Sapacitabine (CS682; CYC682)   中文名称: 沙帕他滨

nucleoside analog

达到IC50所需的沙帕他滨的量各不相同，范围从结肠癌细胞系HCT116的3±0.6μM到乳腺癌细胞系MDA-MB-435的67±14μM。根据细胞周期分析，用沙帕他滨处理的细胞有41%被阻滞在G₂/M期，35%被阻滞在晚期S期。沙帕西他滨 (IC50 = 20±6 μM) 对表达脱氧胞苷激酶 (dCK) 的 L1210 细胞敏感。当在两种细胞系中先于沙帕西他滨施用多西紫杉醇时，两种药物的组合会产生协同效应（CI<1）[1]。

第 14 天时，沙帕他滨 (5 mg/kg) 加伏立诺他 (33 mg/kg) 治疗组的平均肿瘤体积为 245 mm³，肿瘤生长抑制 (TGI) 为 92% ，而沙帕西他滨 (15 mg/kg) 加伏立诺他 (33 mg/kg) 治疗组的平均肿瘤体积为 107 mm³，TGI 为 112%(2)。

在本研究中，使用了一组来自结肠（HT29、HCT116、COLO205、HCC2998）、乳腺癌（MCF7、MDA-MB-435）、肺癌（HOP62、HOP92）和卵巢（OVCAR3、IGROV1）的癌细胞系。使用流式细胞术评估细胞周期阶段和凋亡细胞的百分比。简而言之，将细胞接种到 25 cm³ 烧瓶中，然后不进行处理或进行不同水平的沙帕他滨处理。按指定时间间隔收获贴壁和非贴壁细胞，用 PBS 清洗，保存在 70% 乙醇中，并保存在 4°C 直至需要。在 PBS 中重新水化后，将细胞在室温 (25°C) 下与 250 μg/mL RNAse A 和 Triton X-100 一起孵育 20 分钟，并在黑暗中在 4°C 下用 50 μg/mL 孵育另外 20 分钟。 mL 碘化丙啶。 FACS Calibur 用于分析细胞周期分布和凋亡细胞百分比，这两者均使用流式细胞仪测量[1]。

Subcutaneous injections of 1×10⁷ MV4-11 cells resuspended in 50% Matrigel are administered subcutaneously to female (nu/nu) mice at a single flank injection site. Animals are paired according to tumor size into treatment groups (no more than six mice per group) once tumor volumes reach 126 to 256 mm³ (16 days after implantation), with an average tumor size of about 190 mm³. The formula for measuring tumors is volume (mm³) = width² (mm)×length (mm)×0.5. Dosing begins the same day as distribution to the treatment groups. Sapacitabine is given orally once daily (5 or 15 mg/kg) for 4 days, followed by a 3-day break before another 4 days of treatment[2].

[1]. Antiproliferative effects of sapacitabine (CYC682), a novel 2'-deoxycytidine-derivative, in human cancer cells. Br J Cancer. 2007 Sep 3;97(5):628-36.

[2]. Combination of sapacitabine and HDAC inhibitors stimulates cell death in AML and other tumour types. Br J Cancer. 2010 Oct 26;103(9):1391-9.

Sapacitabine is a nucleoside analogue resulting from the formal condensation of the carboxy group of hexadecanoic acid with the amino group of CNDAC. It is the prodrug of CNDAC and is currently in clinical development for the treatment of acute myeloid leukemia (AML). It has a role as an antimetabolite, an antineoplastic agent, a prodrug and a DNA synthesis inhibitor. It is a nucleoside analogue, a nitrile and a secondary carboxamide. It is functionally related to a hexadecanoic acid and a CNDAC.
Sapacitabine is an orally bioavailable pyrimidine analogue prodrug with potential antineoplastic activity. Sapacitabine is hydrolyzed by amidases to the deoxycytosine analogue CNDAC (2'-Cyano-2'-deoxyarabinofuranosylcytosine), which is then phosphorylated into the active triphosphate form. As an analogue of deoxycytidine triphosphate, CNDAC triphosphate incorporates into DNA strands during replication, resulting in single-stranded DNA breaks during polymerization due to beta-elimination during the fidelity checkpoint process; cell cycle arrest in the G2 phase and apoptosis ensue. The unmetabolized prodrug may exhibit antineoplastic activity as well.

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Drug Indication
Investigated for use/treatment in solid tumors, cutaneous t-cell lymphoma, myelodysplastic syndrome, and leukemia (lymphoid).

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Mechanism of Action
Sapacitabine appears to act through a dual mechanism. It interferes with DNA synthesis by causing single-strand DNA breaks and also induces arrest of cell cycle progression mainly at G2/M-Phase. Both sapacitabine and CNDAC, its major metabolite or a substance into which the drugs converts after ingestion by patients, have demonstrated potent anti-tumor activity in preclinical studies.

C26H42N4O5

490.63548

490.315

C, 63.65; H, 8.63; N, 11.42; O, 16.30

151823-14-2

151823-14-2

153970

White to off-white solid powder

1.2±0.1 g/cm3

1.575

5.67

137.47

3

6

17

35

775

4

O=C(N=C(NC(CCCCCCCCCCCCCCC)=O)C=C1)N1[C@H]2[C@@H](C#N)[C@H](O)[C@@H](CO)O2

LBGFKUUHOPIEMA-PEARBKPGSA-N

InChI=1S/C26H42N4O5/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-23(32)28-22-16-17-30(26(34)29-22)25-20(18-27)24(33)21(19-31)35-25/h16-17,20-21,24-25,31,33H,2-15,19H2,1H3,(H,28,29,32,34)/t20-,21+,24-,25+/m0/s1

N-[1-[(2R,3S,4S,5R)-3-cyano-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]hexadecanamide

CYC682; CYC-682; CYC 682; CS682; CYC682; CYC-682; Sapacitabine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: ~33.3 mg/mL (~67.9 mM)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。