Didanosine
Overview
Description
Didanosine, also known as 2’,3’-dideoxyinosine, is a synthetic nucleoside analogue of adenosine. It is primarily used as an antiretroviral medication for the treatment of Human Immunodeficiency Virus (HIV) infection. This compound works by inhibiting the reverse transcriptase enzyme, which is essential for the replication of HIV. This compound was first described in 1975 and approved for use in the United States in 1991 .
Scientific Research Applications
Didanosine has a wide range of applications in scientific research:
Chemistry: Used as a model compound for studying nucleoside analogues and their chemical properties.
Biology: Employed in studies of nucleic acid metabolism and enzyme interactions.
Medicine: Extensively used in research on HIV treatment and resistance mechanisms.
Industry: Utilized in the development of antiretroviral therapies and in the study of drug-drug interactions.
Mechanism of Action
Target of Action
Didanosine, also known as ddI, is a potent inhibitor of HIV replication . Its primary target is the HIV-1 reverse transcriptase enzyme . This enzyme plays a crucial role in the life cycle of the HIV virus, as it is responsible for converting the virus’s RNA into DNA, a necessary step for the virus to replicate within the host’s cells .
Mode of Action
This compound acts as a chain-terminator of viral DNA by binding to the reverse transcriptase enzyme . It is metabolized intracellularly to its active form, dideoxyadenosine triphosphate (ddATP) . This active metabolite competes with natural deoxyadenosine triphosphate (dATP) for incorporation into the growing viral DNA chain . When incorporated, it prevents the addition of further nucleotides, thereby terminating the DNA chain and blocking viral DNA synthesis .
Biochemical Pathways
This compound is a dideoxynucleoside analogue, which undergoes intracellular conversion to its active triphosphate metabolite . This conversion involves a series of cellular enzymes and biochemical pathways . The active metabolite, ddATP, then inhibits the HIV reverse transcriptase enzyme and terminates the proviral DNA, producing virustatic inhibition of actively replicating HIV .
Pharmacokinetics
This compound is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing . It has an elimination half-life of 1.5 hours . This compound is subject to degradation by the acidic pH of the stomach, and some formulations are buffered to resist this acidic pH . It is excreted by the kidneys .
Result of Action
The result of this compound’s action is the suppression of HIV replication . By acting as a chain terminator of viral DNA, it blocks the synthesis of viral DNA, thereby preventing the virus from replicating within the host’s cells . This leads to a decrease in the viral load and an increase in CD4 cell counts, improving the immune response against the virus .
Action Environment
The efficacy and stability of this compound can be influenced by various environmental factors. For example, this compound is unstable in acidic solutions . Therefore, the pH of the stomach can affect the stability and absorption of this compound . Additionally, co-administration with other drugs can lead to interactions that may affect the action of this compound . For instance, alcohol can exacerbate this compound’s toxicity, and avoiding drinking alcohol while taking this compound is recommended .
Safety and Hazards
Biochemical Analysis
Biochemical Properties
Didanosine is a nucleoside analogue of adenosine . It does not have any of the regular bases, instead it has hypoxanthine attached to the sugar ring . Within the cell, this compound is phosphorylated to the active metabolite of dideoxyadenosine triphosphate, ddATP, by cellular enzymes . This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains .
Cellular Effects
This compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA by binding to reverse transcriptase . It is then metabolized to dideoxyadenosine triphosphate, its putative active metabolite . This compound is used, in combination with other antiretroviral agents, in the treatment of HIV-1 infection in adults . It has been associated with serious side-effects in some people who have taken it .
Molecular Mechanism
This compound is metabolized intracellularly by a series of cellular enzymes to its active moiety, dideoxyadenosine triphosphate (ddATP), which inhibits the HIV reverse transcriptase enzyme competitively by competing with natural dATP . It acts as a chain terminator of viral DNA synthesis and suppresses HIV replication .
Temporal Effects in Laboratory Settings
This compound is rapidly metabolized intracellularly to its active moiety, 2,3-dideoxyadenosine-5-triphosphate (ddA-TP). It is then further metabolized hepatically to yield hypoxanthine, xanthine, and uric acid .
Dosage Effects in Animal Models
In animal models, this compound has been shown to cause sensory neuropathy. This was associated with mitochondrial injury on neurons and reduced BDNF production by Schwann cells in dorsal root ganglia .
Metabolic Pathways
This compound is converted within the cell to the mono-, di-, and triphosphates of dideoxyadenosine . These dideoxyadenosine triphosphates act as substrate and inhibitor of HIV reverse transcriptase, thereby blocking viral DNA synthesis and suppressing HIV replication .
Transport and Distribution
This compound enters the target cell by means of a nucleoside transporter protein . Once in the cytoplasm, it is converted to the active compound, dideoxyadenosine-5’-triphosphate (ddATP), through a multistep process carried out by cellular enzymes .
Subcellular Localization
The appropriate subcellular localization of proteins is crucial because it provides the physiological context for their function
Preparation Methods
Synthetic Routes and Reaction Conditions: Didanosine is synthesized through a multi-step process starting from inosine. The key steps involve the selective removal of hydroxyl groups at the 2’ and 3’ positions of the ribose moiety. This is typically achieved through a series of chemical reactions including protection, deprotection, and selective reduction steps.
Industrial Production Methods: Industrial production of this compound involves large-scale synthesis using similar chemical routes as in laboratory synthesis but optimized for higher yields and purity. The process includes rigorous quality control measures to ensure the final product meets pharmaceutical standards.
Types of Reactions:
Oxidation: this compound can undergo oxidation reactions, although these are not typically relevant to its pharmacological activity.
Reduction: The compound itself is a reduced form of inosine, achieved through selective reduction steps during synthesis.
Substitution: this compound can participate in nucleophilic substitution reactions, particularly at the purine ring.
Common Reagents and Conditions:
Oxidation: Common oxidizing agents like hydrogen peroxide or potassium permanganate.
Reduction: Reducing agents such as sodium borohydride or lithium aluminum hydride.
Substitution: Nucleophiles like amines or thiols under basic conditions.
Major Products Formed: The major product of these reactions is typically this compound itself or its derivatives, depending on the specific reaction conditions and reagents used.
Comparison with Similar Compounds
Zidovudine (AZT): Another nucleoside reverse transcriptase inhibitor used in HIV treatment.
Stavudine (d4T): Similar mechanism of action but different side effect profile.
Lamivudine (3TC): Often used in combination with other antiretrovirals for synergistic effects.
Uniqueness: Didanosine is unique in its specific structural modifications, which confer its activity against HIV. Unlike other nucleoside analogues, this compound has a hypoxanthine base attached to the sugar ring, which is crucial for its mechanism of action .
Properties
IUPAC Name |
9-[5-(hydroxymethyl)oxolan-2-yl]-1H-purin-6-one |
Source
|
|---|---|---|
| Details | Computed by Lexichem TK 2.7.0 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C10H12N4O3/c15-3-6-1-2-7(17-6)14-5-13-8-9(14)11-4-12-10(8)16/h4-7,15H,1-3H2,(H,11,12,16) |
Source
|
| Details | Computed by InChI 1.0.6 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
BXZVVICBKDXVGW-UHFFFAOYSA-N |
Source
|
| Details | Computed by InChI 1.0.6 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1CC(OC1CO)N2C=NC3=C2N=CNC3=O |
Source
|
| Details | Computed by OEChem 2.3.0 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C10H12N4O3 |
Source
|
| Details | Computed by PubChem 2.1 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID80860902 |
Source
|
| Record name | 9-[5-(Hydroxymethyl)oxolan-2-yl]-1,9-dihydro-6H-purin-6-one | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID80860902 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
236.23 g/mol |
Source
|
| Details | Computed by PubChem 2.1 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
CAS No. |
69655-05-6 |
Source
|
| Record name | 2', hydrate | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=612049 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. | |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
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