DNA synthesis
Prodrug of gemcitabine. Its ultimate mechanism of action is through intracellular conversion to gemcitabine, which is subsequently phosphorylated by deoxycytidine kinase (dCK) to active metabolites (dFdCTP) that inhibit DNA/RNA synthesis. [1]

Gemcitabine elaidate (0.2 nM-1 mM；72 h) 抑制对吉西他滨敏感和耐药的细胞的生长。对于 L1210/L5、L4A6、BCLO、Bara-C、C26-A、C26-G、A2780、AG6000、THX、LOX、MOLT4 和 MOLT4/C8 细胞，IC50 为 0.0033、16.0、0.0042、13.0、0.0015，分别为 0.03、0.0025、91、0.0040、0.028 和 0.088 μM[1]。 Gemcitabine elaidate（0.5 nM-1 μM；72 小时）会增加 A549 和 WiDR 细胞中 S 期积累和剂量依赖性细胞死亡[2]。

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CP-4126 对一系列白血病和实体瘤细胞系表现出抗增殖活性，其IC50值通常与吉西他滨相当或略有差异。例如，在L1210/L5白血病细胞中，IC50为0.0033 µM（CP-4126）对比0.0019 µM（吉西他滨）；在BCLO白血病细胞中，为0.0042 µM对比0.0083 µM。[1]

- 在脱氧胞苷激酶（dCK）缺陷的细胞系（如L4A6、Bara-C、AG6000）中，CP-4126 和吉西他滨均无活性或活性大幅降低，证实了 CP-4126 的活化依赖于dCK。[1]

- CP-4126 的细胞毒活性在很大程度上不依赖于核苷转运体功能。在核苷转运抑制剂NBMPR（100 µM）或双嘧达莫（4 µg/ml）存在下，吉西他滨的IC50增加了高达273倍（例如在MOLT4细胞中），而 CP-4126 的IC50仅略微增加（例如在MOLT4细胞中，NBMPR存在下增加1.8倍）或没有变化。[1]

- 在NCI60体外筛选中，CP-4126 在所有60个细胞系中的平均IC50为0.1 µM，总生长抑制浓度（TGI）为12.6 µM，半数致死浓度（LC50）为70.9 µM。白血病、肾癌和非小细胞肺癌（NSCLC）细胞系属于最敏感的谱系。[1]

- NCI60数据的COMPARE分析表明，CP-4126 的生长抑制谱与DNA抗代谢物和拓扑异构酶抑制剂的谱图相关，并且与吉西他滨本身的谱图高度相关，提示其作用模式相似。[1]

吉西他滨反式酯（25-120 mg/kg；腹膜内注射，每 3 天一次，共 5 剂）抑制某些实体瘤异种移植物的生长，包括纤维组织细胞瘤 (TAX II-1)、非小细胞肺癌 (EKVX)、不可分类的肉瘤 (MHMX)、恶性黑色素瘤 (THX)、前列腺癌 (CRL–1435) 和胰腺癌 (PANC-1)[1]。
吉西他滨（10–20 mg/kg；口服，每 3 天一次，持续 5 次）剂量）在结肠癌 Co6044 移植小鼠中表现出相当大的毒性和显着的抗肿瘤活性[1]。
吉西他滨（口服，每日一次，共 5 剂）表现出良好的毒性和抗肿瘤活性；然而，15 mg/kg 的剂量对人类结肠癌异种移植物 Co6044 具有剧毒[1]。

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以每三天一次、共五次的腹腔注射方案在其最大耐受剂量（MTD, 40 mg/kg）下给药，CP-4126 在裸鼠的一系列人源肿瘤异种移植模型中显示出与吉西他滨（MTD 120 mg/kg i.p.）相当的抗肿瘤疗效。在黑色素瘤（THX）、肉瘤（MHMX, TAXII-1, OHS）、肺癌（EKVX, H-146）、乳腺癌（MA-11）、前列腺癌（CRL-1435）和胰腺癌（PANC-1, MiaPaCa-2）模型中观察到了积极的抗肿瘤效果（T/C < 25% 和/或 SGD > 2）。[1]

- CP-4126 显示出显著的口服抗肿瘤活性，这与吉西他滨（口服生物利用度低/无且毒性高）形成鲜明对比。在人结肠癌异种移植模型Co6044中，口服 CP-4126（通过灌胃给药）显示出依赖于给药方案和剂量的抗肿瘤活性和毒性。例如，每三天一次、共五次（第1,4,7,10,13天）口服20 mg/kg，导致T/C为16%，且毒性极低。[1]

- 在同一Co6044模型中，在最佳方案和剂量下，CP-4126 的口服抗肿瘤活性与其腹腔注射活性相当。[1]

- 口服 CP-4126 在非小细胞肺癌异种移植模型（EKVX和MAKSAX模型）中也显示出活性。[1]

脱氧胞苷脱氨酶（dCDA）抑制实验： 测定了 CP-4126 对纯化的dCDA酶活性的影响。在37°C下，以500 µM脱氧胞苷（dCyd）或吉西他滨为底物，在存在或不存在500 µM CP-4126 或吉西他滨作为竞争化合物的情况下测定酶活性。反应在15或25分钟后通过加入三氯乙酸（TCA）沉淀蛋白质而终止。上清液中和后，通过反相高效液相色谱法（HPLC）定量分析底物（dCyd或吉西他滨）及其脱氨产物（脱氧尿苷或dFdU）。CP-4126 有效抑制了dCyd和吉西他滨的脱氨。[1]

细胞系：A549 和 WiDR 细胞
浓度：0.0005、0.001、0.005、0.01、0.05、0.1、0.5、1.0 μM
孵育时间：72 小时
结果：诱导 G2/M 和 S 期积累。

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悬浮细胞（如白血病细胞系L1210, BCLO）的化学敏感性测试： 将细胞以根据其倍增时间调整的密度接种于24孔板中。接种后立即加入药物，终浓度范围为2x10^-10 M至10^-3 M。连续暴露72小时后，使用自动细胞计数器计数细胞。相对于对照组（接种时细胞数=0%，72小时无药细胞数=100%）绘制生长抑制曲线，并通过插值法确定IC50值。[1]

- 贴壁单层细胞（如实体瘤细胞系A2780, C26-A）的化学敏感性测试： 将细胞接种于96孔板中。24小时后，加入药物的系列稀释液，终浓度范围为2x10^-10 M至2x10^-3 M。细胞暴露于药物72小时。然后，用冷三氯乙酸（TCA）固定细胞并用磺酰罗丹明B（SRB）染色。测量溶解染料的吸光度，并生成生长抑制曲线以计算IC50值。[1]

- 核苷转运体抑制研究： 接种细胞并用亚毒性浓度的核苷转运抑制剂NBMPR（100 µM）或双嘧达莫（4 µg/ml）进行预处理。然后加入 CP-4126 或吉西他滨的系列稀释液。72小时后，评估细胞活力（悬浮细胞用计数法，贴壁细胞用SRB法），并确定在抑制剂存在和不存在情况下的IC50值。[1]

Female BALB/c nude (nu/nu) mice (5-8 weeks; 20-27 g) were bearing tumor of EKVX, H-146, MHMX, TAX II-1, OHS, THX, MA-11, CRL-1435, PANC-1 and MiaPaCa-2, respectively
25-120 mg/kg
I.p. every 3 days for 5 doses

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Xenograft establishment: Fragments (approx. 2x2x2 mm) of human tumor xenografts were implanted subcutaneously into both flanks of female BALB/c nude mice. Treatment began when tumors reached a minimum diameter of 4 mm (volume ~32 mm³). [1]

- Intraperitoneal (i.p.) efficacy studies: Mice bearing various xenografts were treated i.p. with CP-4126 or gemcitabine every third day for a total of five doses (q3dx5 schedule). The maximum tolerated dose (MTD) for i.p. CP-4126 was determined to be 40 mg/kg, and for gemcitabine 120 mg/kg. Tumor volume was measured regularly and calculated as 0.5 x length x width². Antitumor effect was evaluated by T/C% (median tumor volume of treated/control x 100%) and Specific Growth Delay (SGD). [1]

- Oral (p.o.) efficacy and schedule studies: Mice bearing the human colon cancer xenograft Co6044 or lung cancer xenografts were treated with CP-4126 via oral gavage using different schedules: weekly (days 1 & 8), every third day for five doses (days 1,4,7,10,13), or daily for five days (days 1-5). Doses ranged from 5 mg/kg to 150 mg/kg per administration for dose-finding. Toxicity (body weight loss, deaths) and antitumor activity (T/C%) were monitored. [1]

- Drug formulation for in vivo studies: CP-4126 was supplied as a ready-to-use, sterile colloidal suspension (liposomal formulation). For in vitro studies, it was dissolved in DMSO to make a 20 mM stock solution. Gemcitabine was used in its clinical formulation. [1]

A preliminary bioavailability study was conducted in two male beagle dogs. Following a single intravenous (i.v.) dose of CP-4126 (4 mg/kg) and, after a washout period, an oral dose (4.3 mg/kg encapsulated), plasma and urine were collected. [1]

- After i.v. administration, the plasma half-life of CP-4126 itself was very short (0.05-0.07 hours), while the half-life of gemcitabine (released from CP-4126) was 1.7-3.4 hours, and that of the metabolite dFdU was 10.8-11.2 hours. [1]

- The area under the curve (AUC) for gemcitabine in plasma was similar after i.v. (11.9-14.4 µM·h) and oral (10.7-21.8 µM·h) administration of CP-4126, suggesting oral bioavailability of the prodrug. [1]

- Urinary excretion of the inactive metabolite dFdU was lower after oral administration of CP-4126 compared to i.v. administration, consistent with the prodrug's inhibition of dCDA-mediated deamination. [1]

The maximum tolerated dose (MTD) for intraperitoneal CP-4126 in nude mice was 40 mg/kg when administered every third day for five doses, defined by causing less than 10% body weight loss. [1]

- Oral administration of CP-4126 showed dose- and schedule-dependent toxicity. For example, in the Co6044 colon cancer model, daily oral dosing (qd1-5) of 40 mg/kg caused 5/7 deaths, whereas 20 mg/kg on an every-third-day schedule (q3dx5) caused no deaths and only 1% mean body weight loss. [1]

- In contrast, oral gemcitabine was highly toxic even at lower doses (e.g., 40 mg/kg q3dx3 caused 6/6 deaths in the Co6044 model). [1]

[1]. Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro and in vivo tumor models. Invest New Drugs. 2011 Jun;29(3):456-66.

[2]. Cell cycle effects of fatty acid derivatives of cytarabine, CP-4055, and of gemcitabine, CP-4126, as basis for the interaction with oxaliplatin and docetaxel. Int J Oncol. 2010 Jan;36(1):285-94.

Gemcitabine elaidate is a pyrimidine 2'-deoxyribonucleoside.
Gemcitabine elaidate has been used in trials studying the treatment of Solid Tumor, Lung Cancer, Non-small-cell Lung Cancer, and Metastatic Pancreatic Adenocarcinoma.
Gemcitabine Elaidate is a lipophilic, unsaturated fatty acid ester derivative of gemcitabine (dFdC), an antimetabolite deoxynucleoside analogue, with potential antineoplastic activity. Upon hydrolysis intracellularly by esterases, the prodrug gemcitabine is converted into the active metabolites difluorodeoxycytidine di- and tri-phosphate (dFdCDP and dFdCTP) by deoxycytidine kinase. dFdCDP inhibits ribonucleotide reductase, thereby decreasing the deoxynucleotide pool available for DNA synthesis; dFdCTP is incorporated into DNA, resulting in DNA strand termination and apoptosis. Due to its lipophilicity, gemcitabine 5'-elaidic acid ester exhibits an increased cellular uptake and accumulation, resulting in an increased conversion to active metabolites, compared to gemcitabine. In addition, this formulation of gemcitabine may be less susceptible to deamination and deactivation by deoxycytidine deaminase.

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CP-4126 is a fatty acid ester prodrug of gemcitabine, specifically with elaidic acid (trans-9-octadecenoic acid) coupled to the 5'-position of the sugar moiety. It was designed to overcome resistance mechanisms related to reduced nucleoside transporter activity and to facilitate cellular uptake and retention. [1]

- It is a lipophilic compound that can cross cell membranes independently of nucleoside transporters. Inside cells, it must be hydrolyzed by esterases to release gemcitabine, which is then activated by dCK. [1]

- CP-4126 itself is not a substrate for deoxycytidine deaminase (dCDA) and can inhibit the deamination of gemcitabine, potentially leading to higher intracellular levels of the active parent drug. [1]

- The study concludes that CP-4126 is a promising anticancer drug candidate due to its transporter-independent activity, oral bioavailability, and efficacy profile comparable to intravenous gemcitabine in preclinical models. [1]

C27H43N3O5F2

527.64422

527.317

C, 61.46; H, 8.21; F, 7.20; N, 7.96; O, 15.16

210829-30-4

95058-81-4; 122111-03-9 (HCl); 116371-67-6 (Gemcitabine monophosphate free acid); 1638288-31-9 (Gemcitabine monophosphate disodium salt); 840506-29-8 [Acelarin (NUC-1031) is a ProTide transformation and enhancement of the widely-used nucleoside analogue, gemcitabine]; 892128-60-8 (LY2334737, an orally bioavailable prodrug of gemcitabine)

9828310

White solid powder

1.2±0.1 g/cm3

631.4±65.0 °C at 760 mmHg

335.7±34.3 °C

0.0±4.2 mmHg at 25°C

1.536

7.7

117.66

2

7

19

37

803

3

O[C@@H](C(F)(F)[C@H](N1C(N=C(C=C1)N)=O)O2)[C@H]2COC(CCCCCCC/C=C/CCCCCCCC)=O

HESSNRGIEVBPRB-QDDPNBLJSA-N

InChI=1S/C27H43F2N3O5/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-23(33)36-20-21-24(34)27(28,29)25(37-21)32-19-18-22(30)31-26(32)35/h9-10,18-19,21,24-25,34H,2-8,11-17,20H2,1H3,(H2,30,31,35)/b10-9+/t21-,24-,25-/m1/s1

[(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-4,4-difluoro-3-hydroxyoxolan-2-yl]methyl (E)-octadec-9-enoate

Gemcitabine elaidate; CO101; CP4126; CO-101; CP-4126; CO 101; CO-101; Gemcitabine (elaidate); CP-4126 (LVT DERIVATIVE OF GEMCITABINE); CO-1.01; 231C73W7LG; CP 4126

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: ≥ 100 mg/mL (~189.52 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.74 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 25.0 mg/mL澄清DMSO储备液加入到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: 2.5 mg/mL (4.74 mM) 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), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 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: ≥ 2.5 mg/mL (4.74 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 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。