Tubercidin
(Synonyms: 结核菌素; 7-Deazaadenosine) 目录号 : GC16879
A nucleoside analog with diverse biological activities
Cas No.:69-33-0
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
|
Cell lines |
Human bone marrow cells |
|
Preparation Method |
In the protection studies, cells are exposed to 10 nM of tubercidin in the presence or absence of various doses of NBMPR-P. Cells are continuously exposed to drugs for 14 days in a humidified atmosphere of 5% C02-95% air at 37°c. Colonies of CFU-GM (250 cells) and BFU-E (30 hemoglobinized cells) are counted with an inverted microscope. |
|
Reaction Conditions |
10 nM of tubercidin ；14 days in a humidified atmosphere of 5% C02-95% air at 37°c |
|
Applications |
Tubercidin alone had a direct dose-dependent inhibitory effect on myeloid and erythroid human bone marrow progenitor cells, and consistent inhibition (50%) of granulocyte-macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E) occurred at 2 to 3 nM tubercidin. At higher doses, BFU-E were more sensitive to tubercidin toxicity than CFU-GM. Complete inhibition (99%) of BFU-E colonies occurred at 10 nM tubercidin, while complete inhibition of CFU-GM occurred at 100 nM. NBMPR-P at 10 to 100 nM protected CFU-GM and BFU-E from tubercidin toxicity in a dose-dependent matter. |
| Animal experiment [2]: | |
|
Animal models |
35 female (20- to 25-g) CD1 mice |
|
Preparation Method |
Three groups of mice were used, each consisting of 35 female (20- to 25-g) CD1 mice, The first group received four successive daily intraperitoneal injections of tubercidin (5 mg/kg per dose) plus NBMPR-P (25 mg/kg per dose) ; the regimen was repeated after a 10-day rest period . The second group received four daily injections of tubercidin (5 mg/kg per dose) alone, but the regimen could not be repeated owing to the death of mice within 3 to 5 days of the initiation of treatment. The third group (controls) received saline solution (0.9% NaCI). Drugs were prepared and administered as previously described. All mice that survived were sacrificed 4 days after the last injection. Whole blood was obtained by cardiac puncture and collected in a Unopette microcollection system. |
|
Dosage form |
5 mg/kg per dose |
|
Applications |
Tubercidin (7-deazaadenosine) plus nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) used in combination therapy of schistosomiasis was examined in vivo in mice and in vitro with human bone marrow progenitor cells. Four successive daily intraperitoneal injections of tubercidin at 5 mg/kg per day produced 100% mortality in mice within 3 to 5 days following the first injection, with massive peritonitis and intestinal obstruction secondary to abdominal adhesions. Coadministration of NBMPR-P (25 mg/kg per day) protected the mice from the lethality of tubercidin and allowed the repetition of the regimen for a second time with 100% survival until the mice were sacrificed 22 days following the first injection. Blood chemistry, hematological studies, and histological examinations showed no evidence for injury to the liver, kidney, spleen, pancreas, mesentery, or peritoneal mesothelium. |
|
References: [1]. el Kouni MH, Diop D, et,al. Prevention of tubercidin host toxicity by nitrobenzylthioinosine 5'-monophosphate for the treatment of schistosomiasis. Antimicrob Agents Chemother. 1989 Jun;33(6):824-7. doi: 10.1128/AAC.33.6.824. PMID: 2764531; PMCID: PMC284239. |
|
Tubercidin is a pyrrolopyrimidine nucleoside analog with significant activity against schistosomal infections.?It has also been tested as a cancer chemotherapeutic agent, but its utility has been limited by nephrotoxicity[8].?As one of the most potent inhibitors of human liver SAH-hydrolase, Tubercidin enters cells via nucleoside transporters[7].?Upon intracellular metabolism of tubercidin to its mono, di, and tri-phosphate esters, it can substitute for adenosine nucleotides, and thereby interfere in the synthesis of DNA, RNA, and protein. As a toxic adenosine analog with antiviral, antitrypanosomal, and antifungal functions.?Inhibits multiple metabolic processes which includes: RNA processing, nucleic acid synthesis, protein synthesis, and methylation of tRNA through intracellular incorporation into nucleic acids.?Acts as a plant antifungal, inhibits mammalian SAHH (SAH hydrolase), and blocks purine biosynthesis in Candida famata[1].Tubercidin has been studied for antiviral and anticancer properties, is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties[4,5].
In vitro, tubercidin alone had a direct dose-dependent inhibitory effect on myeloid and erythroid human bone marrow progenitor cells, and consistent inhibition (50%) of granulocyte-macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E) occurred at 2 to 3 nM tubercidin.?At higher doses, BFU-E were more sensitive to tubercidin toxicity than CFU-GM.?Complete inhibition (99%) of BFU-E colonies occurred at 10 nM tubercidin, while complete inhibition of CFU-GM occurred at 100 nM.?NBMPR-P at 10 to 100 nM protected CFU-GM and BFU-E from tubercidin toxicity in a dose-dependent matter[3].Continuous exposure for 14 days to tubercidin alone is highly toxic to both human CFU-GM and BFU-E.?The IC50s of tubercidin are 3.4±1.7 and 3.7±0.2 nM for CFU-GM and BFU-E, respectively.?Tubercidin also has a direct dose-dependent inhibitory effect on myeloid and erythroid human bone marrow progenitor cells in vitro[6].?The inhibitor tubercidin proved to be highly antiviral against SARS-CoV-2, Tubercidin is a broad-spectrum MTase inhibitor active against both NSP16 and MTr1.tubercidin potently inhibited both NSP16 and MTr1 in vitro, further emphasizing that a concomitant inhibition of NSP16 and MTr1 is pivotal for effective antiviral treatment.[2,3]
Host toxicity of the dose regimen of tubercidin plus nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) used in combination therapy of schistosomiasis.?Coadministration of NBMPR-P (25 mg/kg per day) protected the mice from the lethality of tubercidin and allowed the repetition of the regimen for a second time with 100% survival until the mice were sacrificed 22 days following the first injection.?Blood chemistry, hematological studies, and histological examinations showed no evidence for injury to the liver, kidney, spleen, pancreas, mesentery, or peritoneal mesothelium.
References:
[1]: Stahmann KP, Revuelta JL,et,al. Three biotechnical processes using Ashbya gossypii, Candida famata, or Bacillus subtilis compete with chemical riboflavin production. Appl Microbiol Biotechnol. 2000 May;53(5):509-16. doi: 10.1007/s002530051649. PMID: 10855708.
[2]:Bergant V, Yamada S, et,al. Attenuation of SARS-CoV-2 replication and associated inflammation by concomitant targeting of viral and host cap 2'-O-ribose methyltransferases. EMBO J. 2022 Jul 14:e111608. doi: 10.15252/embj.2022111608. Epub ahead of print. PMID: 35833542; PMCID: PMC9350232.
[3]:Schultz DC, Johnson RM, et,al. Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2. Nature. 2022 Apr;604(7904):134-140. doi: 10.1038/s41586-022-04482-x. Epub 2022 Feb 7. PMID: 35130559.
[4]:Olsen DB, Eldrup AB, et,al. A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrob Agents Chemother. 2004 Oct;48(10):3944-53. doi: 10.1128/AAC.48.10.3944-3953.2004. PMID: 15388457; PMCID: PMC521892.
[5]: Vittori S, Dal Ben D, et,al. Antiviral properties of deazaadenine nucleoside derivatives. Curr Med Chem. 2006;13(29):3529-52. doi: 10.2174/092986706779026228. PMID: 17168721.
[6]: el Kouni MH, Diop D, et,al. Prevention of tubercidin host toxicity by nitrobenzylthioinosine 5'-monophosphate for the treatment of schistosomiasis. Antimicrob Agents Chemother. 1989 Jun;33(6):824-7. doi: 10.1128/AAC.33.6.824. PMID: 2764531; PMCID: PMC284239.
[7]: Fabianowska-Majewska K, Duley JA, et,al. Effects of novel anti-viral adenosine analogues on the activity of S-adenosylhomocysteine hydrolase from human liver. Biochem Pharmacol. 1994 Aug 30;48(5):897-903. doi: 10.1016/0006-2952(94)90360-3. PMID: 8093102.
[8]: Bisel HF, Ansfield FJ, et,al. Clinical studies with tubercidin administered by direct intravenous injection. Cancer Res. 1970 Jan;30(1):76-8. PMID: 4917978.
Tubercidin 是一种吡咯并嘧啶核苷类似物，对血吸虫感染具有显着活性。它还作为癌症化疗剂进行了测试，但其实用性受到肾毒性的限制[8]。作为人类肝脏 SAH 水解酶最有效的抑制剂之一，Tubercidin 通过核苷转运蛋白进入细胞[7]。结核菌素在细胞内代谢为单磷酸酯、二磷酸酯和三磷酸酯后，可替代腺苷核苷酸，从而干扰 DNA、RNA 和蛋白质的合成。作为具有抗病毒、抗锥虫和抗真菌功能的有毒腺苷类似物。抑制多种代谢过程，包括:RNA 加工、核酸合成、蛋白质合成和通过细胞内掺入核酸的 tRNA 甲基化。作为植物抗真菌剂，抑制哺乳动物 SAHH（SAH 水解酶），并阻断 Candida famata[1] 中的嘌呤生物合成。已研究结核菌素的抗病毒和抗癌特性，是一种有效的选择性肝炎抑制剂具有优良药代动力学特性的C病毒复制[4,5].
在体外，单独使用结核菌素对骨髓和红系人骨髓祖细胞具有直接的剂量依赖性抑制作用，并且对粒细胞-巨噬细胞 CFU (CFU-GM) 和红系爆发形成单位具有一致的抑制作用 (50%) ( BFU-E) 发生在 2 至 3 nM 结核菌素。在较高剂量下，BFU-E 比 CFU-GM 对结核菌素毒性更敏感。 BFU-E 菌落的完全抑制 (99%) 发生在 10 nM 结核菌素，而 CFU-GM 的完全抑制发生在 100 nM。 10 至 100 nM 的 NBMPR-P 以剂量依赖性方式保护 CFU-GM 和 BFU-E 免受结核菌素的毒性[3]。单独连续暴露于结核菌素 14 天对人类和人类都有剧毒CFU-GM 和 BFU-E。结核菌素对 CFU-GM 和 BFU-E 的 IC50 分别为 3.4±1.7 和 3.7±0.2 nM。 Tubercidin 在体外对髓系和红系人骨髓祖细胞也具有直接的剂量依赖性抑制作用[6]。抑制剂 tubercidin 被证明对 SARS-CoV-2 具有高度抗病毒作用，Tubercidin 是一种广谱 MTase 抑制剂，对 NSP16 和 MTr1 均有活性。tubercidin 在体外有效抑制 NSP16 和 MTr1，进一步强调同时抑制 NSP16 和 MTr1是有效抗病毒治疗的关键。[2,3]
用于联合治疗血吸虫病的结核菌素加硝基苄硫肌苷 5'-单磷酸盐 (NBMPR-P) 剂量方案的宿主毒性。 NBMPR-P（每天 25 毫克/千克）的共同给药保护小鼠免受结核菌素的致死性，并允许第二次重复该方案，存活率为 100%，直到小鼠在第一次注射后 22 天被处死。血液化学、血液学研究和组织学检查均未显示肝脏、肾脏、脾脏、胰腺、肠系膜或腹膜间皮损伤的证据。
| Cas No. | 69-33-0 | SDF | |
| 别名 | 结核菌素; 7-Deazaadenosine | ||
| 化学名 | (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol | ||
| Canonical SMILES | NC1=NC=NC2=C1C=CN2[C@H]3[C@H](O)[C@H](O)[C@@H](CO)O3 | ||
| 分子式 | C11H14N4O4 | 分子量 | 266.25 |
| 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。 |
||
| 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 | 3.7559 mL | 18.7793 mL | 37.5587 mL |
| 5 mM | 0.7512 mL | 3.7559 mL | 7.5117 mL |
| 10 mM | 0.3756 mL | 1.8779 mL | 3.7559 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。
First Total Synthesis of 5'- O-α-d-Glucopyranosyl Tubercidin
The first total synthesis of 5'-O-α-d-glucopyranosyl tubercidin was successfully developed. It is a structurally unique disaccharide 7-deazapurine nucleoside exhibiting fungicidal activity, and was isolated from blue-green algae. The total synthesis was accomplished in eight steps with 27% overall yield from commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribose. The key step involves stereoselective α-O-glycosylation of the corresponding 7-bromo-6-chloro-2',3'-O-isopropylidene-β-d-tubercidin with 2,3,4,6-tetra-O-benzyl-glucopyranosyl trichloroacetimidate. All spectra are in accordance with the reported data for natural 5'-O-α-d-glucopyranosyl tubercidin. Meanwhile, 5'-O-β-d-glucopyranosyl tubercidin was also prepared using the same strategy.
TUBERCIDIN
Identification of natural compounds tubercidin and lycorine HCl against small-cell lung cancer and BCAT1 as a therapeutic target
Although small-cell lung cancer (SCLC) accounts for a small fraction of lung cancer cases (~15%), the prognosis of patients with SCLC is poor with an average overall survival period of a few months without treatment. Current treatments include standard chemotherapy, which has minimal efficacy and a newly developed immunotherapy that thus far, benefits a limited number of patients. In the current study, we screened a natural product library and identified 5 natural compounds, in particular tubercidin and lycorine HCl, that display prominent anti-SCLC activities in vitro and in vivo. Subsequent RNA-sequencing and functional validation assays revealed the anti-SCLC mechanisms of these new compounds, and further identified new cellular factors such as BCAT1 as a potential therapeutic target with clinical implication in SCLC patients. Taken together, our study provides promising new directions for fighting this aggressive lung cancer.
Halogen Bonding in Haspin-Halogenated Tubercidin Complexes: Molecular Dynamics and Quantum Chemical Calculations
Haspin, an atypical serine/threonine protein kinase, is a potential target for cancer therapy. 5-iodotubercidin (5-iTU), an adenosine derivative, has been identified as a potent Haspin inhibitor in vitro. In this paper, quantum chemical calculations and molecular dynamics (MD) simulations were employed to identify and quantitatively confirm the presence of halogen bonding (XB), specifically halogen???π (aromatic) interaction between halogenated tubercidin ligands with Haspin. Consistent with previous theoretical finding, the site specificity of the XB binding over the ortho-carbon is identified in all cases. A systematic increase of the interaction energy down Group 17, based on both quantum chemical and MD results, supports the important role of halogen bonding in this series of inhibitors. The observed trend is consistent with the experimental observation of the trend of activity within the halogenated tubercidin ligands (F < Cl < Br < I). Furthermore, non-covalent interaction (NCI) plots show that cooperative non-covalent interactions, namely, hydrogen and halogen bonds, contribute to the binding of tubercidin ligands toward Haspin. The understanding of the role of halogen bonding interaction in the ligand-protein complexes may shed light on rational design of potent ligands in the future.
The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2'-Deoxyuridine and Tubercidin Analogues
Among the scarce validated drug targets against Chagas disease (CD), caused by Trypanosoma cruzi, the parasite's nucleoside salvage system has recently attracted considerable attention. Although the trypanocidal activity of tubercidin (7-deazapurine) has long been known, the identification of a class of 7-substituted tubercidin analogs with potent in vitro and in vivo activity and much-enhanced selectivity has made nucleoside analogs among the most promising lead compounds against CD. Here, we investigate the recently identified TcrNT2 nucleoside transporter and its potential role in antimetabolite chemotherapy. TcrNT2, expressed in a Leishmania mexicana cell line lacking the NT1 nucleoside transporter locus, displayed very high selectivity and affinity for thymidine with a Km of 0.26 ± 0.05 ?M. The selectivity was explained by interactions of 2-oxo, 4-oxo, 5-Me, 3'-hydroxy and 5'-hydroxy with the transporter binding pocket, whereas a hydroxy group at the 2' position was deleterious to binding. This made 5-halogenated 2'-deoxyuridine analogues good substrates but 5-F-2'-deoxyuridine displayed disappointing activity against T. cruzi trypomastigotes. By comparing the EC50 values of tubercidin and its 7-substituted analogues against L. mexicana Cas9, Cas9ΔNT1 and Cas9ΔNT1+TcrNT2 it was shown that TcrNT2 can take up tubercidin and, at a minimum, a subset of the analogs.