CI-898 (hydrochloride)
(Synonyms: CI-898 trihydrochloride) 目录号 : GC43267
Trimetrexate (CI-898) trihydrochloride 是一种抗生素，也是一种有效且具有口服活性的二氢叶酸还原酶 (DHFR) 抑制剂，可减少 DNA 和 RNA 前体的产生并导致细胞死亡，对人 DHFR 的 IC50 值为 4.74 nM 和 1.35 nM和弓形虫DHFR。
Cas No.:1658520-97-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
CI-898 is a lipophilic antifolate inhibitor of dihydrofolate reductase (DHFR; Kds = 4.5, 1.4, and 0.1 nM for the bovine, murine, and E. coli enzyme, respectively). It has enhanced binding to DHFR in the presence of the cofactor NADPH (Kds = 0.03, 0.43, and 0.03 nM, respectively, for the bovine, murine, and E. coli enzyme). Cl-898 (30 nM) inhibits growth (IC50 = 20 nM after two days) and halts the cell cycle at the G1/S phase in L1210 mouse lymphocytic leukemia cells and is active against methotrexate-resistant cancer cell lines. It also inhibits the growth of S. faecalis and S. aureus when used at concentrations less than 0.25 μg/ml. In vivo, Cl-898 (0.44 mg/kg per day, p.o.) suppresses malarial effects in a mouse model of P. berghei infection and increases median survival time in a mouse model of T. gondii infection when administered at a dose of 180 mg/kg. It also enhances the activity of doxorubicin , cyclophosphamide , and 6-thioguanine in mice with advanced stage P338 leukemia.
| Cas No. | 1658520-97-8 | SDF | |
| 别名 | CI-898 trihydrochloride | ||
| Canonical SMILES | COC1=C(OC)C(OC)=CC(NCC2=C(C)C(C(N)=NC(N)=N3)=C3C=C2)=C1.Cl.Cl.Cl | ||
| 分子式 | C19H23N5O3•3HCl | 分子量 | 478.8 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.0886 mL | 10.4428 mL | 20.8855 mL |
| 5 mM | 0.4177 mL | 2.0886 mL | 4.1771 mL |
| 10 mM | 0.2089 mL | 1.0443 mL | 2.0886 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Gateways to clinical trials
Methods Find Exp Clin Pharmacol 2010 Dec;32(10):749-73.PMID:21225012DOI:10.1358/mf.2010.32.10.1573763.
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Thomson Reuters Integrity(SM), the drug discovery and development portal, http://www.thomsonreutersintegrity.com. This issue focuses on the following selection of drugs: 17-Hydroxyprogesterone caproate; Abacavir sulfate/lamivudine, Aclidinium bromide, Adalimumab, Adefovir, Alemtuzumab, Alkaline phosphatase, Amlodipine, Apilimod mesylate, Aripiprazole, Axitinib, Azacitidine; Belotecan hydrochloride, Berberine iodide, Bevacizumab, Bortezomib, Bosentan, Bryostatin 1; Calcipotriol/hydrocortisone, Carglumic acid, Certolizumab pegol, Cetuximab, Cinacalcet hydrochloride, Cixutumumab, Coumarin, Custirsen sodium; Darbepoetin alfa, Darifenacin hydrobromide, Darunavir, Dasatinib, Denibulin hydrochloride, Denosumab, Diacetylmorphine, Dulanermin, Duloxetine hydrochloride; Ecogramostim, Enfuvirtide, Entecavir, Enzastaurin hydrochloride, Eplerenone, Escitalopram oxalate, Esomeprazole sodium, Etravirine, Everolimus, Ezetimibe; Fenofibrate/pravastatin sodium, Ferric carboxymaltose, Flavangenol, Fondaparinux sodium; Glutamine, GSK-1024850A; Hepatitis B hyperimmunoglobulin, Hib-MenC, HIV-LIPO-5; Immunoglobulin intravenous (human), Indacaterol maleate, Indibulin, Indium 111 (¹¹¹In) ibritumomab tiuxetan, Influenza A (H1N1) 2009 Monovalent vaccine, Inhalable human insulin, Insulin glulisine; Lapatinib ditosylate, Leucovorin/UFT; Maraviroc, Mecasermin, MMR-V, Morphine hydrochloride, Morphine sulfate/naltrexone hydrochloride, Mycophenolic acid sodium salt; Naproxen/esomeprazole magnesium, Natalizumab; Oncolytic HSV; Paliperidone, PAN-811, Paroxetine, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b/ribavirin, Pegvisomant, Pemetrexed disodium, Pimecrolimus, Posaconazole, Pregabalin; Raltegravir potassium, Ranelic acid distrontium salt, Rasburicase, Rilpivirine hydrochloride; Sertindole, Sivelestat sodium hydrate, Sorafenib, Sumatriptan succinate/naproxen sodium, Sunitinib malate; Tafluprost, Telithromycin, Temsirolimus, Tenofovir disoproxil fumavate, Tenofovir disoproxil fumarate/emtricitabine, Teriparatide, Ticagrelor, Tigecycline, Tipranavir, Tirapazamine, Trimetrexate; Ulipristal acetate; Valganciclovir hydrochloride, Vicriviroc, Vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan.
Gateways to clinical trials
Methods Find Exp Clin Pharmacol 2002 Dec;24(10):703-29.PMID:12616965doi
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, adalimumab, AERx morphine sulphate, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, almotriptan, amprenavir, aripiprazole, atenolol, atorvastatin calcium; BSYX-A110; Cantuzumab mertansine, capravirine, CDP-571, CDP-870, celecoxib; Delavirdine mesilate, docetaxel, dofetilide, donepezil hydrochloride, duloxetine hydrochloride, dutasteride, dydrogesterone; Efavirenz, emtricitabine, enjuvia, enteryx, epristeride, erlotinib hydrochloride, escitalopram oxalate, etanercept, etonogestrel, etoricoxib; Fesoterodine, finasteride, flt3ligand; Galantamine hydrobromide, gemtuzumab ozogamicin, genistein, gepirone hydrochloride; Indinavir sulfate, infliximab; Lamivudine, lamivudine/zidovudine/abacavir sulfate, leteprinim potassium, levetiracetam, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, losartan potassium; MCC-465, MRA; Nebivolol, nesiritide, nevirapine; Olanzapine, OROS(R)-Methylphenidate hydrochloride; Peginterferon alfa-2a, peginterferon alfa-2b, Pimecrolimus, polyethylene glycol 3350, pramlintide acetate, pregabalin, PRO-2000; Risedronate sodium, risperidone, ritonavir, rituximab, rivastigmine tartrate, rofecoxib, rosuvastatin calcium; Saquinavir mesilate, Stavudine; Tacrolimus, tadalafil, tamsulosin hydrochloride, telmisartan, tomoxetine hydrochloride, treprostinil sodium, trimegestone, trimetrexate; Valdecoxib, venlafaxine hydrochloride; Zoledronic acid monohydrate.
A meta-analysis of salvage therapy for Pneumocystis carinii pneumonia
Arch Intern Med 2001 Jun 25;161(12):1529-33.PMID:11427101DOI:10.1001/archinte.161.12.1529.
Objective: To determine the relative efficacies of alternative antipneumocystis agents in human immunodeficiency virus (HIV)-infected patients with Pneumocystis carinii pneumonia unresponsive to primary drug treatment with a combination product of trimethoprim and sulfamethoxazole or parenteral pentamidine. Methods: Meta-analysis of 27 published clinical drug trials, case series, and case reports involving P carinii pneumonia. Data extracted included underlying disease, primary antipneumocystis treatment, days of failed primary treatment, salvage regimen, use of systemic corticosteroids and antiretroviral drugs, and clinical outcome. Results: In 497 patients with microbiologically confirmed P carinii pneumonia (456 with HIV or acquired immunodeficiency syndrome), initial antipneumocystis treatment failed and they therefore required alternative drug therapy. Failed regimens included trimethoprim-sulfamethoxazole (160 patients), intravenous pentamidine (63 patients), trimethoprim-sulfamethoxazole and/or pentamidine (258 patients), aerosolized pentamidine (6 patients), atovaquone (3 patients), dapsone (3 patients), a combination product of trimethoprim and dapsone (2 patients), and trimethoprim-sulfamethoxazole followed by a combination of clindamycin and primaquine phosphate (2 patients). Efficacies of salvage regimens were as follows: clindamycin-primaquine (42 to 44 [88%-92%] of 48 patients; P<10(-8)), atovaquone (4 [80%] of 5), eflornithine hydrochloride (40 [57%] of 70; P<.01), trimethoprim-sulfamethoxazole (27 [53%] of 51; P<.08), pentamidine (64 [39%] of 164), and trimetrexate (47 [30%] of 159). Conclusion: The combination of clindamycin plus primaquine appears to be the most effective alternative treatment for patients with P carinii pneumonia who are unresponsive to conventional antipneumocystis agents.
2,4-Diaminothieno[2,3-d]pyrimidine analogues of trimetrexate and piritrexim as potential inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase
J Med Chem 1993 Oct 15;36(21):3103-12.PMID:8230096DOI:10.1021/jm00073a009.
A series of eight previously undescribed 2,4-diaminothieno[2,3-d]pyrimidine analogues of the potent dihydrofolate reductase (DHFR) inhibitors trimetrexate (TMQ) and piritrexim (PTX) were synthesized as potential drugs against Pneumocystis carinii and Toxoplasma gondii, which are major causes of severe opportunistic infections in AIDS patients. 2,4-Diamino-5-methyl-6-(aryl/aralkyl)thieno[2,3-d]pyrimidines with 3,4,5-trimethoxy or 2,5-dimethoxy substitution in the aryl/aralkyl moiety and 2,4-diamino-5-(aryl/aralkyl)thieno[2,3-d]pyrimidines with 2,5-dimethoxy substitution in the aryl/aralkyl moiety were obtained by reaction of the corresponding 2-amino-3-cyanothiophenes with chloroformamidine hydrochloride. The aryl group in the 5,6-disubstituted analogues was either attached directly to the hetero ring or was separated from it by one or two carbons, whereas the aryl group in the 5-monosubstituted analogues was separated from the hetero ring by two or three carbons. 2-Amino-3-cyano-5-methyl-6-(aryl/alkyl)thiophene intermediates for the preparation of the 5,6-disubstituted analogues were prepared from omega-aryl-2-alkylidene-malononitriles and sulfur in the presence of a secondary amine, and 2-amino-3-cyano-4-(aryl/aralkyl)thiophene intermediates for the preparation of the 5-monosubstituted analogues were obtained from omega-aryl-1-chloro-2-alkylidenemalononitriles and sodium hydrosulfide. Synthetic routes to the heretofore unknown ylidenemalononitriles, and the ketone precursors thereof, were developed. The final products were tested in vitro as inhibitors of DHFR from Pneumocystis carinii, Toxoplasma gondii, rat liver, beef liver, and Lactobacillus casei. A selected number of previously known 2,4-diaminothieno[2,3-d]pyrimidines lacking the 3,4,5-trimethoxyphenyl and 2,5-dimethoxyphenyl substitution pattern of TMQ and PTX, respectively, were also tested for comparison. None of the compounds was as potent as TMQ or PTX, and while some of them showed some selectivity in their binding to Pneumocystis carinii and Toxoplasma gondii versus rat liver DHFR, this effect was not deemed large enough to warrant further preclinical evaluation.
6-Substituted 2,4-diaminopyrido[3,2-d]pyrimidine analogues of piritrexim as inhibitors of dihydrofolate reductase from rat liver, Pneumocystis carinii, and Toxoplasma gondii and as antitumor agents
J Med Chem 1998 Nov 5;41(23):4533-41.PMID:9804692DOI:10.1021/jm980206z.
The synthesis and biological activity are reported for 21 6-substituted 2,4-diaminopyrido[3,2-d]pyrimidine analogues (4-24) of piritrexim (PTX) as inhibitors of dihydrofolate reductase (DHFR) and as antitumor agents. Recombinant DHFR from Pneumocystis carinii (pc) and native DHFR from Toxoplasma gondii (tg) were the target enzymes tested; these organisms are responsible for fatal opportunistic infections in AIDS patients. Rat liver (rl) DHFR served as the mammalian reference enzyme to determine selectivity for the pathogenic DHFR. The synthesis of S9-bridged compounds 4-6 was achieved by aryl displacement of 2,4-diamino-6-chloropyrido[3, 2-d]pyrimidine (27) with thiol nucleophiles. Oxidation of 4-6 with hydrogen peroxide in glacial acetic acid afforded the corresponding sulfone analogues 7-9. The N9-bridged compounds 10-24 were synthesized from their precursor 3-amino-6-(arylamino)-2-pyridinecarbonitriles via a thermal cyclization with chloroformamidine hydrochloride. Unlike the S9-bridged compounds, the arylamino side chains of the N9-bridged analogues were introduced prior to the formation of the 2, 4-diaminopyrido[3,2-d]pyrimidine nucleus. A reversed two-atom-bridged analogue (25) was also synthesized using a synthetic strategy similar to that utilized for compounds 10-24. The IC50 values of these compounds against pcDHFR ranged from 0.0023 x 10(-6) M for 2,4-diamino-6-(N-methyl-3',4'-dimethoxyanilino)pyrido[3, 2-d]pyrimidine (21), which was the most potent, to 90.4 x 10(-6) M for 2,4-diamino-6-(4'-methoxyanilino)pyrido[3,2-d]pyrimidine (12), which was the least potent. The three S9-bridged compounds tested were more potent than the corresponding sulfone-bridged compounds for all three DHFRs. N9-Methylation increased the potency by as much as 17 000-fold (compounds 15 and 21). None of the analogues were selective for pcDHFR. Against tgDHFR the most potent analogue was again 21 with an IC50 value of 0.00088 x 10(-6) M and the least potent was 12 with an IC50 of 2.8 x 10(-6) M. N9-Methylation afforded an increase in potency of up to 770-fold (compound 15 NH vs 21 N-CH3) compared to the corresponding N9-H analogue. In contrast to pcDHFR, several analogues had a greater selectivity ratio for tgDHFR compared to trimetrexate (TMQ) or PTX, most notably 2, 4-diamino-6-[(3',4'- dimethoxyphenyl)thio]pyrido[3,2-d]pyrimidine (4), 2,4-diamino-6-[(2'-methoxyphenyl)sulfonyl]pyrido[3, 2-d]pyrimidine (7), and 2,4-diamino-6-(2', 5'-dimethoxyanilino)pyrido[3,2-d]pyrimidine (14) which combined relatively high potency at 10(-7)-10(-8) M along with selectivity ratios of 3.97, 6.67, and 4.93, respectively. Several analogues synthesized had better selectivity ratios than TMQ or PTX for both pcDHFR and tgDHFR, and the potencies of the N9-methylated compounds were comparable to or greater than that of TMQ or PTX. Selected compounds were evaluated as inhibitors of the growth of a variety of tumor cells in culture. The N9-CH3 analogues were, in general, highly potent with GI50 values in the nanomolar range. The N9-H and S9 analogues were less potent with GI50 values in the millimolar to micromolar range.