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4291-63-8 分子结构
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(2R,3S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol

ChemBase编号:127
分子式:C10H12ClN5O3
平均质量:285.68698
单一同位素质量:285.06286695
SMILES和InChIs

SMILES:
Clc1nc2n([C@@H]3O[C@@H]([C@@H](O)C3)CO)cnc2c(n1)N
Canonical SMILES:
OC[C@H]1O[C@H](C[C@@H]1O)n1cnc2c1nc(Cl)nc2N
InChI:
InChI=1S/C10H12ClN5O3/c11-10-14-8(12)7-9(15-10)16(3-13-7)6-1-4(18)5(2-17)19-6/h3-6,17-18H,1-2H2,(H2,12,14,15)/t4-,5+,6+/m0/s1
InChIKey:
PTOAARAWEBMLNO-KVQBGUIXSA-N

引用这个纪录

CBID:127 http://www.chembase.cn/molecule-127.html

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名称和登记号

名称和登记号

名称 登记号
IUPAC标准名
(2R,3S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol
IUPAC传统名
cladribine
商标名
Leustatin
Mylinax
别名
2-Chloro-2'-deoxy-beta-adenosine
2-CdA
2-Chloro-2'-deoxyadenosine
2-Chlorodeoxyadenosine
Chlorodeoxyadenosine
cladribine
Cladribine
2-Chloro-2'-deoxyadenosine
CdA
2-Chloro-2′-deoxyadenosine
Leustatin
CAS号
4291-63-8
MDL号
MFCD00153939
PubChem SID
160963590
46504588
24892693
PubChem CID
20279

理论计算性质

理论计算性质

JChem ALOGPS 2.1
Acid pKa 13.886716  质子受体
质子供体 LogD (pH = 5.5) -0.2817818 
LogD (pH = 7.4) -0.28177568  Log P -0.28177547 
摩尔折射率 67.1835 cm3 极化性 25.93346 Å3
极化表面积 119.31 Å2 可自由旋转的化学键
里宾斯基五规则 true 
Log P -0.12  LOG S -1.65 
溶解度 6.35e+00 g/l 

分子性质

分子性质

理化性质 安全信息 药理学性质 产品相关信息 生物活性(PubChem)
溶解度
DMSO expand 查看数据来源
疏水性(logP)
-0.1 expand 查看数据来源
保存条件
-20°C expand 查看数据来源
保存注意事项
IRRITANT expand 查看数据来源
RTECS编号
AU7357560 expand 查看数据来源
欧盟危险性物质标志
有毒(Toxic) 有毒(Toxic) (T) expand 查看数据来源
MSDS下载
下载链接 expand 查看数据来源
德国WGK号
3 expand 查看数据来源
危险公开号
23/24/25-36/37/38 expand 查看数据来源
安全公开号
22-26-36-45 expand 查看数据来源
TSCA收录
false expand 查看数据来源
GHS危险品标识
GHS06 expand 查看数据来源
GHS警示词
Danger expand 查看数据来源
GHS危险声明
H301-H311-H315-H319-H331-H335 expand 查看数据来源
GHS警示性声明
P261-P280-P301 + P310-P305 + P351 + P338-P311 expand 查看数据来源
个人保护装置
Eyeshields, Faceshields, Gloves, type P2 (EN 143) respirator cartridges expand 查看数据来源
保存温度
2-8°C expand 查看数据来源
作用靶点
Antimetabolites expand 查看数据来源
相关基因信息
human ... NP(4860)rat ... Adora1(29290), Adora2a(25369), Adora3(25370) expand 查看数据来源
纯度
95+% expand 查看数据来源
成盐信息
Free Base expand 查看数据来源

详细说明

详细说明

DrugBank DrugBank Sigma Aldrich Sigma Aldrich Selleck Chemicals Selleck Chemicals
DrugBank -  DB00242 external link
Item Information
Drug Groups approved; investigational
Description An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia. [PubChem]
Indication For the treatment of active hairy cell leukemia (leukemic reticuloendotheliosis) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms. Also used as an alternative agent for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma.
Pharmacology Cladribine is a synthetic purine nucleoside that acts as an antineoplastic agent with immunosuppressive effects. Cladribine differs structurally from deoxyadenosine only by the presence of a chlorine atom at position 2 of the purine ring, which results in resistance to enzymatic degradation by adenosine deaminase. Due to this resistance, cladribine exhibits a more prolonged cytotoxic effect than deoxyadenosine against resting and proliferating lymphocytes. Cladribine is one of a group of chemotherapy drugs known as the anti-metabolites. Anti-metabolites stop cells from making and repairing DNA, which are processes that are necessary for cancer cells to grow and multiply.
Toxicity Symptoms of overdose include irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia.
Affected Organisms
Humans and other mammals
Biotransformation Metabolized in all cells with deoxycytidine kinase activity to 2-chloro-2'-deoxyadenosine-5'-triphosphate
Absorption Oral bioavailability is 34 to 48%.
Half Life 5.4 hours
Protein Binding 20%
Distribution * 4.5 ± 2.8 L/kg [patients with hematologic malignancies]
* 9 L/kg
Clearance * 978 +/- 422 mL/h/kg
References
Warnke C, Wiendl H, Hartung HP, Stuve O, Kieseier BC: Identification of targets and new developments in the treatment of multiple sclerosis - focus on cladribine. Drug Des Devel Ther. 2010 Jul 21;4:117-26. [Pubmed]
Sigal DS, Miller HJ, Schram ED, Saven A: Beyond hairy cell: the activity of cladribine in other hematologic malignancies. Blood. 2010 Jul 15. [Pubmed]
Khalid BA, Hamilton NT, Cauchi MN: Binding of thyroid microsomes by lymphocytes from patients with thyroid disease and normal subjects. Clin Exp Immunol. 1976 Jan;23(1):28-32. [Pubmed]
Sampat K, Kantarjian H, Borthakur G: Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009 Oct;18(10):1559-64. [Pubmed]
Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. [Pubmed]
Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. [Pubmed]
Larson ML, Venugopal P: Clofarabine: a new treatment option for patients with acute myeloid leukemia. Expert Opin Pharmacother. 2009 Jun;10(8):1353-7. [Pubmed]
External Links
Wikipedia
RxList
Drugs.com
Sigma Aldrich -  C4438 external link
Biochem/physiol Actions
Deoxyadenosine analog resistant to adenosine deaminase; antileukemic with immunosuppressive activity
Application
2-Chloro-2′-deoxyadenosine (2-CdA) is a chlorinated purine nucleoside with activity against lymphoproliferative disorders, such as hairy cell leukemia (HCL) and multiple myeloma (MM). 2-CdA resists ADA degradation and is phosphorylated to CdATP in lymphocytes. CdATP incorporation into DNA induces strand breaks and the activation of apoptosis. 2-CdA may also be used in studies involving the inhibition of DNA polymerase(s).Cladribiane, like fludarabine, is a prodrug that is must be phosphorylated intracellularly to the monophosphate by the nuclear/cytosol enzyme deoxycytidine kinase (dCK) and possibly by the mitochondrial enzyme deoxyguanosine kinase (dGK).
Cladribiane, like fludarabine, is a prodrug that is must be phosphorylated intracellularly to the monophosphate by the nuclear/cytosol enzyme deoxycytidine kinase (dCK) and possibly by the mitochondrial enzyme deoxyguanosine kinase (dGK). Clinically used for treatment of hairy cell leukemia, chronic lymphocytic leukemia and other indolent leukemias.
Selleck Chemicals -  S1199 external link
Research Area
Description Multiple sclerosis
Biological Activity
Description Cladribine (Leustatin, Litak, 2CDA) is an adenosine deaminase inhibitor for U266, RPMI8226, and MM1.S cells with IC50 of approximately 2.43 μM, 0.75 μM, and 0.18 μM, respectively.
Targets U266 cells RPMI8226 cells MM1.S cells
IC50 2.43 μM 0.75 μM 0.18 μM [1]
In Vitro Cladribine exerts remarkable activity in hairy cell leukemia (HCL), a chronic B-cell lymphoproliferative disorder, producing prolonged complete remissions. Cladribine induces accumulation of DNA strand breaks, and subsequently activates the tumor suppressor p53 in lymphocytes. Cladribine may modulate STAT3 activity in MM cells. Cladribine inhibits proliferation/survival of U266, RPMI8226 and MM1.S cells in a dose-dependent manner. While U266 is the least sensitive cell line, MM1.S is the most sensitive one to cladribine. Treatment with cladribine gradually increases the percentage of cells in the G1 phase of the cell cycle and reduces the percentage of cells in S phase. Cladribine appears to increase G2-M phase in U266 cells upon 24 hour-treatment. A dose-dependent increase in apoptosis induced by cladribine is seen in both RPMI8226 and MM1.S cells. Treatment with cladribine at 0.2 μM dramatically induces activation of caspase-3, -8, and -9 and PARP cleavage in a time-dependent manner in MM1.S. Cladribine significantly decreases the phospho-STAT3 (P-STAT3) levels in a dose-dependent manner, but has no effect on the total STAT3 protein levels. [1] Cladribine possesses concentration-dependent apoptosis-inducing potential in the HSB2 cells. [2] Cladribine inhibits growth of primary mast cell (MC) and the MC line HMC-1 in a dose-dependent manner, with lower IC50 values recorded in HMC-1.2 cells harboring KIT D816V compared to HMC-1.1 cells lacking KIT D816V. [3] Cladribine decreases the migratory capacity of CD14+ monocytes, as well as of CD4+ and CD8+ T lymphocytes. [4]
In Vivo Cladribine (0.7-3.5 mM) and/or diltiazem (2.4 mM), is injected intraperitoneally into adult zebrafish and red blood cell (RBC) lysates are assayed by HPLC for levels of purine nucleotides (e.g. ATP), potential biomarkers of cardiovascular health. Diltiazem increased RBC ATP concentrations, which are inhibited by co-injection of cladribine. [5] Plasma concentrations of Cladribine decreases rapidly following a biphasic decline after both ia and s.c. administrations. The AUC and t 1/2 beta after a single 1 mg/kg ia and 2 mg/kg s.c. injection of Cladribine are 0.66 vs 1.2 μg × h/mL and 3.5 vs 4.5 hours, respectively. [6]
Clinical Trials Cladribine plus Rituximab has entered in a phase II clinical trial in the treatment of leukemia.
Features Cladribine is primarily active in lymphoid tissues.
Protocol
Cell Assay [1]
Cell Lines U266, RPMI8226 and MM1.S
Concentrations 0 μM - 32 μM
Incubation Time 72 hours
Methods The non-radioactive cell proliferation kit is used to determine cell viability. In brief, Human MM cell line U266, RPMI8226 and MM1.S are seeded onto 96-well plates with either 0.1 mL complete medium (5% FBS) as control, or 0.1 mL of the same medium containing a series of doses of cladribine, and incubated for 72 hours. After reading all wells at 490 nm with a micro-plate reader, the percentages of surviving cells from each group relative to controls, defined as 100% survival, are determined by reduction of MTS.
Animal Study [5]
Animal Models Adult wild-type (AB) zebrafish
Formulation Saline
Doses 0.7 mM - 3.5?mM
Administration Administered via i.p.
References
[1] Ma J, et al. BMC Cancer. 2011, 11, 255.
[2] Guchelaar HJ, et al. Cancer Chemother Pharmacol. 1998, 42(1), 77-83.
[3] Böhm A, et al. Exp Hematol. 2010, 38(9), 744-755.
[4] Kopadze T, et al. Eur J Neurol. 2009, 16(3), 409-412.
[5] Klein LC, et al. Biomarkers. 2009, 14(8), 554-559.
[6] Yeung PK, et al. Drug Metabol Drug Interact. 2008, 23(3-4), 291-298.
[7] Szmigielska-Kaplon A, et al. Ann Hematol. 2002, 81(9), 508-513.

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参考文献

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