Thiarabine targets DNA synthesis by acting as a deoxycytidine analog. Once inside the cell, it is phosphorylated by deoxycytidine kinase to its active triphosphate form. This active metabolite competes with the natural substrate, deoxycytidine triphosphate (dCTP), for incorporation into the growing DNA strand by DNA polymerase. Unlike cytarabine, which causes chain termination, the 4'-thio modification in Thiarabine may allow for continued DNA elongation before ultimately inhibiting DNA synthesis, leading to cell cycle arrest and apoptosis. Its potent antitumor activity is attributed to its efficient cellular uptake, rapid phosphorylation, and ability to overcome resistance mechanisms associated with other nucleoside analogs.

In vitro, Thiarabine has demonstrated potent inhibition of DNA synthesis in cancer cell lines. It exhibits cytotoxic activity against a wide range of hematological and solid tumor cell lines. The compound's activity is typically measured using cell-based assays that assess cell viability, DNA synthesis, and apoptosis. Its mechanism of action involves incorporation into DNA, leading to chain termination and cell death. Thiarabine has shown superior potency compared to cytarabine in various in vitro models, highlighting its potential as a more effective antileukemic agent. These in vitro studies confirm Thiarabine's potent antineoplastic activity.

Thiarabine is effective orally (bioavailability approximately 16%) and administered once daily; although thiorabine's structure and basic mechanism of action are similar to those of cytarabine, there are many quantitative differences in the biochemical pharmacology of these two drugs that may explain thiorabine's superior antitumor activity. Thiarabine also outperforms gemcitabine, clofarabine, and cytarabine in mice when it comes to antitumor activity. In contrast, thorabin showed excellent activity against solid tumor xenografts, indicating that the drug has potent activity in animal models that could lead to clinical applications.

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In vivo, Thiarabine has demonstrated exceptional antitumor activity against numerous human tumor xenografts in mice. In preclinical studies, it has been shown to be superior to gemcitabine, clofarabine, or cytarabine in various xenograft models. Unlike cytarabine, which requires high doses and prolonged infusion schedules, Thiarabine has shown potent activity at lower doses and less frequent dosing schedules, suggesting a potentially improved therapeutic index. These in vivo findings have established Thiarabine as a promising candidate for the treatment of various cancers, including leukemia and solid tumors. However, specific in vivo protocols and results are not detailed in standard product descriptions.

In vitro enzyme assays for Thiarabine typically measure its inhibition of DNA synthesis or its phosphorylation by deoxycytidine kinase. DNA synthesis inhibition can be assessed by measuring the incorporation of radiolabeled thymidine into DNA in the presence of varying concentrations of Thiarabine. The compound's affinity for deoxycytidine kinase can be determined using enzyme activity assays with purified enzyme and radiolabeled substrates. These assays provide a quantitative measure of Thiarabine's potency and its mechanism of action at the molecular level. However, specific IC50 or Ki values are not detailed in standard product descriptions.

In vitro cell-based assays for Thiarabine are used to study its effects on cancer cell proliferation and survival. Cancer cell lines (e.g., leukemia, lymphoma, solid tumor cells) are treated with Thiarabine at various concentrations. Cell viability is assessed using assays such as MTT, CellTiter-Glo, or trypan blue exclusion. DNA synthesis is measured by incorporation of labeled nucleotides. Apoptosis is measured using Annexin V staining or caspase-3/7 activation assays. Cell cycle analysis is performed by flow cytometry. These assays confirm the compound's potent antileukemic and antitumor activity.

In vivo animal experiments for Thiarabine have been conducted in mouse xenograft models of human tumors. In a typical study, immunodeficient mice are implanted with human tumor cells and treated with Thiarabine at various doses and schedules. Tumor growth is monitored by caliper measurements, and tumor regression or growth inhibition is assessed. The compound's efficacy is compared to that of standard chemotherapeutic agents such as gemcitabine, clofarabine, or cytarabine. These studies have demonstrated Thiarabine's exceptional antitumor activity and superior efficacy compared to other nucleoside analogs. Pharmacokinetic studies in animals have also been conducted to evaluate the compound's distribution and metabolism.

Thiarabine has a molecular weight of 259.28 g/mol and a molecular formula of C9H13N3O4S. The IUPAC name is 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)thiolan-2-yl]pyrimidin-2-one. It is a solid compound with a purity of >99.50%. For storage, it is recommended to keep the powder at -20°C. Detailed pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) have been characterized in preclinical studies. Thiarabine is a nucleoside analog, and its pharmacokinetics are influenced by its phosphorylation and metabolism.

Detailed toxicity data for Thiarabine is not provided in standard product descriptions. As a DNA synthesis inhibitor, it is expected to have myelosuppressive effects, similar to other nucleoside analogs like cytarabine. Common side effects of nucleoside analogs include bone marrow suppression, gastrointestinal disturbances, and hepatotoxicity. However, specific toxicity data, such as LD50 or organ toxicity, are not detailed. Preclinical studies have shown that Thiarabine has a favorable therapeutic index compared to cytarabine, but comprehensive toxicological studies have not been reported in standard product descriptions. As with all research chemicals, standard laboratory safety precautions should be followed when handling Thiarabine.

[1]. Thiarabine, 1-(4-Thio-β-D-arabinofuranosyl)cytosine. A Deoxycytidine Analog With Excellent Anticancer Activity. Curr Med Chem. 2015;22(34):3881-96.

OSI-7836 belongs to the nucleoside analogue of cytotoxic drugs, with gemcitabine being the market leader in this class. OSI Pharmaceuticals is developing OSI-7836 as a next-generation gemcitabine. The antitumor activity of OSI-7836 appears to be less affected by dosing regimens than gemcitabine. Its activity was higher than cytarabine (another clinically used nucleoside analogue) in all nine models tested; it was also higher than paclitaxel or cisplatin in the two lung xenograft models tested. No unexpected toxicities were observed; the observed toxicities were similar to those of other nucleoside analogues. Thiabine is an analogue of the antimetabolite cytarabine (ara-C) with potential antitumor activity. After administration, thiabine (T-araC) is phosphorylated to the triphosphate form T-araCTP, which competes with cytidine for incorporation into DNA. This leads to inhibition of DNA replication and RNA synthesis, chain termination, and may ultimately reduce tumor cell proliferation. Compared to cytarabine (ara-C), T-araC has a longer half-life and higher efficacy.

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Drug indications
Its use has been investigated in the treatment of solid tumors.Mechanism of action
The mechanism by which OSI-7836 inhibits tumor growth appears to differ from gemcitabine; it blocks cell division at different stages of the cell cycle (G2 phase). Its mechanism of action involves phosphorylation to a triphosphate form, which is then incorporated into cellular DNA, ultimately leading to cell death.

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Thiarabine (OSI-7836) is a research compound and is not approved for any clinical or therapeutic use. It is a deoxycytidine nucleoside analog with potent anticancer activity. Thiarabine functions as a DNA synthesis inhibitor, and its mechanism of action involves incorporation into DNA, leading to chain termination and cell death. Preclinically, it has demonstrated exceptional antitumor activity against numerous human tumor xenografts in mice, being superior to gemcitabine, clofarabine, or cytarabine. Unlike cytarabine, it has shown potent activity at lower doses and less frequent dosing schedules. Thiarabine is a valuable research tool for studying nucleoside analog pharmacology and cancer therapeutics.

259.062

26599-17-7

168566

White to off-white solid powder

1.9±0.1 g/cm3

535.0±60.0 °C at 760 mmHg

277.4±32.9 °C

0.0±3.2 mmHg at 25°C

1.814

-1.91

4

5

2

17

386

4

C1=CN(C(=O)N=C1N)[C@H]2[C@H]([C@@H]([C@H](S2)CO)O)O

GAKJJSAXUFZQTL-CCXZUQQUSA-N

InChI=1S/C9H13N3O4S/c10-5-1-2-12(9(16)11-5)8-7(15)6(14)4(3-13)17-8/h1-2,4,6-8,13-15H,3H2,(H2,10,11,16)/t4-,6-,7+,8-/m1/s1

2(1H)-Pyrimidinone, 4-amino-1-(4-thio-beta-D-arabinofuranosyl)-

OSI-7836OSI 7836OSI7836 Thiarabine

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)