hHDAC3 ( IC50 = 157 nM ); hHDAC1 ( IC50 = 198 nM ); hHDAC11 ( IC50 = 292 nM ); hHDAC6 ( IC50 = 315 nM ); hHDAC2 ( IC50 = 325 nM ); hHDAC10 ( IC50 = 340 nM ); hHDAC7 ( IC50 = 524 nM ); hHDAC5 ( IC50 = 532 nM ); hHDAC9 ( IC50 = 541 nM ); hHDAC8 ( IC50 = 854 nM ); hHDAC4 ( IC50 = 1059 nM ); HD1-B ( IC50 = 7.5 nM ); HD1-A ( IC50 = 16 nM ); HD2 ( IC50 = 10 nM )

体外活性：在 LPS 刺激的培养人外周血单核细胞 (PBMC) 中，ITF2357 减少 TNFα、IL-1α、IL-1β 和 IFNγ 的释放，IC50 分别为 10-25 nM。使用 IL-12 与 IL-18 的组合，ITF2357 减少 IFNγ 和 IL-6 的产生，IC50 为 12.5-25 nM，与 IL-1 或 TNFα 的减少无关。 ITF2357 在多发性骨髓瘤 (MM) 细胞系（RPMI8226、NCI-H929、JJN3、KMS 11、KMS 12、KMS 18 和 KMS 20）和急性髓性白血病 (AML) 细胞系（HL-60、THP-1）中具有细胞毒性、U937、KASUMI、KG-1 和 TF-1），IC50 为 200 nM。 ITF2357 激活内在的细胞凋亡途径，上调 p21 并下调 Bcl-2 和 Mcl-1。 ITF2357 可抑制间充质基质细胞 (MSC) 中 IL-6、VEGF 和 IFNγ 的产生 80-95%。 ITF2357 有利于炎症条件下 β 细胞的存活。浓度为 25 和 250 nM 的 ITF2357 可增加胰岛细胞活力，增强胰岛素分泌，抑制 MIP-1α 和 MIP-2 的释放，减少 NO 产生并降低细胞凋亡率。激酶测定：加入 100 μL 底物（2×105 cpm）、40 μL 缓冲液（50 mM Tris-HCl，pH 8.0，750 mM NaCl，5 mM PMSF，50% 甘油）和 95 μL 蒸馏水进行测定。粗细胞提取物（5 μL）。添加 ITF2357 (50 μL) 以测试 HDAC 抑制。将混合物在室温下孵育过夜，并通过添加 50 μL 1 mL 蒸馏水中含有 259 μL 37% HCl 和 28 μL 乙酸的溶液来淬灭反应。从底物中释放的[3H]乙酰基残基通过用600μL乙酸乙酯进行有机萃取来分离，将200μL有机相添加到标准闪烁液中，并通过β计数器测量放射性。 HDAC 的抑制表示为抑制 50% 对照活性的浓度（通过将含有抑制剂的样品的放射性与仅含有细胞粗提取物的对照的放射性进行比较）。细胞测定：洗涤后，将分离的PBMC以5×106/mL重悬于含有5%FCS的RPMI中，加入到50mL锥形聚丙烯管中，并在4℃下放置过夜。第二天早上将 PBMC 重悬并添加到 96 孔平板微量滴定板中（每孔 100 μL）。然后添加 ITF2357 进行抑制研究，并将板在 37°C 下孵育 1 小时，然后用 LPS 或其他刺激剂以每孔终体积 200 μL 刺激细胞。 37℃孵育24小时后除去上清液，并冷冻在-80℃直至测定细胞因子。

Givinostat (ITF-2357) (1-10 mg/kg) 可使小鼠 LPS 诱导的血清 TNFα 和 IFNγ 降低 50% 以上。小鼠循环中的 PBMC 中的 ITF2357 不会抑制抗 CD3 诱导的细胞因子。在刀豆蛋白 A 诱导的肝炎中，ITF2357（1 或 5 mg/kg）可显着减轻肝损伤。 ITF2357 (10 mg/kg) 显着延长接种 AML-PS 体内传代细胞系的严重联合免疫缺陷小鼠的存活时间。在闭合性头部损伤 (CHI) 小鼠模型中，ITF2357 (10 mg/kg) 可改善神经行为恢复、减少神经元变性、缩小病变体积并诱导神经胶质细胞凋亡。+

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Con A急性肝炎模型[1]
小鼠灌胃100 μL水或Givinostat (ITF-2357) (5 mg/kg)， 1 h后静脉注射ConA 200 μg/只。对照组小鼠静脉注射生理盐水。如前所述，小鼠在24小时后放血以评估血清ALT水平（33,34）。如图15所示，经ITF2357预处理后，ALT水平降低80%以上。在另一项实验中，对口服ITF2357 1和10 mg/kg进行了比较。如图16所示，通过ALT水平测量，1 mg/kg剂量的ITF2357与10 mg/kg剂量的ITF2357在减少ConA型肝炎方面同样有效。

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Givinostat (ITF-2357)可延长白血病SCID小鼠的生存期[2]
为了证明ITF2357的治疗活性，我们建立了AML的体内模型。AML- ps是一种来源于AML患者的细胞系，通过腹腔注射在SCID小鼠体内传代建立。28,29经静脉注射后，AML-PS细胞进入血液、脾脏、骨髓和肝脏，导致动物在35-40天内死亡。每组7-10只SCID小鼠静脉接种5 × 106个AML-PS细胞，4 d后每天口服不同剂量的ITF2357。记录动物的存活情况。结果表明，ITF2357在1 mg/kg剂量下无显著疗效（P=0.36），但在10 mg/kg中等剂量下有明显的治疗活性，中位生存期为46天，而对照组为40天（P=0.0057）。治疗效果在100 mg/kg时更大，中位生存时间为50天(与对照组相比P<0.0001；图7)。动物尸检和随机选择病例（CD45和CD33）的免疫表型分析显示，所有动物死于肿瘤（数据未显示）。

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Givinostat (ITF-2357)在stz诱导的β-细胞毒性小鼠模型中预防高血糖的发生并降低血清亚硝酸盐水平[3]
C57BL/6小鼠在单次注射STZ （225 mg/kg, i.p）前12和24 h口服1.25、2.5或5.0 mg/kg ITF2357或水（0.1 mL，灌胃），然后在STZ后12、24和36 h再次注射。注射STZ 48 h后，测定小鼠葡萄糖水平，葡萄糖耐量试验（GTT），采集血清亚硝酸盐水平。取脾进行离体脾细胞刺激。如图1A所示，三种口服剂量的ITF2357均可降低血糖，其中2.5 mg/kg时效果最佳（从348±64 mg/dL降至120±16 mg/dL，平均值±SE， P = 0.039）。将ITF2357剂量加倍至5 mg/kg，血糖水平降至200±37 mg/dL。

测定程序包括将粗细胞提取物 (5 μL) 与 100 μL 底物 (2×105 cpm)、40 μL 缓冲液（50 mM Tris-HCl，pH 8.0、750 mM NaCl、5 mM PMSF、50% 甘油）混合）和95μL蒸馏水。要检查 HDAC 抑制情况，请添加 50 μL ITF2357。混合物在室温下孵育整晚后，加入 50 μL 由 259 μL 37% HCl、28 μL 乙酸和 1 mL 蒸馏水组成的溶液以猝灭反应。有机萃取方法用于分离从底物中释放的[3H]乙酰基残基。将 200 μL 有机相添加到标准闪烁液中后，使用 β 计数器测量放射性。通过测量含有抑制剂的样品和仅含有细胞粗提物的对照样品的放射性差异，可以确定抑制50%对照活性的HDAC的浓度。

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玉米HDAC测定[1]
HD2， HD-1B和HD-1A从玉米中提取，用于评估Givinostat (ITF-2357)的组蛋白脱乙酰酶活性，如Koelle等人所述。

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细胞粗提物对总HDAC活性和蛋白质乙酰化的测定[1]
将人外周血单个核细胞（PBMCs）（见下文）在含有1% FCS和0.05% DMSO （vol/vol）的RPMI 1640培养基中以2.5 × 106个细胞/mL的浓度加入到50 mL的圆锥体管中，并与所述浓度的测试化合物（由0.05% DMSO组成）在37℃下孵育。60 min后，加入终浓度为10 ng/mL的LPS， 37℃孵育。孵育结束后，400g离心15 min，收集上清，- 80℃保存至测定TNFα，并用冰冷的磷酸盐缓冲液洗涤细胞2次。
将微球悬浮于200 μL改性裂解缓冲液（50 mM Tris HCl, pH 7.4, 1% NP-40, 0.25% na -脱氧胆酸盐，150 mM NaCl, 1 mM EDTA, 1 mM PMSF, 1 mM Na3VO4, 1 mM NaF）中，与可作为片剂的蛋白酶抑制剂混合，在4℃下悬浮30 min，得到粗提物。提取液在4℃下14000 rpm离心10 min澄清，上清液用于测定总HDAC活性和蛋白乙酰化。采用BCA蛋白测定试剂盒测定提取物的蛋白质含量。

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总HDAC活性测定[1]
如前所述，该分析是基于从肽底物释放的氚化乙酰基残基，内在标记为[3H]乙酸。本实验中使用的合成肽是组蛋白H4的n端序列（SGRGKGGKGLGKGGAKRHRC）。采用放射性标记法：将100 μg肽加入62.5 μL [3H]乙酸钠盐（5.0 mCi/0.5 mL乙醇，比活性5.1 Ci/mol）中。然后，加入5 μL BOP溶液（0.24 M BOP和0.2 M三甲胺乙腈）。得到的溶液在室温下轻度搅拌孵育过夜，然后将放射性标记的肽溶液上传到Microcon-SCX自旋柱上，之前用500 μL的10 mM HCl在甲醇中冲洗。用50 μL HCl 3N在50%异丙醇溶液中洗脱放射性标记肽。包含放射性标记的肽的洗脱方案提交到8个周期的有机溶剂萃取乙酸乙酯(8×1毫升)分离其余自由[3 h]醋酸。得到的水溶液在室温下真空离心干燥30 min，然后悬浮在200 μL蒸馏水中，分离成等分，在- 20℃保存。

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蛋白的乙酰化[1]
细胞粗提物的蛋白乙酰化用Western blotting测定。简单地说，将样品（200 μg/lane）通过SDS-PAGE（12.5%）分离，然后电转移到硝化纤维素膜上。膜用3%脱脂乳在磷酸盐缓冲液中饱和，并根据制造商的说明用抗乙酰赖氨酸单克隆抗体孵育。然后使用化学发光检测系统ECL Plus在x射线胶片上检测蛋白质条带。

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合成化合物抑制HDAC活性的酶促测定[1]
在细胞粗提液（5 μL）中加入100 μL底物（20万cpm）、40 μL缓冲液（50 mM Tris-HCl、pH 8.0、750 mM NaCl、5 mM PMSF、50%甘油）和95 μL蒸馏水。加入抑制HDAC的化合物（50 μL）。室温孵育过夜，在1 mL蒸馏水中加入50 μL含259 μL 37% HCl和28 μL乙酸的溶液，使反应猝灭。通过加入600 μL乙酸乙酯有机萃取分离底物释放的[3H]乙酰基残基，在标准闪烁液中加入200 μL有机相，用β -计数器测定放射性。hdac的抑制作用表现为抑制50%对照活性的浓度（通过将含有抑制剂的样品与仅含有细胞粗提物的样品的放射性进行比较）。

将分离的PBMC清洗干净，然后以5×10⁶/mL重悬于含5%FCS的RPMI中，转移至50mL锥形聚丙烯管中，并在4℃下保存过夜。前一天早上重悬后，将 100 μL PBMC 填充到 96 孔平板微量滴定板中。添加 ITF2357 后，将板在 37°C 下孵育一小时以进行抑制研究。然后用 LPS 或其他刺激剂刺激细胞，最终体积为每孔 200 μL。 37°C 孵育 24 小时后，取出上清液并冷冻于 -80°C，直至检测细胞因子。

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细胞毒性测定[2]
27 .细胞毒性试验用alamar蓝活性染料进行，基本如所述简单地说，细胞系或间充质干细胞在0.1-1 μ M Givinostat (ITF2357)或SAHA存在或不存在的情况下被镀。培养2天后，加入alamar蓝溶液。过夜孵育后，在荧光仪中读取，激发波长为535 nm，发射波长为590 nm。

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FACS分析[2]
Annexin V-PE/ 7AAD双染色，荧光活化细胞分选仪（FACS）检测细胞凋亡。根据制造商的说明和FACS分析，使用alexafluor488标记的抗裂解Caspase 3抗体测量Caspase 3的活化。为测定α-微管蛋白乙酰化程度，用Givinostat (ITF2357)或培养基处理细胞1小时，用抗微管蛋白或乙酰微管蛋白抗体渗透染色，然后用fitc标记的兔抗小鼠多克隆抗体染色。

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菌落测定[2]
将3000个MM或AML细胞加入3ml甲基纤维素中，并在55 MM培养皿中一式两份镀。37℃孵育15-21天，倒置显微镜下计数菌落。

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白血病细胞与MSCs共培养[2]
对于所有共培养，将MSCs以5000/孔的速度在96孔板中进行接种，并在37℃下孵育48-72小时以达到融合。然后将CMA-03细胞以5000/孔和AML细胞以1 × 105细胞/孔的速度加入存在或不存在MSCs或10 ng/ml rhIL-6的培养基中，并加入不同浓度的Givinostat (ITF2357), 每周更换两次。在不同的时间间隔后，收集非贴壁细胞，用碘化丙啶（5 μg/ml, Sigma）和fitc偶联的抗cd138（针对CMA-03）或抗cd33单抗（针对AML）进行染色。在流式细胞仪上分析染色细胞，以确定细胞活力和身份。台盼蓝排除法计数活细胞总数。

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免疫印迹[3]
随机选取500个胰岛，培养2-3 h，预暴露于Givinostat (ITF2357)或vehicle 1 h，加入IL-1β (160 pg/mL)和IFNγ (5 ng/mL) 6 h，然后裂解胰岛，用Bradford法测定蛋白质含量。溶菌产物受到所述凝胶电泳。

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形态学分析[3]
细胞因子处理前培养30万个INS-1细胞2 d。实验当天，更换培养液，在加入IL-1β (250 pg/mL)和IFNγ (10 ng/mL)前30分钟加入Givinostat (ITF2357)

Mice: For a minimum of five days prior to usage, C57BL/6 mice are kept in the animal facility. Givinostat (ITF2357) is injected intraperitoneally for the comparison study, and it is also given orally at a dose of 10 mg/kg. LPS from Salmonella typhimurium is administered intraperitoneally to the animals at a dose of 2.5 mg/kg one hour after the compounds are administered. Serum is collected and kept at -80°C until further examination of cytokine production, and mice are sacrificed 90 minutes after the LPS treatment.[1]

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In vivo model [2]
In vivo passaged AML-PS cells (5 × 106) were inoculated in the tail vein of 5-week-old severe combined immunodeficient (SCID) mice. Mice were randomized and divided into four groups: Vehicle (ten mice), Givinostat (ITF2357) 1 mg/kg (nine mice), ITF2357 10 mg/kg (ten mice) and ITF2357 100 mg/kg (seven mice). On the 4th day after tumor cells injection, the drug treatment was started and maintained until day 55. ITF 2357 was suspended in 5% methylcellulose and administered daily by gavage in a volume of 0.2 ml/mouse. Survival of the animals was recorded daily and necropsy was performed on all animals. The presence of CD33+ tumor cells was confirmed in several animals by immunophenotypic analysis of spleen cells.

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In Vivo STZ Model [3]
STZ was reconstituted in cold sodium-citrate buffer pH 4.3 immediately before use. Mice were injected intraperitoneally (i.p.) with STZ (225 mg/kg). Givinostat (ITF2357) (1.25, 2.5 and 5 mg/kg) or water (vehicle) was administered by gavage (0.1 mL), 12 h and 4 h prior to STZ, and every 12 h thereafter. Forty-eight h after STZ injection, β-cell function was assessed by glucose challenge and serum was collected for nitrite levels, as described below.

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Drug treatment protocol[4]
Givinostat (ITF2357) was dissolved in DMSO. Prior to use, the compound was diluted in sterile saline, heated to boiling for complete dissolution, and cooled to ∼30°C before injection. Control for these studies was 0.5% DMSO saline solution. ITF2357 solutions were freshly prepared for each experiment. To initially substantiate a functional effect of ITF2357 on neurobehavioral outcome after brain trauma, the drug was given either as pretreatment (a single injection at 30 min prior to the induction of injury) or administered following the impact. Postinjury injections were carried out at either at 1 or 24 h after trauma. In each group of mice, animals with a similar initial severity of injury (NSS at 1 h after trauma; n≥9 mice/group) were dosed i.p. with 100 μl containing either 10 mg/kg of ITF2357 or vehicle. This dose was selected in accordance with previous studies utilizing ITF2357 in mice, and no adverse effects or mortality were observed among treated mice in all experiments included in the current report.

[1]. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med. 2005 Jan-Dec;11(1-12):1-15.

[2]. The histone deacetylase inhibitor ITF2357 has anti-leukemic activity in vitro and in vivo and inhibits IL-6 and VEGF production by stromal cells. Leukemia. 2007 Sep;21(9):1892-900.

[3]. The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet β cells in vivo and in vitro. Mol Med. 2011 May-Jun;17(5-6):369-77.

[4]. Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury. FASEB J. 2009 Dec;23(12):4266-75.

Givinostat hydrochloride monohydrate is the monohydrate form of givinostat hydrochloride. It is a histone deacetylase inhibitor indicated for the treatment of Duchenne muscular dystrophy in patients 6 years of age and older. It has a role as an angiogenesis inhibitor, an anti-inflammatory agent, an antineoplastic agent, an apoptosis inducer and an EC 3.5.1.98 (histone deacetylase) inhibitor. It contains a givinostat hydrochloride.
See also: Givinostat (annotation moved to); Givinostat hydrochloride (annotation moved to).

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We studied inhibition of histone deacetylases (HDACs), which results in the unraveling of chromatin, facilitating increased gene expression. ITF2357, an orally active, synthetic inhibitor of HDACs, was evaluated as an anti-inflammatory agent. In lipopolysaccharide (LPS)-stimulated cultured human peripheral blood mononuclear cells (PBMCs), ITF2357 reduced by 50% the release of tumor necrosis factor-alpha (TNFalpha) at 10 to 22 nM, the release of intracellular interleukin (IL)-1alpha at 12 nM, the secretion of IL-1beta at 12.5 to 25 nM, and the production of interferon-gamma (IFNgamma) at 25 nM. There was no reduction in IL-8 in these same cultures. Using the combination of IL-12 plus IL-18, IFNgamma and IL-6 production was reduced by 50% at 12.5 to 25 nM, independent of decreased IL-1 or TNFalpha. There was no evidence of cell death in LPS-stimulated PBMCs at 100 nM ITF2357, using assays for DNA degradation, annexin V, and caspase-3/7. By Northern blotting of PBMCs, there was a 50% to 90% reduction in LPS-induced steady-state levels of TNFalpha and IFNgamma mRNA but no effect on IL-1beta or IL-8 levels. Real-time PCR confirmed the reduction in TNFalpha RNA by ITF2357. Oral administration of 1.0 to 10 mg/kg ITF2357 to mice reduced LPS-induced serum TNFalpha and IFNgamma by more than 50%. Anti-CD3-induced cytokines were not suppressed by ITF2357 in PBMCs either in vitro or in the circulation in mice. In concanavalin-A-induced hepatitis, 1 or 5 mg/kg of oral ITF2357 significantly reduced liver damage. Thus, low, nonapoptotic concentrations of the HDAC inhibitor ITF2357 reduce pro-inflammatory cytokine production in primary cells in vitro and exhibit anti-inflammatory effects in vivo.[1]

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We have investigated the activity of ITF2357, a novel hydroxamate histone deacetylase inhibitor, on multiple myeloma (MM) and acute myelogenous leukemia (AML) cells in vitro and in vivo. ITF2357 induced apoptosis in 8/9 MM and 6/7 AML cell lines, as well as 4/4 MM and 18/20 AML freshly isolated cases, with a mean IC(50) of 0.2 microM. ITF2357 activated the intrinsic apoptotic pathway, upregulated p21 and downmodulated Bcl-2 and Mcl-1. The drug induced hyperacetylation of histone H3, H4 and tubulin. When studied in more physiological conditions, ITF2357 was still strongly cytotoxic for the interleukin-6 (IL-6)-dependent MM cell line CMA-03, or for AML samples maximally stimulated by co-culture on mesenchymal stromal cells (MSCs), but not for the MSCs themselves. Interestingly, ITF2357 inhibited the production of IL-6, vascular endothelial growth factor (VEGF) and interferon-gamma by MSCs by 80-95%. Finally, the drug significantly prolonged survival of severe combined immunodeficient mice inoculated with the AML-PS in vivo passaged cell line already at the 10 mg/kg oral dose. These data demonstrate that ITF2357 has potent anti-neoplastic activity in vitro and in vivo through direct induction of leukemic cell apoptosis. Furthermore, the drug inhibits production of growth and angiogenic factors by bone marrow stromal cells, in particular IL-6 and VEGF.[2]

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In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1β (IL-1β), IL-12, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ); each contribute to β-cell destruction, mediated in part by nitric oxide. Inhibitors of histone deacetylases (HDAC) are used commonly in humans but also possess antiinflammatory and cytokine-suppressing properties. Here we show that oral administration of the HDAC inhibitor ITF2357 to mice normalized streptozotocin (STZ)-induced hyperglycemia at the clinically relevant doses of 1.25-2.5 mg/kg. Serum nitrite levels returned to nondiabetic values, islet function improved and glucose clearance increased from 14% (STZ) to 50% (STZ + ITF2357). In vitro, at 25 and 250 nmol/L, ITF2357 increased islet cell viability, enhanced insulin secretion, inhibited MIP-1α and MIP-2 release, reduced nitric oxide production and decreased apoptosis rates from 14.3% (vehicle) to 2.6% (ITF2357). Inducible nitric oxide synthase (iNOS) levels decreased in association with reduced islet-derived nitrite levels. In peritoneal macrophages and splenocytes, ITF2357 inhibited the production of nitrite, as well as that of TNFα and IFNγ at an IC(50) of 25-50 nmol/L. In the insulin-producing INS cells challenged with the combination of IL-1β plus IFNγ, apoptosis was reduced by 50% (P < 0.01). Thus at clinically relevant doses, the orally active HDAC inhibitor ITF2357 favors β-cell survival during inflammatory conditions.[3]

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Despite efforts aimed at developing novel therapeutics for traumatic brain injury (TBI), no specific pharmacological agent is currently clinically available. Here, we show that the pan-histone deacetylase (HDAC) inhibitor ITF2357, a compound shown to be safe and effective in humans, improves functional recovery and attenuates tissue damage when administered as late as 24 h postinjury. Using a well-characterized, clinically relevant mouse model of closed head injury (CHI), we demonstrate that a single dose of ITF2357 administered 24 h postinjury improves neurobehavioral recovery from d 6 up to 14 d postinjury (improved neurological score vs. vehicle; P< or =0.05), and that this functional benefit is accompanied by decreased neuronal degeneration, reduced lesion volume (22% reduction vs. vehicle; P< or =0.01), and is preceded by increased acetylated histone H3 levels and attenuation of injury-induced decreases in cytoprotective heat-shock protein 70 kDa and phosphorylated Akt. Moreover, reduced glial accumulation and activation were observed 3 d postinjury, and total p53 levels at the area of injury and caspase-3 immunoreactivity within microglia/macrophages at the trauma area were elevated, suggesting enhanced clearance of these cells via apoptosis following treatment. Hence, our findings underscore the relevance of HDAC inhibitors for ameliorating trauma-induced functional deficits and warrant consideration of applying ITF2357 for this indication.[4]

C24H27N3O4.HCL.H2O

475.97

475.187

C, 60.56; H, 6.35; Cl, 7.45; N, 8.83; O, 16.81

732302-99-7

199657-29-9 (HCl); 497833-27-9; 732302-99-7(HCl monohydrate);

9804991

White to beige solid powder

5.75

100.13

5

6

9

33

575

0

O=C(OCC1=CC=C2C=C(CN(CC)CC)C=CC2=C1)NC3=CC=C(C(NO)=O)C=C3.[H]Cl.O

FKGKZBBDJSKCIS-UHFFFAOYSA-N

InChI=1S/C24H27N3O4.ClH.H2O/c1-3-27(4-2)15-17-5-7-21-14-18(6-8-20(21)13-17)16-31-24(29)25-22-11-9-19(10-12-22)23(28)26-30;;/h5-14,30H,3-4,15-16H2,1-2H3,(H,25,29)(H,26,28);1H;1H2

[6-(diethylaminomethyl)naphthalen-2-yl]methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate;hydrate;hydrochloride

ITF 2357; ITF2357; 732302-99-7; Givinostat hydrochloride monohydrate; Givinostat Hydrochloride Hydrate; Givinostat (ITF2357); ITF2357; ITF2357 (Givinostat); (6-((diethylamino)methyl)naphthalen-2-yl)methyl (4-(hydroxycarbamoyl)phenyl)carbamate hydrochloride hydrate; DUVYZAT; ITF-2357; Givinostat; gavinostat; ITF2357 HCl; ITF2357 hydrochloride; Givinostat HCl

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.17 mg/mL (4.56 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 21.7 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.17 mg/mL (4.56 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 21.7 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.17 mg/mL (4.56 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 21.7 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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配方 4 中的溶解度: 30% propylene glycol, 5% Tween 80, 65% D5W: 30mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。