FL118 (C09-1133-779)

FL118 (10,11-(Methylenedioxy)-20(S)-camptothecin), a Camptothecin ( HY-16560 ) analogue, is a potent and orally active survivin inhibitor. FL118 binds to oncoprotein DDX5 (p68) to dephosphorylates and degrades DDX5. FL118 can be used for the research of cancer.In VitroFL118 (0-200 nM; 24, 48 and 72 h ) inhibits the cell proliferation of ES-2 and SK-O-V 3 cells. FL118 (0-100 nM; 0 and 24 h) inhibits the migration of ES-2 and SK-O-V 3 cells. FL118 (0-100 nM; 48 h) affects the expression level of cytoglobin (CYGB). FL118 (10 and 100 nM; 48 h) inhibits PI3K/AKT/mTOR signaling pathway, and affects the expression level of vimentin and E-cadherin in ovarian cancer cells. FL118 (0-100 nM; 6 and 24 h) dephosphorylates and degrades DDX5. FL118 (0-500 nM; 24, 48, 72 h) regulates survivin, McL-1, XIAP, cIAP2, c-MYc and mKras by regulating DDX5. FL118 (0-1 μM, 24 h) shows significant cytotoxic activity against the three tumor cell lines (A549, MDA-MB-231, and RM-1 cells). FL118 (0-10 nM, 48 h) increases the production of PARP cleavage, and induces apoptosis in A549. FL118 (0-10 nM, 48 h) arrests A549 cells mainly at the G2/M phase. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Western Blot AnalysisCell Line: ES-2 and SK-O-V 3 cell lines Concentration: 10 and 100 nM Incubation Time: 48 h Result: Effectively inhibited the activation of PI3K/AKT/mTOR signaling pathway in ovarian cancer cells and also inhibited the migration of ES-2 and SK-O-V 3 cells. Cell Migration AssayCell Line: ES-2 and SK-O-V 3 cell lines Concentration: 0, 10 and 100 nM Incubation Time: 0 and 24 h Result: Inhibited the migration of ES-2 and SK-O-V 3 cells dose-dependenly. RT-PCRCell Line: ES-2 and SK-O-V 3 cell lines Concentration: 0, 10 and 100 nM Incubation Time: 48 h Result: Promoted CYGB expression. Cell Proliferation AssayCell Line: ES-2 and SK-O-V 3 cell lines Concentration: 0, 1, 10, 50, 100 and 200 nM Incubation Time: 24, 48 and 72 h Result: Inhibited the cell proliferation of ES-2 and SK-O-V 3 cells time- and dose-dependently. Western Blot AnalysisCell Line: SW620 and Mia Paca-2 Concentration: 0, 10 and 100 nM Incubation Time: 6 and 24 h Result: Induced dephosphorylation of DDX5 through the ubiquitin-proteasome degradation pathway and degraded DDX5 time-dependently. Western Blot AnalysisCell Line: PDAC Panc1, CRC HCT-8, SW620, Mia Paca-2, Panc-1, HCT-8 cell lines Concentration: 0, 10, 100 and 500 nM Incubation Time: 24, 48, 72 h Result: Controled the expression of survivin, Mcl-1, XIAP, cIAP2, c-Myc and mKras by regulated/nDDX5, as an upstream master regulator in cancer development and malignant networks. Cell Cytotoxicity AssayCell Line: A549, MDA-MB-231, RM-1 Concentration: 0-1 μM Incubation Time: 24 h Result: Showed cytotoxicity in A-549 (human lung carcinoma), MDA-MB-231 (human breast carcinoma) and RM-1 (mouse prostate carcinoma), with IC 50 values of 8.94 ± 1.54/t, 24.73 ± 13.82, and 69.19 ± 8.34 nM, respectively. Apoptosis AnalysisCell Line: A549 cells Concentration: 0, 2.5, 5, 10 nM Incubation Time: 48 h Result: Resulted in the downregulation of survivin. Increased the production of PARP cleavage in a concentration-dependent manner, which is the hallmark of apoptosis. Induced apoptosis in A549. Cell Cycle AnalysisCell Line: A549 cells Concentration: 0, 2.5, 5, 10 nM Incubation Time: 48 h Result: Increased G2/M cell population in a concentration-dependent manner, and arrested A549 cells mainly at the G2/M phase.In VivoFL118 (5 and 10 mg/kg; p.o. once a week for 20 days) inhibits antitumor activity . FL118 (0-1.5 mg/kg, i.p. once every other day for five times) effectively eliminates human colon and head-and-neck tumors that acquire irinotecan or topotecan resistance. FL118 (1.5 mg/kg, i.v. once) exhibits favorable pharmacokinetics profiles. Pharmacokinetic Parameters of FL118 in female SCID mice. Sample FaDu SW620 Plasma T 1/2 (hr) 6.852 12.75 1.788 T max (hr) 0.167 0.167 0.167 C max (ng/g, mL) 115 158 43 AUC (hr*ng/g) 413 842 82 AUC ∞ (hr*ng/g) 448 897 104 AUC% Extrap (%) 7.74 6.17 21.7 Vz (g/kg) (ml/kg) 33052 30742 36849 Cl (g/hr/kg) (ml/hr/kg) 3343 1671 14287 MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Fmale BALB/c nude mice Dosage: 5 and 10 mg/kg Administration: Oral gavage; 5 mg/kg for once a week; 10 mg/kg for once a week; for 20 days Result: Showed better antitumor activity than topotecan and dose-dependenly suppressed the growth of ES-2 tumors by upregulating the expression level of CYGB. Animal Model: SCID (severe combined immunodeficiency) mice bearing human SW620 (colon) and FaDu (head-and-neck) xenograft tumors (ten-week-old, female, 20-25 g, 5 mice per cage)Dosage: 0, 0.75, 1, 1.5 mg/kg Administration: IP, once every other day for five times as one cycle (If tumors relapse, mice were treated with FL118 for second or third cycles) Result: Eliminated human xenograft tumors that acquired irinotecan or topotecan resistance, and was also effective after multiple cycles of treatment without the generation of FL118 resistance. Animal Model: SCID (severe combined immunodeficiency) mice bearing human SW620 (colon) and FaDu SCID mice bearing human SW620 (colon) and FaDu (head-and-neck) xenograft tumors (ten-week-old, female, 20-25 g, 5 mice per cage)Dosage: 1.5 mg/kg Administration: IV, once Result: Exhibited favorable pharmacokinetics profiles.Form:Solid. Specification: 0.97 Molecular Formula: C21H16N2O6 Molecular Weight: 392.36 PubChem CID: 72403 Isomeric SMILES: CC[C@@]1(C2=C(COC1=O)C(=O)N3CC4=C(C3=C2)N=C5C=C6C(=CC5=C4)OCO6)O