ジダノシン
説明
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. Didanosine 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 .
作用機序
ジダノシンは細胞内で活性型であるジデオキシアデノシン三リン酸 (ddATP) に代謝されます。この活性代謝物は、天然の基質であるデオキシアデノシン三リン酸 (dATP) と競合することにより、HIV逆転写酵素を阻害します。 ウイルスDNAに組み込まれることで、ddATPは鎖の終結を引き起こし、ウイルスの複製を防ぎます .
類似化合物:
ジドブジン (AZT): HIV治療に使用される別のヌクレオシド逆転写酵素阻害剤。
スタブジン (d4T): 作用機序は似ていますが、副作用のプロフィールは異なります。
ラミブジン (3TC): 相乗効果のために、他の抗レトロウイルス薬と組み合わせて使用されることが多いです。
独自性: ジダノシンは、HIVに対する活性を付与する特定の構造修飾において独自です。 他のヌクレオシド類似体とは異なり、ジダノシンは糖環にヒポキサンチン塩基が結合しており、これはその作用機序に不可欠です .
科学的研究の応用
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.
生化学分析
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, Didanosine 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
Didanosine 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 . Didanosine 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
Didanosine 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
Didanosine 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, Didanosine 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
Didanosine 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
Didanosine 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
準備方法
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 didanosine 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: Didanosine 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: Didanosine 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 didanosine itself or its derivatives, depending on the specific reaction conditions and reagents used.
類似化合物との比較
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, didanosine has a hypoxanthine base attached to the sugar ring, which is crucial for its mechanism of action .
特性
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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