DNA synthesis

Gemcitabine elaidate (0.2 nM-1 mM; 72 h) hydrochloride is useful against L1210/L5, L4A6, BCLO, Bara-C, C26-A, C26-G, A2780, AG6000, THX, and other cells that are susceptible to or resistant to gemcitabine. For LOX, MOLT4, and MOLT4/C8 cells, the corresponding IC50 values are 0.0033, 16.0, 0.0042, 13.0, 0.0015, 0.03, 0.0025, 91, 0.0040, 0.0077, 0.028, and 0.088 μM [1]. A549 and WiDR cell death is dose-dependent and increases with gemcitabine elaidate hydrochloride (0.5 nM-1 μM; 72 hours) [2].

Gemcitabine elaidate hydrochloride (ip every 3 days for 5 doses; 25–120 mg/kg) inhibits solid tumor xenografts in malignant melanoma (THX), fibrous histiocytoma (TAX II–), sarcoma unclassifiable (MHMX), non-small cell lung cancer (EKVX), prostate cancer (CRL-1435), and pancreatic cancer (PANC-1) [1]. In Co6044 colon cancer xenograft mice, gemcitabine elaidate hydrochloride (10–20 mg/kg; po every 3 days for 5 doses) showed respectable toxicity and noteworthy antitumor efficacy [1]. When applied topically once daily for five doses, gemcitabine elaidate hydrochloride demonstrated good antitumor efficacy and toxicity, with a dose of 15 mg/kg being extremely lethal against the human colon cancer xenograft Co6044 [1].

Cell Cycle Analysis[2]
Cell Types: A549 and WiDR cells
Tested Concentrations: 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1.0 μM
Incubation Duration: 72 h
Experimental Results: Induced a G2/M and S phase accumulation.

Animal/Disease Models: 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[1]
Doses: 25-120 mg/kg
Route of Administration: Ip every 3 days for 5 doses
Experimental Results: Inhibited the growth of EKVX, MHMX, TAX II-1, THX, CRL-1435 and PANC-1, with T/C values of 7%, 1%, 30%, 7%, 9%, and 12%, respectively.

[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 is a deoxycytidine (dCyd) analog active against leukemia and solid tumors, and its action requires phosphorylation by deoxycytidine kinase (dCK). Reduced membrane transport is one of the mechanisms of gemcitabine resistance. To promote gemcitabine uptake and prolong its intracellular retention time, we synthesized a lipophilic prodrug (CP-4126) with transoleic acid esterified at the 5' position. We tested CP-4126 in cell lines resistant to cytarabine (another dCyd analog) or gemcitabine. In parental cell lines, gemcitabine and its derivatives showed comparable activity, while all compounds were inactive in dCK-deficient cells. However, inhibition of nucleoside transport increased the IC50 value of gemcitabine by up to 200-fold, but the IC50 value of CP-4126 did not increase, indicating that the activity of CP-4126 is independent of nucleoside transporters. For in vivo evaluation, nude mice carrying human xenograft tumors were intraperitoneally injected five times every three days at the maximum tolerated dose. In melanoma, sarcoma, lung cancer, prostate cancer, pancreatic cancer, and breast cancer xenografts, gemcitabine and CP-4126 showed comparable and significant efficacy; in the other four xenograft tumors, their efficacy was moderate but comparable. Unlike gemcitabine, CP-4126 can be administered orally, and its toxicity and antitumor activity are dose-dependent. In colon cancer xenograft tumors, the antitumor activity of oral CP-4126 was comparable to that of intraperitoneal administration. In summary, CP-4126 is independent of membrane transporters. Intraperitoneal injection of CP-4126 showed comparable efficacy to gemcitabine in various xenograft tumors, and oral CP-4126 was well tolerated. CP-4126 appears to be a promising new anticancer drug. [1]

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To overcome drug resistance caused by restricted cell entry, researchers developed cytarabine derivatives (CP-4055, also known as ilacytarabine) and gemcitabine derivatives (CP-4126) with a fatty acid chain at the 5' position of the nucleoside. CP-4055 showed increased retention of the active metabolite triphosphate. This property is considered beneficial for its combination with various drugs, such as the microtubule antagonist docetaxel, the platinum drug oxaliplatin, and the antifolate drug pemetrexed. Researchers determined the effects of the cell cycle effects of CP-4055 and CP-4126 on the efficacy of combination therapy with docetaxel or pemetrexed. In addition, researchers evaluated the effects of combination therapy of CP-4055 with oxaliplatin and docetaxel in a mouse xenograft model. CP-4055 induced cell accumulation in the G2/M and S phases, while CP-4126 induced cell accumulation in the S phase. Both analogues induced dose-dependent cell death (apoptosis and necrosis). No synergistic effect was observed in any combination of docetaxel. Docetaxel in combination with CP-4055 or CP-4126 induced G2/M phase cell accumulation in the A549 (lung cancer) cell line, but induced G0/G1 phase cell accumulation in the WiDR (colon cancer) cell line. Pre-incubation with docetaxel enhanced cell death in both cell lines. Synergistic effects were observed in combination with oxaliplatin in both cell lines. Antagonistic effects were observed in combination with pemetrexed in both cell lines. In the A549 cell line, pemetrexed in combination with CP-4055 increased the proportion of cells in both G0/G1 and S phases. In the WiDR study, pemetrexed in combination with CP-4055 increased the proportion of cells in the G0/G1 phase and enhanced cytotoxicity. The combination of pemetrexed and CP-4126 can increase the proportion of cells in the G0/G1 and S phases in the A549 cell line. In xenograft studies, the combination of CP-4055 and docetaxel showed the best efficacy in both colon cancer and lung metastasis models. In the lung metastasis model, treatment with CP-4055 followed by docetaxel 4 hours after treatment reduced metastatic lesions and had good toxicity. In summary, the combination with oxaliplatin showed a synergistic effect in the combination drug studies. Although the combination with docetaxel did not show enhanced efficacy in in vitro studies, the combination regimen showed enhanced efficacy in xenograft models. [2]

C27H44CLF2N3O5

564.105174064636

563.293

2918768-08-6

Gemcitabine elaidate;210829-30-4

155977587

White to off-white solid powder

3

7

19

38

803

3

Cl.FC1([C@H](N2C(N=C(C=C2)N)=O)O[C@H](COC(CCCCCCC/C=C/CCCCCCCC)=O)[C@H]1O)F

LYTHDWBFDKMMPL-SDCWGXALSA-N

InChI=1S/C27H43F2N3O5.ClH/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);1H/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;hydrochloride

Gemcitabine elaidate hydrochloride; Gemcitabine elaidate (hydrochloride); 2918768-08-6; CO-101 hydrochloride; EX-A8562;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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 (177.27 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)