体外研究 (In Vitro) | HDAC-IN-31 (compound 24g) (2 μM) shows growth-inhibitory activities with the inhibition rate of 2.32%, 44.01%, 48.53%, 64.94% for TMD-8, HCT 116, A549, MDA-MB-231 cells[1]. HDAC-IN-31 (1 μM) shows selectivity with the IC50s of 84.9, 168.0, 442.7, >10000 nM for HDAC 1, HDAC 2, HDAC 3, HDAC 8, and 81.20%, 84.43%, 88.07%, 92.34%, 96.88%, 91.98% enzyme activity for HDAC4, HDAC 5,HDAC 7, HDAC9, HDAC 6, HDAC 11, respectively[1]. HDAC-IN-31 (2.5, 5, 7.5, 10 μM; 24 h) increases the expression of HDAC1, Ace-H3, Ace-H4, Cleaved PARP, Cleaved Caspase-3 in a dose-dependent manner[1]. HDAC-IN-31 (0-4 μM; 24 h)induce apoptosis and cell cycle arrests in G2/M phase in a dose-dependent manner[1].
Cell Proliferation Assay[1] Cell Line: | MDA-MB-231, A549, NCI-H460, HCT-116,SK-OV-3, HT-29, COLO 678, NCI-H441, 22Rv1, 786-O, TMD-8, DOHH-2, CCRF-CEM, SU-DHL-2, REC-1, MOLT-4, HUT-78, RS4;11 cells | Concentration: | 0-20 μM | Incubation Time: | 72 h | Result: | Showed a broad spectrum of antitumor activity with the IC50s of 2.29, 2.85, 1.58, 1.16, 3.17, 2.41, 8.02, 2.62, 1.14, 0.60, 0.31, 0.39, 0.48, 0.51, 0.33, 0.38, 0.80, 0.47 μM for MDA-MB-231, A549, NCI-H460, HCT-116, SK-OV-3, HT-29, COLO 678, NCI-H441, 22Rv1, 786-O, TMD-8, DOHH-2, CCRF-CEM, SU-DHL-2, REC-1, MOLT-4, HUT-78, RS4;11 cells, respectively. |
Western Blot Analysis[1] Cell Line: | TMD-8 cells | Concentration: | 2.5, 5, 7.5, 10 μM | Incubation Time: | 24 h | Result: | Promoted the HDAC1, HDAC2, HDAC3 substrate Ace-H3 and Ace-H4 acetylation with a dose-dependent manner. |
Apoptosis Analysis[1] Cell Line: | TMD-8 cells | Concentration: | 0.5, 1, 2, 4 μM | Incubation Time: | 24 h | Result: | Induced cell apoptosis at a concentration-dependent manner. |
Cell Cycle Analysis[1] Cell Line: | TMD-8 cells | Concentration: | 250, 500, 1000 nM | Incubation Time: | 24 h | Result: | Arrested the cell cycle at G2/M phase in a dose-dependent manner. |
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体内研究 (In Vivo) | HDAC-IN-31 (2 mg/kg for i.v.; 10, 100 mg/kg for p.o.) shows good bioavailability with a significant dose dependent manner[1]. HDAC-IN-31 (50, 100 mg/kg; p.o, daily for 21 consecutive days) shows good antitumor efficacy in a TMD-8 xenograft model without obvious toxicity[1]. Pharmacokinetic Parameters of HDAC-IN-31 in mice[1].
Parameters | Unit | 24 g (25 mg/kg) | Cmax | ng·h·mL-1 | 3100±231 | T1/2(po) | h | 4.4±0.3 | AUC0-inf(iv) | ng·h·mL-1 | 1040±142 | AUC0-inf(po) | ng·h·mL-1 | 5180±252 | MRTPO | h | 2.6±0.4 | F | % | 39.9±2.1 |
ICR mouse; 2 mg/kg for i.v.; 25 mg/kg for p.o. [1]. Pharmacokinetic Parameters of HDAC-IN-31 in tumor models[1]. Parameters | Unit | po (25 mg/kg) | po (50 mg/kg) | po (100 mg/kg) | Cmax | ng·h·mL-1 | 1700±317 | 14700±1024 | 10700±1001 | AUC0-t | ng·h·mL-1 | 1220±242 | 9710±314 | 9740±230 | AUC0-inf | ng·h·mL-1 | 1230±165 | 9730±341 | 9770±332 | MRT0-t | h | 0.750±0.043 | 0.812±0.023 | 1.43±0.56 | MRT0-inf | h | 0.805±0.086 | 0.821±0.041 | 1.51±0.32 |
Mouse; 25, 50, 100 mg/kg for p.o. [1]. Pharmacokinetic Parameters of HDAC-IN-31 in tumor models[1]. PK parameters | Unit | iv (2 mg/kg) | po (10 mg/kg) | po (100 mg/kg) | Cmax | ng·h·mL-1 | | 3960±413 | 58300±1352 | T1/2 | h | 0.427±0.016 | 1.31±0.27 | 1.63±0.52 | AUC0-inf | ng·h·mL-1 | 1250±132 | 2670±286 | 57200±1047 | MRT | h | 0.402±0.032 | 0.919±0.052 | 0.897±0.041 | CL | mL·kg·min-1 | 27.2±1.2 | | | F | % | | 45.6±1.2 | 91.8±2.3 |
ICR mice; 2 mg/kg for i.v.; 10, 100 mg/kg for p.o. [1]. Pharmacokinetic Parameters of HDAC-IN-31 in tumor models[1]. PK parameters | Unit | Monkey | Dog | | | iv (1 mg/kg) | po (10 mg/kg) | iv (1 mg/kg) | po (10 mg/kg) | Cmax | ng·h·mL-1 | | 8520±301 | | 4740±243 | T1/2 | h | 4.31±0.56 | 9.14±0.32 | 1.65±0.41 | 1.51±0.33 | AUC0-inf | ng·h·mL-1 | 15700±1842 | 53200±1241 | 2550±365 | 15100±2004 | MRT | h | 3.41±0.12 | 8.28±0.32 | 2.26±0.41 | 2.71±0.32 | CL | mL·kg·min-1 | 1.35±0.21 | | 6.72±0.35 | | Vdss | L·kg-1 | 0.34±0.22 | | 0.55±0.04 | | F | % | | 27.6±2.1 | | 58.9±1.2 |
Dogs and monkeys; 1 mg/kg for i.v., 10 mg/kg for p.o. for monkey; 1 mg/kg for i.v., 10 mg/kg for p.o. for dog [1].
Animal Model: | ICR mice[1] | Dosage: | 2 mg/kg for i.v.; 25 mg/kg for p.o.(DMSO/PEG200/saline = 20:20:60, v/v/v) | Administration: | I.v. or p.o. | Result: | Showed high oral bioavailability (F=40%). |
Animal Model: | Mouse[1] | Dosage: | 25, 50, 100 mg/kg | Administration: | P.o. | Result: | Did not exhibit a significant dose dependent for oral administration. |
Animal Model: | ICR mice[1] | Dosage: | 2, 10, 100 mg/kg (into the form of hydrochloride) | Administration: | 2 mg/kg for i.v.; 10, 100 mg/kg for p.o. | Result: | Showed good bioavailability with a significant dose dependent. |
Animal Model: | Dogs and monkeys[1] | Dosage: | 1, 10 mg/kg | Administration: | 1 mg/kg for i.v.; 10 mg/kg for p.o. | Result: | Showed good pharmacokinetic characteristics for different species. |
Animal Model: | 5-6 weeks, female CB.17 SCID mice (TMD-8 tumor xenografts)[1] | Dosage: | 50, 100 mg/kg | Administration: | P.o, daily for 21 consecutive days | Result: | Inhibited the tumor growth with the inhibition rate of 77% and had no significant effect on the internal organs of mice at 100 mg/kg/d. |
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