WR99210
(Synonyms: BRL 6231 free base) 目录号 : GC37938
WR99210 是一种有效的二氢叶酸还原酶 (DHFR) 抑制剂，IC50 为 Plasmodium falciparum)。
Cas No.:47326-86-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
WR99210 is a effective inhibitor of dihydrofolate reductase (DHFR) with an IC50 of Plasmodium falciparum strains[2]. IC50: <0.075 nM (DHFR)[1]
[1]. Kiara SM, et al. In vitro activity of antifolate and polymorphism in dihydrofolate reductase of Plasmodium falciparum isolates from the Kenyan coast: emergence of parasites with Ile-164-Leu mutation. Antimicrob Agents Chemother. 2009 Sep;53(9):3793-8. [2]. Hastings MD, et al. Pyrimethamine and WR99210 exert opposing selection on dihydrofolatereductase from Plasmodium vivax. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13137-41.
| Cas No. | 47326-86-3 | SDF | |
| 别名 | BRL 6231 free base | ||
| Canonical SMILES | CC1(N=C(N=C(N1OCCCOC2=C(C=C(C(Cl)=C2)Cl)Cl)N)N)C | ||
| 分子式 | C14H18Cl3N5O2 | 分子量 | 394.68 |
| 溶解度 | DMSO: 5 mg/mL (12.67 mM) | 储存条件 | Store at -20°C,unstable in solution, ready to use. |
| 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 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.5337 mL | 12.6685 mL | 25.337 mL |
| 5 mM | 0.5067 mL | 2.5337 mL | 5.0674 mL |
| 10 mM | 0.2534 mL | 1.2668 mL | 2.5337 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。
Regioisomerization of Antimalarial Drug WR99210 Explains the Inactivity of a Commercial Stock
Antimicrob Agents Chemother 2020 Dec 16;65(1):e01385-20.PMID:33077647DOI:10.1128/AAC.01385-20.
WR99210, a former antimalarial drug candidate now widely used for the selection of Plasmodium transfectants, selectively targets the parasite's dihydrofolate reductase thymidine synthase bifunctional enzyme (DHFR-TS) but not human DHFR, which is not fused with TS. Accordingly, WR99210 and plasmids expressing the human dhfr gene have become valued tools for the genetic modification of parasites in the laboratory. Concerns over the ineffectiveness of WR99210 from some sources encouraged us to investigate the biological and chemical differences of supplies from two different companies (compounds 1 and 2). Compound 1 proved effective at low nanomolar concentrations against Plasmodium falciparum parasites, whereas compound 2 was ineffective, even at micromolar concentrations. Intact and fragmented mass spectra indicated identical molecular formulae of the unprotonated (free base) structures of compounds 1 and 2; however, the compounds displayed differences by thin-layer chromatography, reverse-phase high-performance liquid chromatography, and UV-visible spectroscopy, indicating important isomeric differences. Structural evaluations by 1H, 13C, and 15N nuclear magnetic resonance spectroscopy confirmed compound 1 as WR99210 and compound 2 as a dihydrotriazine regioisomer. Induced fit computational docking models showed that compound 1 binds tightly and specifically in the P. falciparum DHFR active site, whereas compound 2 fits poorly to the active site in loose and varied orientations. Stocks and concentrates of WR99210 should be monitored for the presence of regioisomer 2, particularly when they are not supplied as the hydrochloride salt or are exposed to basic conditions that may promote rearrangement. Absorption spectroscopy can serve for assays of the unrearranged and rearranged triazines.
Activity of PS-15 and its metabolite, WR99210, against Plasmodium falciparum in an in vivo-in vitro model
Trans R Soc Trop Med Hyg 1996 Sep-Oct;90(5):568-71.PMID:8944276DOI:10.1016/s0035-9203(96)90326-0.
An in vivo-in vitro model was used to assess the antimalarial activity of PS-15 and its metabolite, WR99210, against Plasmodium falciparum. WR99210, an antifolate triazine compound, was given as a single oral dose of 30 mg/kg to 8 Saimiri sciureus monkeys and, 3 months later, the parent compound, PS-15, was given similarly to the same monkeys. Serum samples were collected at various times after drug administration, serially diluted with control serum, and their antimalarial activity in vitro was determined against the multidrug-resistant K1 isolate of P. falciparum. Serum concentrations of PS-15 and WR99210 were estimated by high performance liquid chromatography. The maximum dilutions of serum that inhibited parasite growth were 20- to 86-fold higher 3 and 6 h after administration of PS-15 than following WR99210 administration. Substantial serum antimalarial activity was observed even at 48 h after medication with PS-15. Serum drug concentrations provided further evidence that PS-15 was absorbed far better from the gastrointestinal tract than WR99210. The substantial and sustained activity of PS-15 suggests that a single dose, or several smaller doses given once a day, should be effective in curing drug-resistant infections of P. falciparum.
The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate mode of action of the prodrug
Am J Trop Med Hyg 1999 Jun;60(6):943-7.PMID:10403325DOI:10.4269/ajtmh.1999.60.943.
We have studied the reversal of activity against Plasmodium falciparum of WR99210, a triazine antimalarial drug, and of the pro-drug PS-15 by folic acid (FA) and folinic acid (FNA). Folic acid and FNA inhibit the growth of P. falciparum in vitro at concentrations > 10(-4.5) and 10(-3.5) mol/L, respectively. The activity of pyrimethamine against Kenyan strains M24 and K39 is reduced 10-12-fold by 10(-5) mol/L of FA, and virtually eliminated by 10(-5) mol/L of FNA. Folates do not antagonise the action of WR99210 against Kenyan strains, and only partially antagonize the action of WR99210 action against the Southeast Asian strains V1/S and W282. Similarly, FA and FNA exerted weak or no antagonism of the action of PS-15. The inability of folates to antagonize the action of WR99210 can be explained in terms of high drug-enzyme affinity, but this does not account for the inability of FA and FNA to antagonize PS-15. These results suggest that action of PS-15 against P. falciparum is primarily due to a non-folate mechanism.
Novel Saccharomyces cerevisiae screen identifies WR99210 analogues that inhibit Mycobacterium tuberculosis dihydrofolate reductase
Antimicrob Agents Chemother 2002 Nov;46(11):3362-9.PMID:12384337DOI:10.1128/AAC.46.11.3362-3369.2002.
The ongoing selection of multidrug-resistant strains of Mycobacterium tuberculosis has markedly reduced the effectiveness of the standard treatment regimens. Thus, there is an urgent need for new drugs that are potent inhibitors of M. tuberculosis, that exhibit favorable resistance profiles, and that are well tolerated by patients. One promising drug target for treatment of mycobacterial infections is dihydrofolate reductase (DHFR; EC 1.5.1.3), a key enzyme in folate utilization. DHFR is an important drug target in many pathogens, but it has not been exploited in the search for drugs effective against M. tuberculosis. The triazine DHFR inhibitor WR99210 has been shown to be effective against other mycobacteria. We show here that WR99210 is also a potent inhibitor of M. tuberculosis and Mycobacterium bovis BCG growth in vitro and that resistance to WR99210 occurred less frequently than resistance to either rifampin or isoniazid. Screening of drugs with M. tuberculosis cultures is slow and requires biosafety level 3 facilities and procedures. We have developed an alternative strategy: initial screening in an engineered strain of the budding yeast Saccharomyces cerevisiae that is dependent on the M. tuberculosis DHFR for its growth. Using this system, we have screened 19 compounds related to WR99210 and found that 7 of these related compounds are also potent inhibitors of the M. tuberculosis DHFR. These studies suggest that compounds of this class are excellent potential leads for further development of drugs effective against M. tuberculosis.
Pyrimethamine and WR99210 exert opposing selection on dihydrofolate reductase from Plasmodium vivax
Proc Natl Acad Sci U S A 2002 Oct 1;99(20):13137-41.PMID:12198181DOI:10.1073/pnas.182295999.
Plasmodium vivax is a major public health problem in Asia and South and Central America where it is most prevalent. Until very recently, the parasite has been effectively treated with chloroquine, but resistance to this drug has now been reported in several areas. Affordable alternative treatments for vivax malaria are urgently needed. Pyrimethamine-sulfadoxine is an inhibitor of dihydrofolate reductase (DHFR) that has been widely used to treat chloroquine-resistant Plasmodium falciparum malaria. DHFR inhibitors have not been considered for treatment of vivax malaria, because initial trials showed poor efficacy against P. vivax. P. vivax cannot be grown in culture; the reason for its resistance to DHFR inhibitors is unknown. We show that, like P. falciparum, point mutations in the dhfr gene can cause resistance to pyrimethamine in P. vivax. WR99210 is a novel inhibitor of DHFR, effective even against the most pyrimethamine-resistant P. falciparum strains. We have found that it is also an extremely effective inhibitor of the P. vivax DHFR, and mutations that confer high-level resistance to pyrimethamine render the P. vivax enzyme exquisitely sensitive to WR99210. These data suggest that pyrimethamine and WR99210 would exert opposing selective forces on the P. vivax population. If used in combination, these two drugs could greatly slow the selection of parasites resistant to both drugs. If that is the case, this novel class of DHFR inhibitors could provide effective and affordable treatment for chloroquine- and pyrimethamine-resistant vivax and falciparum malaria for many years to come.