PNU159682
中文名称:
PNU159682
中文同义词:
拓扑异构酶抑制剂(PNU-159682);(8S,10S)-7,8,9,10-四氢-6,8,11-三羟基-8-(2-羟基乙酰基)-1-甲氧基-10-[[(1S,3R,4AS,9S,9AR,10AS)-八氢-9-甲氧基-1-甲基-1H-吡喃并[4,3:4,5]恶唑并[2,3-C][1,4]恶嗪-3-基]氧基] - 5,12-萘二酮
英文名称:
PNU-159682
英文同义词:
PNU-159682;PNU-159682 >95%;(8S,10S)-7,8,9,10-Tetrahydro-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10-[[(1S,3R,4aS,9S,9aR,10aS)-octahydro-9-methoxy-1-methyl-1H-pyrano[4,3:4,5]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy]-5,12-naphthacenedione;PNU-159682 95%;5,12-Naphthacenedione, 7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10-[[(1S,3R,4aS,9S,9aR,10aS)-octahydro-9-methoxy-1-methyl-1H-pyrano[4,3:4,5]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy]-, (8S,10S)-
CAS号:
202350-68-3
分子式:
C32H35NO13
分子量:
641.62
EINECS号:
相关类别:
医药原料药;科研原药系列;原料药【仅供科研】;细胞生物学试剂
Mol文件:
202350-68-3.mol
沸点
838.5±65.0 °C(Predicted)
密度
1.58±0.1 g/cm3(Predicted)
储存条件
Keep in dark place,Inert atmosphere,2-8°C
酸度系数(pKa)
7.34±0.60(Predicted)
生物活性
PNU-159682 是蒽环类新霉素代谢产物的代谢产物，是一种 DNA 拓扑异构酶 I (Topo I) 抑制剂，具有出色的细胞毒性。在ADC 合成中，PNU-159682 是一种比阿霉素更有效和耐受性更高的 ADC 细胞毒素 (ADC cytotoxin)。PNU-159682 可用于 EDV 纳米细胞技术，克服耐药性。
靶点
Daunorubicins/Doxorubicins
Topoisomerase I
Daunorubicins/Doxorubicins
Topoisomerase I
体外研究
PNU-159682 (0-500 nM; exposed to the compounds for 1 hour and then cultured in compound-free medium for 72 hours) has cytotoxic effects on human tumor cell lines in a sulforhodamine B assay. The IC 70 values are 0.577 nM, 0.39 nM, 0.128 nM, and 0.081 nM, 0.086 nM and 0.075 nM for HT-29, A2780, DU145, EM-2, Jurkat and CEM cells, respectively. It against human tumor cell lines with IC 70 in the ranging 68 nM-578 nM and 181 nM-1717 nM towards MMDX and doxorubicin, respectively. PNU-159682 is more potent than MMAE on NHL cell lines. In a cell viability assay, PNU-159682 is against BJAB.Luc, Granta-519, SuDHL4.Luc, and WSU-DLCL2 with IC 50 values of 0.10 nM, 0.020 nM, 0.055 nM, and 0.1 nM, respectively. While MMAE is against BJAB.Luc, Granta-519, SuDHL4.Luc, and WSU-DLCL2 with IC 50 values of 0.54 nM, 0.25 nM, 1.19 nM and 0.25 nM, respectively.PNU-159682 is thousands of times more cytotoxic than doxorubicin and can be used to develop a new class of ADCs. PNU159682 to anti-CD22 antibody (anti-CD22-NMS249) exhibits strong anti-tumor effects in vitro . Anti-CD22-NMS249 (PNU159682 to anti-CD22 antibody) is active in in vitro viability assays of NHL cell lines and is 2 to 20 fold more potent than pinatuzumab vedotin, the ADC anti-CD22-NMS249 is against BJAB.Luc, Granta-519, SuDHL4.Luc, and WSU-DLCL2 with IC 50 values of 0.058 nM, 0.030 nM, 0.0221 nM, and 0.01 nM, respectively.PNU-159682 (100 μM) weakly inhibits topoisomerase II unknotting activity. PNU-159682 shows cytotoxic effect on CAIX-expressing SKRC-52 cells with IC 50 of 25 nM.
Cell Viability Assay
Cell Line: HT-29, A2780, DU145, EM-2, Jurkat and CEM cells
Concentration: 0-500 nM
Incubation Time: Exposed to the PNU-159682 for 1 hour and then cultured in compound-free medium for 72 hours
Result: Was 2,360- to 790-fold and 6,420- to 2,100-fold more potent than MMDX and doxorubicin, respectively. Exhibited IC 70 values of PNU-159682 are in the subnanomolar range (0.07-0.58 nM) and noticeably lower than that recorded for both MMDX and doxorubicin.
Cell Line:
HT-29, A2780, DU145, EM-2, Jurkat and CEM cells
Concentration:
0-500 nM
Incubation Time:
Exposed to the PNU-159682 for 1 hour and then cultured in compound-free medium for 72 hours
Result:
Was 2,360- to 790-fold and 6,420- to 2,100-fold more potent than MMDX and doxorubicin, respectively. Exhibited IC 70 values of PNU-159682 are in the subnanomolar range (0.07-0.58 nM) and noticeably lower than that recorded for both MMDX and doxorubicin.
体内研究
PNU-159682 (single-dose; i.v.15 μg/kg) is a maximum tolerated dose in murine L1210 leukemia model. PNU-159682 shows an improved antitumor activity in vivo. The antitumor effect of PNU-159682 (increase in life span=29%) is comparable to that afforded by 90 μg/kg MMDX (increase in life=36%).PNU-159682 (i.v. 4 μg/kg; q7dx3; 40 days) has a therapeutic response in MX-1 human mammary carcinoma mice. What’s more, from day 39, four out of seven mice receiving PNU-159682 exhibits complete tumor regression.PNU-159682 is more cytotoxic than doxorubicin and can be used to develop a new class of ADCs. PNU159682 to anti-CD22 antibody (anti-CD22-NMS249) exhibits strong anti-tumor effects in vivo . ADC dose (anti-CD22-NMS249; 50 µg/m2 conjugated PNU-159682) is well tolerated in mice and results in less than 10% weight loss.In the BJAB.Luc model the efficacy of antiCD22-NMS249 (single dose; 2 mg/kg) is similar to anti-CD22-vc-MMAE. At 2 mg/kg dosage, antiCD22-NMS249 gives complete remission of the tumors (NMS249: 110-134%TGI vs. vc-MMAE: 114-143%TGI). Additionally, a single dose of antiCD22-NMS249 at 2 mg/kg results in tumor stasis for three weeks.
Animal Model: Four- to six-week-old female CD-1 athymic nude mice with MX-1 tumor fragments
Dosage: 4 μg/kg
Administration: Intravenous injection; q7dx3; 40 days
Result: Exhibited anti-cancer effects in MX-1 human mammary carcinoma xenografts to PNU-159682.
Animal Model:
Four- to six-week-old female CD-1 athymic nude mice with MX-1 tumor fragments
Dosage:
4 μg/kg
Administration:
Intravenous injection; q7dx3; 40 days
Result:
Exhibited anti-cancer effects in MX-1 human mammary carcinoma xenografts to PNU-159682.
