789-61-7

Usage

Uses

Used in Pharmaceutical Industry:
6-THIO-2'-DEOXYGUANOSINE is used as a chemotherapeutic agent for the treatment of cancer. It works by inhibiting the activity of human RNase H, an enzyme that cleaves RNA from DNA-RNA duplexes, thereby interfering with the replication and transcription processes of cancer cells.
Used in Cancer Research:
6-THIO-2'-DEOXYGUANOSINE is used as a research tool in cancer biology to study the mechanisms of action of RNase H and its role in cancer progression. It can also be used to investigate the potential synergistic effects of 6-THIO-2'-DEOXYGUANOSINE with other chemotherapeutic agents in combination therapies.

Biological Activity

6-thio-dg is a nucleoside analogue [1], is a telomerase-mediated telomere disrupting compound [2]. it is an anti-cancer inhibitor [1]. cancer cells were very sensitive to 6-thio-dg with observed ic50 values ranging from 0.7-2.9 μm, depending on cell types [3].telomeres are found at the end of eukaryotic linear chromosomes. they are essential for genomic stability and chromosome maintenance [3].in hct116 human colon cancer cell line, treatment with 6-thio-dg made progressive telomere shortening independent of telomerase activity inhibition and induced telomere dysfunction. grn163l is a telomerase inhibitor. in hct116 cells, treatment with grn163l and 6-thio-dg together increased telomere shortening. within 1 week, 6-thio-dg killed most of hct116 cells and altered cellular morphology. normal bj fibroblast cells are telomerase silent. after 1 week, treatment with 6-thio-dg showed no effect on cell morphology. after long-term treatment with 6-thio-dg, no effect on telomere shortening was found [1].in murine mode with xenograft derived from a549 lung cancer cell line, as compared to controls, intraperitoneal injection with 2 mg/kg of 6-thio-dg every other day completely prevented progressive tumor growth. ki67 is a biomarker correlating with proliferation levels. compared to controls, 6-thio-dg decreased ki67 staining. treatment with 6-thio-dg through local injection resulted in even more dramatic decrease in the tumor growth rate compared to untreated controls [3].

references

[1]. mender i, gryaznov s, dikmen zg, et al. abstract lb-125: a novel telomerase inhibitor. cancer research, 2013, 73(8 supplement): lb-125-lb-125.[2]. mender i, gryaznov s, shay jw. a novel telomerase substrate precursor rapidly induces telomere dysfunction in telomerase positive cancer cells but not telomerase silent normal cells. oncoscience, 2015, 2(8): 693.[3]. mender i, gryaznov s, dikmen zg, et al. induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2-deoxyguanosine. cancer discovery, 2015, 5(1): 82-95.

InChI:InChI=1/C10H13N5O3S/c11-10-13-8-7(9(19)14-10)12-3-15(8)6-1-4(17)5(2-16)18-6/h3-6,16-17H,1-2H2,(H3,11,13,14,19)

Synthetic route

Isobutyric acid (2R,3S,5R)-5-(2-isobutyrylamino-6-thioxo-1,6-dihydro-purin-9-yl)-2-isobutyryloxymethyl-tetrahydro-furan-3-yl ester (136112-93-1) → 2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7)

Conditions	Yield
With sodium hydroxide In ethanol	100%

2'-Deoxyguanosine (961-07-9) → 2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7)

Conditions	Yield
With sodium hydrogensulfide; trifluoroacetic anhydride In pyridine; N,N-dimethyl-formamide	65%
With pyridine; sodium hydrogensulfide; trifluoroacetic anhydride 1) 40 min, ice-bath, 2) DMF, 24 h; Yield given. Multistep reaction;

2-Amino-6-chloro-9-(2-deoxy-3,5-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)purine (35095-93-3) → 2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7)

Conditions	Yield
With hydrogen sulfide; sodium methylate 1) anhydr. MeOH, reflux, 2 h; 2) MeOH, reflux, 1 h; Yield given. Multistep reaction;

2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride (4330-21-6) → 2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 51 percent / 1) sodium hydride (60percent in oil) / 1) acetonitrile, RT, 30 min; 2) acetonitrile, 20 h 2: 1) H2S/1M sodium methoxide; 2) 1M sodium methoxide / 1) anhydr. MeOH, reflux, 2 h; 2) MeOH, reflux, 1 h View Scheme

2-Amino-6-chloropurin (10310-21-1) → 2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 51 percent / 1) sodium hydride (60percent in oil) / 1) acetonitrile, RT, 30 min; 2) acetonitrile, 20 h 2: 1) H2S/1M sodium methoxide; 2) 1M sodium methoxide / 1) anhydr. MeOH, reflux, 2 h; 2) MeOH, reflux, 1 h View Scheme

2'-deoxy-N2-isobutyrylguanosine 3',5'-diisobutyrate (82921-42-4) → 2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1. triethylamine, dimethylaminopyridine, mesitylenesulphonyl chloride, 2a. N-methyl pyrrolidine, 2b. thiolacetic acid / 1. CH2Cl2, RT, 2a. ice bath, 2b. 30 min 2: 100 percent / 2 M NaOH / ethanol View Scheme

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) → 2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)purine-6-sulfenamide (124416-63-3)

Conditions	Yield
With potassium hydroxide; sodium hydroxide; sodium hypochlorite In water 0 deg C to RT;	86%

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) → 2-amino-9-(β-D-2'-deoxyribofuranosyl)-purine (3616-24-8)

Conditions	Yield
nickel In ethanol; water desulfuration; Heating;	77%
With nickel	75%
With nickel In water at 50℃; for 13h;	73%

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) + triethylamine (121-44-8) → 2'-deoxy-6-thioguanosine-5'-triphosphate triethylammonium salt

Conditions	Yield
Stage #1: 2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine With phosphorous acid trimethyl ester; trichlorophosphate at 0℃; for 3h; phosphorylation; Stage #2: triethylamine With tributyl-amine; bis(tri-n-butylammonium) pyrophosphate In N,N-dimethyl-formamide pH=7.0; phosphorylation;	38%

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) + cobalt(II) nitrate hexahydrate → [Co(2'-deoxy-6-thioguanine)3](NO3)2 dihydrate

Conditions	Yield
In methanol at 60℃; for 24h;	31%

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) + methyl iodide (74-88-4) → 2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-(methylthio)purine (37113-42-1)

Conditions	Yield
In ammonium hydroxide other conditions: phosphate aq. solution, pH 8.5;
With ammonium hydroxide for 0.666667h; Ambient temperature;	90 mg
With ammonium hydroxide for 1.5h;

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) → thioguanine (154-42-7) + 2-deoxy–α-D-ribose 1-phosphate (17039-17-7)

Conditions	Yield
With E. coli purine nucleoside phosphorylase Enzyme kinetics; Substitution;

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) → 9-(2-deoxy-β-D-ribofuranosyl)purine-2-thione

Conditions	Yield
Multi-step reaction with 5 steps 1: 77 percent / Raney nickel / H2O; ethanol / Heating 2: 80 percent / pyridine / 2 h 3: 35 percent / SbCl3; tert-butyl nitrite / CH2Cl2 / 4 h / -5 °C 4: pyridine / 72 h / 75 °C 5: 40 percent / NH3; 2-mercaptoethanol / methanol / 24 h / 20 °C View Scheme

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) → 2-chloro-9-(2-deoxy-3,5-diisobutyryl-β-D-ribofuranosyl)purine (273721-25-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 77 percent / Raney nickel / H2O; ethanol / Heating 2: 80 percent / pyridine / 2 h 3: 35 percent / SbCl3; tert-butyl nitrite / CH2Cl2 / 4 h / -5 °C View Scheme

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) → (R,S)-2-amino-9-(2-deoxy-β-D-erythro-pentafuranosyl)purine-6-sulfinamide (124416-58-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / NaOCl, NaOH, 2N KOH / H2O / 0 deg C to RT 2: 69 percent / MCPBA / CH2Cl2; ethanol / 1.5 h / 0 deg C to RT View Scheme

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) → 2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)purine-6-sulfonamide (124416-64-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / NaOCl, NaOH, 2N KOH / H2O / 0 deg C to RT 2: 50 percent / MCPBA / ethanol / Ambient temperature View Scheme

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) + chloroamine (12190-75-9) → 2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)purine-6-sulfenamide (124416-63-3)

Conditions	Yield
With sodium hypochlorite In potassium hydroxide; ammonium hydroxide; ethanol	2.5 g (84%)

2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-mercapto-9H-purine (789-61-7) + trifluoroethylamine (753-90-2) → 2-amino-N6-(2,2,2-trifluoroethyl)-2'-deoxyadenosine

Conditions	Yield
With sodium periodate at 50℃; for 1h; Darkness;

Upstream product

• 136112-93-1 Isobutyric acid (2R,3S,5R)-5-(2-isobutyrylamino-6-thioxo-1,6-dihydro-purin-9-yl)-2-isobutyryloxymethyl-tetrahydro-furan-3-yl ester 
• 82921-42-4 2'-deoxy-N²-isobutyrylguanosine 3',5'-diisobutyrate 
• 10310-21-1 2-Amino-6-chloropurin 
• 4330-21-6 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride 
• 35095-93-3 2-Amino-6-chloro-9-(2-deoxy-3,5-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)purine 
• 961-07-9 2'-Deoxyguanosine 

Downstream Products

• 37113-42-1 2'-deoxy-6-methylthioguanosine 
• 3616-24-8 2-amino-9-(β-D-2'-deoxyribofuranosyl)-purine 
• 154-42-7 thioguanine 
• 17039-17-7 2-deoxy–α-D-ribose 1-phosphate 

Relevant academic research and scientific papers

6-O-substituted guanosine derivatives

The following species of N6-activated guanosine derivatives are disclosed: 2-N-trifluoroacetamido-6-(4-nitrophenoxy)-9-(2-deoxy-beta-D-erythro-pentofuranosyl)purine 2-N-trifluoroacetamido-6-pentafluorophenoxy-9-(2-deoxy-beta-D-erythro-pentofuranosyl)purine 6-dimethylpyridinium-9-(2-deoxy-beta-D-erythropentofuranosyl)purine These guanosine compounds are useful as precursors in the synthesis of a wide variety of antiviral and anticancer nucleosides such as 2-amino-2-deoxyadenosine or 6-thio-deoxyguanosine. Also disclosed are oligonucleotides containing the above nucleosides which are precursors to modified oligonucleotides which are useful as hybridization probes.

Synthesis of 2'-deoxyisoinosine and related 2'-deoxyribonucleosides

Various 2-substituted purine and pyrrolo[2,3-d]pyrimidine 2'-deoxyribonucleosides with methylthio (13a), chloro (13b), methoxy (9b), and oxo (2, 3) substituents at C(2) are prepared. They are obtained either via stereoselective nucleobase-anion glycosylation or by base transformation. A three-step synthesis of the unknown 2'-deoxyisoinosine (2) from 2'-deoxyguanosine (15) is described. Compound 2 as well as its 7-deazapurine derivative 3 exhibit strong fluorescence.

Simple synthesis of 4-thiothymidine, 4-thiouridine and 6-thio-2′-deoxyguanosine

4-triazolo-pyrimidine nucleosides and 6-O-(mesitylenesulfonyl)-2′-deoxyguanosine, when treated with thiolacetic acid at room temperature, gave the corresponding 4-thiopyrimidine nucleosides and 6-thio-2′-deoxyguanosine with high yields (86-93%). Possible mechanisms are discussed.

One-flask syntheses of 6-thioguanosine and 27′-deoxy-6-thioguanosine

We have previously reported that reaction of guanosine or 2′-deoxyguanosine with trifluoroacetic anhydride in pyridine gives a putative 6-pyridyl intermediate from which several 6-substituted derivatives may be obtained.1 We now report high-yield conversion of guanosine and 2′deoxyguanosine to the corresponding 6-thio compounds in a two-step, one-flask reaction via this 6-pyridyl intermediate. Standard Raney nickel treatment, as reported for the ribonucleoside,2 then gives the 2-aminopurine nucleosides.

A convenient synthesis of 2'-deoxy-6-thioguanosine, ara-guanine, ara-6-thioguanine and certain related purine nucleosides by the stereospecific sodium salt glycosylation procedure [1]

A simple and high-yield synthesis of biologically significant 2'-deoxy-6-thioguanosine, ara-6-thioguanine and araG has been accomplished employing the stereospecific sodium salt glycosylation method. Glycosylation of the sodium salt of 6-chloro- and 2-amino-6-chloropurine (1 and 2, respectively) with 1-chloro-2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranose gave the corresponding N-9 substituted nucleosides as major products with the β-anomeric configuration (4 and 5, respectively) along with a minor amount of the N-7 positional isomers (6 and 7). Treatment of 4 with hydrogen sulfide in methanol containing sodium methoxide gave 2'-deoxy-6-thioinosine in 93% yield. Similarly, 5 was transformed into 2'-deoxy-6-thioguanosine (β-TGdR, 11) in 71% yield. Reaction of the sodium salt of 2 with 1-chloro-2,3,5-tri-O-benzyl-α-D-arabinofuranose gave N-7 and N-9 glycosylated products 13 and 9, respectively. Debenzylation of 9 with boron trichloride at -78° gave the versatile intermediate 2-amino-6-chloro-9-β-D-arabinofuranosylpurine 62% yield. Direct treatment of 14 with sodium hydrosulfide furnished ara-6-thioguanine. Alkaline hydrolysis of 14 readily gave 9-β-D-arabinofuranosylguanine (araG, 17), which on subsequent phosphorylation with phosphorus oxychloride in trimethyl phosphate afforded araG 5'-monophosphate.