34408-14-5

Usage

Uses

Used in Oncology:
8-Chloroadenosine is used as an anticancer agent for its ability to inhibit the growth of various types of cancer cells. It targets the DNA and RNA synthesis of these cells, thereby disrupting their proliferation and survival mechanisms.
Used in Apoptosis Induction:
8-Chloroadenosine is utilized to induce apoptosis, or programmed cell death, in cancer cells, which is a critical aspect of its potential as a therapeutic agent in cancer treatment.
Used in Combination Therapy:
8-Chloroadenosine is also used to enhance the effectiveness of other chemotherapy drugs when used in combination, potentially increasing the overall therapeutic impact on cancer treatment and improving patient outcomes.
Used in Pharmaceutical Research and Development:
In the pharmaceutical industry, 8-Chloroadenosine is used as a subject of research and development for the creation of novel therapeutic agents targeting cancer. Its unique properties make it a valuable compound in the quest for more effective cancer treatments.

InChI:InChI=1/C10H12ClN5O4/c11-10-15-4-7(12)13-2-14-8(4)16(10)9-6(19)5(18)3(1-17)20-9/h2-3,5-6,9,17-19H,1H2,(H2,12,13,14)

Synthetic route

adenosine (58-61-7) → 8-chloroadenosine (34408-14-5)

Conditions	Yield
With N-chloro-succinimide; acetic acid In N,N-dimethyl-formamide at 20℃; for 48h; Concentration; Reagent/catalyst;	52%
With hydrogenchloride; 3-chloro-benzenecarboperoxoic acid In N,N-dimethyl acetamide for 3.5h; Ambient temperature;	50%
With hydrogenchloride; 3-chloro-benzenecarboperoxoic acid In N,N-dimethyl acetamide at 0 - 25℃; for 2.5h;	39%

8-mercaptoadenosine (3001-45-4) → 8-chloroadenosine (34408-14-5)

Conditions	Yield
With N-chloro-succinimide In methanol at 20℃; for 3h;	52%

N6-Benzyladenosine (4294-16-0) → 8-chloroadenosine (34408-14-5) + 6-benzylamino-8-chloro-9-(β-D-ribofuranosyl)purine (1427459-38-8)

Conditions	Yield
With N-chloro-succinimide In N,N-dimethyl-formamide at 45℃; for 18h;	A n/a B 20%

N-chloro-succinamide + water (7732-18-5) + adenosine (58-61-7) → 8-chloroadenosine (34408-14-5)

Conditions	Yield
With acetic acid In methanol; N,N-dimethyl-formamide	0.8 g (65%)

8-bromoadenosine (2946-39-6) → 8-chloroadenosine (34408-14-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: thiourea / ethanol / 1 h / Reflux 2: N-chloro-succinimide / methanol / 3 h / 20 °C View Scheme

8-chloroadenosine (34408-14-5) + methylamine (74-89-5) → 8-Methylaminoadenosine (13389-13-4)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 18.5h;	93%
With triethylamine at 20℃; for 20h;	93%

8-chloroadenosine (34408-14-5) + acetic anhydride (108-24-7) → 8-chloro-2',3',5'-tri-O-acetyladenosine (64344-20-3)

Conditions	Yield
With pyridine for 16h; Ambient temperature;	88%

8-chloroadenosine (34408-14-5) + acetone (67-64-1) → 2’,3’-O-isopropylidene-8-chloroadenosine

Conditions	Yield
With perchloric acid at 20℃; for 0.5h;	79%

8-chloroadenosine (34408-14-5) + Phenoxyacetyl chloride (701-99-5) → N6-phenoxyacetyl-8-chloroadenosine (508179-29-1)

Conditions	Yield
With pyridine; 1,2,4-Triazole; chloro-trimethyl-silane In acetonitrile at 25 - 55℃; for 8h;	71%

phenyl-1-yl-L-glycine benzyl ester phosphorochloridate (926308-62-5) + 8-chloroadenosine (34408-14-5) → benzyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)acetate

Conditions	Yield
With tert-butylmagnesium chloride In tetrahydrofuran at 20℃;	28%

8-chloroadenosine (34408-14-5) + benzyl 2-aminoacetate hydrochloride (2462-31-9) → 8-chloroadenosine 5’-O-bis(benzyloxyglycin-N-yl)phosphate

Conditions	Yield
Stage #1: 8-chloroadenosine With phosphorous acid trimethyl ester; trichlorophosphate at -5 - 20℃; for 4h; Stage #2: benzyl 2-aminoacetate hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at -78 - 20℃; for 20h;	27%

8-chloroadenosine (34408-14-5) + naphth-1-yl-glycine pent-1-yl ester phosphorochloridate → 5’-([(pent-1-yloxy-glycin-N-yl)naphth-1-yl]phosphatyl)-8-chloroadenosine

Conditions	Yield
With tert-butylmagnesium chloride In tetrahydrofuran at 20℃;	15%

8-chloroadenosine (34408-14-5) + phenyl-1-yl-L-glycine cyclohexyl ester phosphorochloridate → cyclohexyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)acetate

Conditions	Yield
With tert-butylmagnesium chloride In tetrahydrofuran at 20℃;	14%

phenyl (benzyloxy-D-alaninyl)phosphorochloridate + 8-chloroadenosine (34408-14-5) → 5’-([(benzyloxy-D-alanin-N-yl)phenyl]phosphatyl)-8-chloroadenosine

Conditions	Yield
Stage #1: 8-chloroadenosine With tert-butylmagnesium chloride In tetrahydrofuran at 20℃; for 0.166667h; Inert atmosphere; Stage #2: phenyl (benzyloxy-D-alaninyl)phosphorochloridate In tetrahydrofuran	11%

8-chloroadenosine (34408-14-5) + naphth-1-yl-glycine benzyl ester phosphorochloridate (1228377-60-3) → 5’-([(benzyloxyglycin-N-yl)naphth-1-yl]phosphatyl)-8-chloroadenosine

Conditions	Yield
With tert-butylmagnesium chloride In tetrahydrofuran at 20℃;	4%

8-chloroadenosine (34408-14-5) + naphth-1-yl-glycine ethyl ester phosphorochloridate → 5’-([(ethyloxy-glycin-N-yl)naphth-1-yl]phosphatyl)-8-chloroadenosine

Conditions	Yield
With tert-butylmagnesium chloride In tetrahydrofuran at 20℃;	4%

8-chloroadenosine (34408-14-5) + phenyl(benzyloxy-L-alaninyl)phosphorochloridate (183370-70-9) → (2S)-benzyl 2-(((((2R,3S,4R,5R)-5-(6-amino-8-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

Conditions	Yield
With tert-butylmagnesium chloride In tetrahydrofuran at 20℃;	2%

8-chloroadenosine (34408-14-5) + O-phenyl-N-(S)-1-(cyclohexoxycarbonyl)ethylphosphoramidic chloride (220592-67-6) → 5’-([(cyclohexyloxy-L-alanin-N-yl)phenyl]phosphatyl)-8-chloroadenosine

Conditions	Yield
Stage #1: 8-chloroadenosine With pyridine; tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: O-phenyl-N-(S)-1-(cyclohexoxycarbonyl)ethylphosphoramidic chloride In tetrahydrofuran for 24h;	2%

8-chloroadenosine (34408-14-5) + C15H23ClNO4P → 5’-([(neopentyloxy-2,2-dimethylglycin-N-yl)phenyl]phosphatyl)-8-chloroadenosine

Conditions	Yield
Stage #1: 8-chloroadenosine With pyridine; tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: C15H23ClNO4P In tetrahydrofuran for 24h;	2%

methyl bromide (74-83-9) + 8-chloroadenosine (34408-14-5) → 6-Amino-8-chloro-9-((2R,3R,4S,5R)-3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-1-methyl-9H-purin-1-ium; bromide

Conditions	Yield
In N,N-dimethyl acetamide for 120h; Ambient temperature;

8-chloroadenosine (34408-14-5) → 8chloroadenosine-5'-phosphate + 8-chloroadenosine-5'-diphosphate + 8-chloroadenosine-5'-triphosphate

Conditions	Yield
With Tetraethyl pyrophosphate; phosphoric acid; N-ethyl-N,N-diisopropylamine; trichlorophosphate Yield given. Multistep reaction. Yields of byproduct given;

8-chloroadenosine (34408-14-5) → N-(9-{5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-3,4-dihydroxy-tetrahydro-furan-2-yl}-8-chloro-9H-purin-6-yl)-2-phenoxy-acetamide (508179-30-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 71 percent / pyridine; chlorotrimethylsilane; 1,2,4-triazole / acetonitrile / 8 h / 25 - 55 °C 2: 58 percent / DMAP / pyridine / 19 h View Scheme

8-chloroadenosine (34408-14-5) → N-{9-[5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-(tert-butyl-dimethyl-silanyloxy)-3-hydroxy-tetrahydro-furan-2-yl]-8-chloro-9H-purin-6-yl}-2-phenoxy-acetamide (508179-32-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 71 percent / pyridine; chlorotrimethylsilane; 1,2,4-triazole / acetonitrile / 8 h / 25 - 55 °C 2: 58 percent / DMAP / pyridine / 19 h 3: 38 percent / pyridine; Et3N; AgNO3 / tetrahydrofuran / 2.83 h / 25 °C View Scheme

8-chloroadenosine (34408-14-5) → N-{9-[5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-3-(tert-butyl-dimethyl-silanyloxy)-4-hydroxy-tetrahydro-furan-2-yl]-8-chloro-9H-purin-6-yl}-2-phenoxy-acetamide (508179-31-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 71 percent / pyridine; chlorotrimethylsilane; 1,2,4-triazole / acetonitrile / 8 h / 25 - 55 °C 2: 58 percent / DMAP / pyridine / 19 h 3: 16 percent / pyridine; Et3N; AgNO3 / tetrahydrofuran / 2.83 h / 25 °C View Scheme

8-chloroadenosine (34408-14-5) → Succinic acid mono-{(2R,3R,4R,5R)-5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-(tert-butyl-dimethyl-silanyloxy)-2-[8-chloro-6-(2-phenoxy-acetylamino)-purin-9-yl]-tetrahydro-furan-3-yl} ester

Conditions	Yield
Multi-step reaction with 4 steps 1: 71 percent / pyridine; chlorotrimethylsilane; 1,2,4-triazole / acetonitrile / 8 h / 25 - 55 °C 2: 58 percent / DMAP / pyridine / 19 h 3: 38 percent / pyridine; Et3N; AgNO3 / tetrahydrofuran / 2.83 h / 25 °C 4: 71 percent / DMAP / pyridine / 12 h / 25 °C View Scheme

8-chloroadenosine (34408-14-5) → Diisopropyl-phosphoramidous acid (2R,3R,4R,5R)-2-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-(tert-butyl-dimethyl-silanyloxy)-5-[8-chloro-6-(2-phenoxy-acetylamino)-purin-9-yl]-tetrahydro-furan-3-yl ester 2-cyano-ethyl ester

Conditions	Yield
Multi-step reaction with 4 steps 1: 71 percent / pyridine; chlorotrimethylsilane; 1,2,4-triazole / acetonitrile / 8 h / 25 - 55 °C 2: 58 percent / DMAP / pyridine / 19 h 3: 16 percent / pyridine; Et3N; AgNO3 / tetrahydrofuran / 2.83 h / 25 °C 4: 50 percent / 2,4,6-collidine; N-methylimidazole / tetrahydrofuran / 4 h / 25 °C View Scheme

8-chloroadenosine (34408-14-5) → 8-Chloro-purine riboside

Conditions	Yield
Multi-step reaction with 3 steps 1: 88 percent / pyridine / 16 h / Ambient temperature 2: 39 percent / t-butyl nitrite / tetrahydrofuran / 1 h / Heating 3: 37 percent / aq. NH4HCO3 / 120 h / Ambient temperature; porcine liver esterase View Scheme

8-chloroadenosine (34408-14-5) → 8-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (157025-49-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 88 percent / pyridine / 16 h / Ambient temperature 2: 39 percent / t-butyl nitrite / tetrahydrofuran / 1 h / Heating View Scheme

8-chloroadenosine (34408-14-5) → 8-chloro-1-methyladenine (92001-48-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: N,N-dimethyl-acetamide / 120 h / Ambient temperature 2: glacial acetic acid / 2.5 h / Heating 3: 232 mg / conc. aq. ammonia View Scheme

8-chloroadenosine (34408-14-5) → 6-Amino-8-chloro-1-methyl-9H-purin-1-ium; bromide

Conditions	Yield
Multi-step reaction with 2 steps 1: N,N-dimethyl-acetamide / 120 h / Ambient temperature 2: glacial acetic acid / 2.5 h / Heating View Scheme

Upstream product

• 2946-39-6 8-bromoadenosine 
• 3001-45-4 8-mercaptoadenosine 
• 4294-16-0 N₆-Benzyladenosine 
• 7732-18-5 water 
• 58-61-7 adenosine 

Downstream Products

• 13389-13-4 8-Methylaminoadenosine 
• 508179-31-5 N-{9-[5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-3-(tert-butyl-dimethyl-silanyloxy)-4-hydroxy-tetrahydro-furan-2-yl]-8-chloro-9H-purin-6-yl}-2-phenoxy-acetamide 

Relevant academic research and scientific papers

ADENOSINE DERIVATIVES FOR USE IN THE TREATMENT OF CANCER

The present invention relates to chemical compounds of formula (I) as defined in the amended claims, their preparation and their use in the treatment of cancer.

α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) Inhibitors

ecto-5′-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor α,β-methylene-ADP (AOPCP, adenosine-5′-O-[(phosphonomethyl)phosphonic acid]) was used as a lead structure, and derivatives modified in various positions were prepared. Products were tested at rat recombinant eN. 6-(Ar)alkylamino substitution led to the largest improvement in potency. N6-Monosubstitution was superior to symmetrical N6,N6-disubstitution. The most potent inhibitors were N6-(4-chlorobenzyl)- (10l, PSB-12441, Ki 7.23 nM), N6-phenylethyl- (10h, PSB-12425, Ki 8.04 nM), and N6-benzyl-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (10g, PSB-12379, Ki 9.03 nM). Replacement of the 6-NH group in 10g by O (10q, PSB-12431) or S (10r, PSB-12553) yielded equally potent inhibitors (10q, 9.20 nM; 10r, 9.50 nM). Selected compounds investigated at the human enzyme did not show species differences; they displayed high selectivity versus other ecto-nucleotidases and ADP-activated P2Y receptors. Moreover, high metabolic stability was observed. These compounds represent the most potent eN inhibitors described to date.

6,8-DISUBSTITUTED PURINE COMPOSITIONS

6,8-Disubstituted purines which can be used in drug and cosmetic compositions and/or applications are provided. These 6,8-disubstituted purines have a wide range of biological activities, including for example anti-inflammatory, anti-senescent, as well as well as other activities which are especially useful in pharmaceutical and cosmetic applications. The 6,8-disubstituted purine compounds and compositions containing such 6,8-disubstituted purines provide growth-regulatory, differentiating, antisenescent and antiaging properties with improved selectivities and efficiencies and lower toxicities than analogues known heretofore.

Synthesis and hybridization properties of RNA containing 8-chloroadenosine.

8-Chloroadenosine (8-Cl-Ado) has shown potential as a chemotherapeutic agent for the treatment of multiple myeloma and certain leukemias. 8-Cl-Ado treatment leads to a decrease in global RNA levels and incorporation of the analog into cellular RNA in malignant cells. To investigate the effects of 8-Cl-Ado modifications on RNA structure and function, an 8-Cl-Ado phosphoramidite and controlled-pore glass support were synthesized and used to introduce 8-Cl-Ado at internal and 3'- terminal positions, respectively. RNA oligonucleotides containing 8-chloroadenine (8-Cl-A) residues were synthesized and hybridized with complementary RNA strands. Circular dichroism spectroscopy of the resulting RNA duplexes revealed that the modified nucleobase does not perturb the overall A-form helix geometry. The thermal stabilities of 8-Cl-Ado modified duplexes were determined by UV thermal denaturation analysis and were compared with analogous natural duplexes containing standard and mismatched base pairs. The 8-Cl-Ado modification destabilizes RNA duplexes by approximately 5 kcal/mole, approximately as much as a U:U mismatched base pair. The duplex destabilization of 8-Cl-A may result from perturbation of Watson-Crick base pairing induced by conformational preferences of 8-halogenated nucleosides.

8-Chloroadenosine 3', 5'-cyclic monophosphate preparations

The compound 8-Chloroadenosine 3',5'-cyclic phosphate is used to treat malignant tumors in warm blooded animals. Two novel single step syntheses of 8-chloroadenosine 3',5'-cyclic phosphate and other related adenine and adenosine compounds from corresponding adenosine 3', 5'-cyclic phosphate and other respective related adenosine compounds are disclosed.