Thioguanine (NSC-752; Tabloid)   中文名称: 6-硫鸟嘌呤

6-Thioguanine (Thioguanine; 2-Amino-6-purinethiol) 是一种抗白血病和免疫抑制剂，可作为 SARS 和 MERS 冠状病毒木瓜蛋白酶 (PLpros) 的抑制剂，还可有效抑制 USP2 活性，IC50 为 25 Pproros 和重组人 USP2 分别为 μM 和 40 μM[1]。 6-硫鸟嘌呤 (Thioguanine) 通过纯化的 DNA 甲基转移酶（包括人 DNMT1 和细菌 HpaII 甲基化酶）影响胞嘧啶残基的甲基化。 6-硫鸟嘌呤 (Thioguanine)（1 或 3 μM）可降低 Jurkat T 细胞中的整体胞嘧啶甲基化，并在 3 μM 时降低人类细胞中的胞嘧啶甲基化[2]。 6-硫鸟嘌呤 (Thioguanine)（18.75、37.50 或 75.00 μM）显着影响细胞活力，但对 LDH 或 ALT 活性没有影响[3]。

在异种移植模型中，硫鸟嘌呤在选择性杀死 BRCA2 缺陷型肿瘤方面与 PARP 抑制剂一样有效。 6-硫鸟嘌呤可有效杀死此类 BRCA1 缺陷型 PARP 抑制剂耐药肿瘤。 6-硫鸟嘌呤可以杀死通过 BRCA2 基因的遗传逆转而对 PARP 抑制剂或顺铂产生耐药性的细胞和肿瘤

Absorption, Distribution and Excretion
Absorption of an oral dose is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%)
Incompletely and variably (about 30%) absorbed from the gastrointestinal tract.
THIOGUANINE IS INCOMPLETELY ABSORBED WHEN GIVEN ORALLY, AVERAGING ABOUT 30% OF AN ADMIN DOSE. ... THE ELIMINATION HALF-LIFE OF THE PARENT DRUG IS 1.5 HR, BUT PEAK PLASMA LEVELS OF METABOLITES ARE REACHED IN 6-8 HR. BETWEEN 24% & 46% IS EXCRETED IN THE URINE AS METABOLITES WITHIN 24 HR. ... THIS DRUG IS CLEARED RAPIDLY FROM PLASMA AFTER IV ADMINISTRATION; MORE THAN 80% EXCRETED WITHIN 24 HR. ALTHOUGH THIOGUANINE.../SRP: HAS LIMITED ACCESS ACROSS/ THE BLOOD-BRAIN BARRIER IN ANIMALS AFTER LARGE DOSES, VERY LITTLE ENTERS THE CEREBROSPINAL FLUID OF HUMANS AFTER THE USUAL CLINICAL DOSES ARE EMPLOYED.
THE METABOLISM AND PHARMACOKINETICS OF 6-THIOGUANINE WERE STUDIED IN DOGS AFTER IV ADMIN OF 5 MG/KG (35)S-THIOGUANINE (TG). THIOGUANINE WAS RAPIDLY & EXTENSIVELY DEGRADED. METABOLITES WERE NOT FOUND IN THE CEREBROSPINAL FLUID IN SIGNIFICANT CONCENTRATIONS.

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Metabolism / Metabolites
Hepatic. First converted to 6-thioguanilyic acid (TGMP). TGMP is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) by the same enzymes that metabolize guanine nucleotides.
... WHEN THIOGUANINE IS ADMIN TO MAN, THE S-METHYLATION PRODUCT, 2-AMINO-6-METHYLTHIOPURINE, RATHER THAN FREE THIOGUANINE APPEARS IN URINE; INORGANIC SULFATE IS ALSO A MAJOR URINARY METABOLITE. LESSER AMT OF 6-THIOURIC ACID ARE FORMED, SUGGESTING THAT DEAMINATION CATALYZED BY THE ENZYME GUANASE DOES NOT HAVE A MAJOR ROLE IN THE METABOLIC INACTIVATION OF THIOGUANINE.
THE PHARMACOKINETICS OF RADIOLABELED 6-THIOGUANINE (TG) WERE COMPARED WITH THAT OF BETA-2'-DEOXYTHIOGUANOSINE (BETA-TGDR) AFTER IV ADMIN. URINARY EXCRETION OF THE RADIOLABEL WAS 75% OF THE DOSE 24 HR AFTER ADMIN. BOTH THIOPURINES WERE RAPIDLY & EXTENSIVELY DEGRADED & EXCRETED AS 6-THIOXANTHINE, INORGANIC SULFATE, S-METHYL-6-THIOXANTHINE, & 6-THIOURIC ACID IN ADDITION TO OTHER PRODUCTS. SMALL AMOUNTS OF UNCHANGED DRUG WERE ALSO EXCRETED. STUDIES SUGGEST THAT BETA-TGDR IS A LATENT FORM OF TG. SINCE RESISTANCE TO ANTILEUKEMIC AGENT 6-THIOGUANINE INEVITABLY DEVELOPS IN ANIMAL TUMORS, THIS NEW AGENT BETA-TGDR IS OF POTENTIAL CLINICAL USE.
Hepatic. First converted to 6-thioguanilyic acid (TGMP). TGMP is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) by the same enzymes that metabolize guanine nucleotides.
Half Life: When the compound was given in singles doses of 65 to 300 mg/m^2, the median plasma half-disappearance time was 80 minutes (range 25-240 minutes)

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Biological Half-Life
When the compound was given in singles doses of 65 to 300 mg/m^2, the median plasma half-disappearance time was 80 minutes (range 25-240 minutes)

Toxicity Summary
Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanilyic acid (TGMP), which reaches high intracellular concentrations at therapeutic doses. TGMP interferes with the synthesis of guanine nucleotides by its inhibition of purine biosynthesis by pseudofeedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway of purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages, and some studies have shown that incorporation of such false bases contributes to the cytotoxicity of thioguanine. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis; inhibition of purine nucleotide interconversions; or incorporation into the DNA and RNA. The overall result of its action is a sequential blockade of the utilization and synthesis of the purine nucleotides.

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Toxicity Data
Rat (ip): LD50 300 mg/kg
Oral, mouse: LD₅₀ = 160 mg/kg.

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Interactions
INDUCTION OF 6-THIOGUANINE RESISTANCE WAS STUDIED IN HUMAN CELLS TREATED WITH THE DIRECT-ACTING CARCINOGEN N-ACETOXY-2-ACETYLAMINOFLUORENE. AT 2.5-7.5 MUMOL INDUCTION OF RESISTANT CLONES WAS LINEAR & FOLLOWED 1-HIT KINETICS, WHILE AT 10 MUMOL THE YIELD OF RESISTANT CLONES WAS HIGHER & APPEARED TO RESULT FROM COMBINATION OF 1-HIT & 2-HIT KINETICS.
6-MERCAPTOPURINE & 6-THIOGUANINE SYNERGISTICALLY INHIBITED MILK XANTHINE OXIDASE.
PRETREATMENT OF L1210 LEUKEMIA CELLS WITH METHOTREXATE ENHANCED CYTOTOXICITY OF 6-THIOGUANINE. METHOTREXATE PRETREATMENT & ENHANCEMENT OF 6-THIOGUANINE CYTOTOXICITY FOLLOWING METHOTREXATE EXPOSURE IS NOT ASSOC WITH 6-THIOGUANINE INCORPORATION INTO DNA, BUT RATHER WITH INCORPORATION OF 6-THIOGUANINE INTO RNA. THIS DRUG SEQUENCE MAY BE BENEFICIAL IN CLINICAL TREATMENT OF LEUKEMIA.

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Non-Human Toxicity Values
LD50 Rat ip 350 mg/kg
LD40 Mouse ip 50 mg/kg

[1]. 6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2. Sci Rep. 2018 Feb 15;8(1):3102.

[2]. 6-Thioguanine perturbs cytosine methylation at the CpG dinucleotide site by DNA methyltransferases in vitro and acts as a DNA demethylating agent in vivo. Biochemistry. 2009 Mar 17;48(10):2290-9.

[3]. Effects of azathioprine, 6-mercaptopurine, and 6-thioguanine on canine primary hepatocytes. Am J Vet Res. 2015 Jul;76(7):649-55.

Therapeutic Uses
Antimetabolites, Antineoplastic
CLINICALLY, THIOGUANINE HAS BEEN USED IN THE TREATMENT OF ACUTE LEUKEMIA AND, IN COMBINATION WITH CYTARABINE, IS ONE OF THE MOST EFFECTIVE AGENTS FOR INDUCTION OF REMISSIONS IN ACUTE GRANULOCYTIC LEUKEMIA; IT HAS NOT BEEN USEFUL IN THE TREATMENT OF PATIENTS WITH SOLID TUMORS. THIS CMPD HAS BEEN USED AS AN IMMUNOSUPPRESSIVE AGENT, PARTICULARLY IN PATIENTS WITH NEPHROSIS AND WITH COLLAGEN-VASCULAR DISORDERS. TOXIC MANIFESTATIONS INCLUDE BONE MARROW DEPRESSION AND GI EFFECTS, ALTHOUGH THE LATTER MAY BE LESS PRONOUNCED THAN WITH MERCAPTOPURINE.
SHORT TERM TREATMENT WITH DOXORUBICIN, CYTARABINE, & 6-THIOGUANINE WAS GIVEN TO 90 PATIENTS WITH ACUTE MYELOGENOUS LEUKEMIA. FIFTY PATIENTS RECEIVED HIGH DOSES (REGIMEN 1) & 41 RECEIVED VERY HIGH DOSES (REGIMEN 2). REMISSION RATE WAS SIGNIFICANTLY HIGHER WITH REGIMEN 1 THAN WITH REGIMEN 2. DURATION OF REMISSION WAS, HOWEVER, SIGNIFICANTLY LONGER WITH REGIMEN 2.
IN ADVANCED COLORECTAL ADENOCARCINOMA, TWO DIFFERENT SCHEDULES OF COMBINATION METHYL-CCNU, 6-THIOGUANINE, & 5-FLUOROURACIL EXHIBITED SIMILAR EFFICACIES, WITH A COMBINED COMPLETE & PARTIAL REMISSION RATE OF 17% & A MEDIAN SURVIVAL OF 53+ WK. SIGNIFICANT SYMPTOMATIC BENEFIT WAS SEEN IN 52% OF PATIENTS. TOXICITY WAS PREDOMINATELY HEMOPOIETIC & GI.
For more Therapeutic Uses (Complete) data for THIOGUANINE (14 total), please visit the HSDB record page.

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Drug Warnings
Risk-benefit should be considered when the following medical problems exist: Bone marrow depression; chickenpox, existing or recent (including recent exposure; herpes zoster (risk of severe generalized disease); gout, history of; urate renal stones, history of (risk of hyperuricemia); hepatic function impairment (reduced biotransformation; lower dosage is recommended); infection; renal function impairment (reduced elimination; lower dosage is recommended); or sensitivity to thioguanine. Caution should be used also in patients who have had cytotoxic drug therapy and radiation therapy within 4 to 6 weeks.
Because normal defense mechanisms may be suppressed by thioguanine therapy, concurrent use with alive virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the thioguanine therapy. The interval between discontinuation of medication that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members.
Because normal defense mechanisms may be suppressed by thioguanine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year.
TOXIC MANIFESTATIONS INCL BONE MARROW DEPRESSION & GI EFFECTS ... .
For more Drug Warnings (Complete) data for THIOGUANINE (9 total), please visit the HSDB record page.

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Pharmacodynamics
Thioguanine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Thioguanine was first synthesized and entered into clinical trial more than 30 years ago. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase).

C5H5N5S

167.1917

167.026

154-42-7

5580-03-0 (hemihydrate);76078-67-6 (mono-Na salt)

2723601

White to yellow solid powder

2.1±0.1 g/cm3

460.7±37.0 °C at 760 mmHg

≥300 °C(lit.)

232.4±26.5 °C

0.0±1.1 mmHg at 25°C

2.071

-0.99

119.28

3

2

0

11

225

0

WYWHKKSPHMUBEB-UHFFFAOYSA-N

InChI=1S/C5H5N5S/c6-5-9-3-2(4(11)10-5)7-1-8-3/h1H,(H4,6,7,8,9,10,11)

2-amino-1H-purine-6(7H)-thione

2-Amino-6-purinethiol; thioguanine; ThioguanineTabloid; Tioguanine. Lanvis; Tioguanin; 6TG; TG. BW 5071; WR1141; X 27.

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 : ~10 mg/mL (~59.81 mM)

配方 1 中的溶解度: ≥ 1.67 mg/mL (9.99 mM) (饱和度未知) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 16.7 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80 +，混匀；然后加入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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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。