1 signaling pathway. This compound is utilized in cancer research.

TOFA-Plasmalogen (compound 1), a derivative of glyceraldehyde, exhibits ferroptosis-inducing properties. This compound promotes lipid peroxidation in cell membranes, leading to cytotoxic effects with an inhibition concentration (IC 50 = 32.87 μM).

GPX4-IN-13 (compound 16), a GPX4 inhibitor, exhibits anticancer properties by diminishing the expression of GPX4, thereby reducing thyroid cell proliferation and inducing ferroptosis. Additionally, this compound effectively inhibits the growth of three distinct thyroid cancer cell lines: N-thy-ori-3-1 (IC 50 =8.39 μM), MDA-T32 (IC 50 =10.28 μM), and MDA-T41 (IC 50 =8.18 μM).

Cetzole (Compound 1) acts as an inducer of ferroptosis (iron-dependent cell death) through the accumulation of ROS, leading to cell death. The compound exhibits varying half-maximal cytotoxic concentrations (CC50) against several cell lines: 2.56 μM in NCI-H522, 10.31 μM in NCI-H522 GFP-SCL7A11 #8, 2.71 μM in NCI-H522 RV-GFP, 3.07 μM in HT-1080, 14.9 μM in NARF2, and 6.28 μM in MDA-MB-231. This highlights Cetzole's potential for research in cancer therapeutics.

Ferrostatin-1 diyne (Fer-1 diyne) (compound 2) serves as an inhibitor of ferroptosis, accumulating in cellular lysosomes, mitochondria, and the endoplasmic reticulum. It notably inhibits ferroptosis independently of lysosomal and mitochondrial activity.

NYY-6a is a ferroptosis (Ferroptosis) inhibitor, demonstrating significant suppression of RSL3-induced ferroptosis in 786-O and HT-1080 cells, with EC50 values of 52 nM and 50 nM, respectively. As a radical-trapping antioxidant (RTA), NYY-6a effectively reduces lipid peroxidation, comparable to ferrostatin-1 and liproxstatin-1, making it useful for research into ferroptosis-related pathologies.

TrxR EGFR-IN-1 (Compound L1Au2) is a TrxR EGFR inhibitor with activity against both gefitinib-sensitive and -resistant lung cancer, effectively suppressing tumor proliferation and promoting apoptosis. It enhances GPX4 degradation through autophagosome-lysosome and proteasome pathways, leading to ferroptosis. Additionally, it induces endoplasmic reticulum stress and triggers immunogenic cell death, making it applicable for studies on gefitinib-resistant lung cancer.

Erastin2 is a ferroptosis inducer and inhibitor of the system xc- cystine glutamate transporter.[1][2] It inhibits glutamate release in CCF-STTG1 cells (IC50 = 0.0035 µM) and induces cell death in HAP1 cells at 5 µM, an effect blocked by ferrostatin-1 or deferoxamine.[1][2] Erastin2 also induces ferroptotic cell death in HT-1080 cells (EC50 = 0.15 µM), an effect blocked by β-mercaptoethanol (EC50 > 20 µM).[3] Additionally, it increases lipid peroxidation in HT-1080 cells at 1 µM.

1(R)-(Trifluoromethyl)oleyl alcohol is an analog of oleic acid .1It inhibits ferroptosis induced by erastin in primary fibroblasts isolated from patients with Friedreich ataxia, a neuro- and cardiodegenerative disorder characterized by loss or impaired activity of frataxin (FXN), when used at concentrations of 5, 10, or 20 μM. 1(R)-(Trifluoromethyl)oleyl alcohol (5 μM) reduces lipid peroxidation induced byFXNsiRNA knockdown in NBT human myoblasts. 1.Cotticelli, M.G., Forestieri, R., Xia, S., et al.Identification of a novel oleic acid analog with protective effects in multiple cellular models of Friedreich ataxiaACS Chem. Neurosci.11(17)2535-2542(2020)

RC363 is an inhibitor of ferroptosis and a derivative of the antioxidant and hypocholesterolemic agent probucol .1It reduces 2,2-diphenyl-1-picrylhydrazyl radicals by approximately 40% in a cell-free assay when used at a concentration of 25 μM. RC363 prevents glutamate-induced toxicity in HT22 cultured hippocampal cells (IC50= 234.5 nM) but does not reduce oxidant levels in these cells. It increases the levels of glutathione peroxidase 1 (GPX1) and the activity of GPX in glutamate-challenged HT22 cells when used at a concentration of 3 μM. RC363 inhibits ferroptosis induced by the GPX4 inhibitor RSL3 in HT22 cells (IC50= 173.6 nM). 1.Bueno, D.C., Canto, R.F.S., de Souza, V., et al.New probucol analogues inhibit ferroptosis, improve mitochondrial parameters, and induce glutathione peroxidase in HT22 cellsMol. Neurobiol.57(8)3273-3290(2020)

RC574 is an inhibitor of ferroptosis and a derivative of the antioxidant and hypocholesterolemic agent probucol .1It inhibits glutamate-induced cell death in HT22 cells (IC50= 276.2 nM) and mouse primary cortical neurons when used at a concentration of 3 μM. RC574 (3 μM) increases glutathione peroxidase 1 (GPX1) levels and GPX activity, as well as inhibits glutamate-induced mitochondrial superoxide anion production, in HT22 cells. It completely inhibits ferroptosis induced by the GPX4 inhibitor RSL3 in HT22 cells when used at concentrations ranging from 62.5 to 1,000 nM. 1.Bueno, D.C., Canto, R.F.S., de Souza, V., et al.New probucol analogues inhibit ferroptosis, improve mitochondrial parameters, and induce glutathione peroxidase in HT22 cellsMol. Neurobiol.57(8)3273-3290(2020)

DTUN is a lipophilic hyponitrite radical initiator.1It initiates co-autoxidation of STY-BODIPY-embedded egg phosphatidylcholine liposomes when used at a concentration of 0.2 mM. DTUN has been used in fluorescence-enabled inhibited autoxidation (FENIX) assays for the development of ferroptosis inhibitors and the study of antioxidants in lipid membranes.1,2 1.Shah, R., Farmer, L.A., Zilka, O., et al.Beyond DPPH: Use of fluorescence-enabled inhibited autoxidation to predict oxidative cell death rescueCell Chem. Biol.26(11)1594-1607(2019) 2.Soula, M., Weber, R.A., Zilka, O., et al.Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducersNat. Chem. Biol.16(12)1351-1360(2020)

CAY10773 is a derivative of the ferroptosis inducer sorafenib .1It selectively inhibits proliferation of BEL-7402, MGC803, and T24 bladder cancer cells (IC50s = 5.77, 5.21 and 3.97 μM, respectively) over non-cancerous HCV-29 cells (IC50= 23.19 μM). CAY10773 induces apoptosis in T24 cells when used at concentrations ranging from 2 to 6 μM but induces ferroptosis at concentrations greater than or equal to 6 μM with 10 hour or longer incubation times. It increases the production of reactive oxygen species (ROS) and decreases the mitochondrial membrane potential in T24 cells. CAY10773 (≥6 μM) also induces autophagy with incubation times longer than eight hours. 1.Chen, J.-N., Li, T., Cheng, L., et al.Synthesis and in vitro anti-bladder cancer activity evaluation of quinazolinyl-arylurea derivativesEur. J. Med. Chem.205112661(2020)