Prodrug (5) 2024-2025 PDF

PRODRUGS 5TH CLASS, 1 ST SEMESTER 2024-2025 Dr. Rafid Mohammed Lec:5 ‫ ﯾﻌﺪ ھﺬا‬، ‫ ﻓﻲ اﻷﻧﻈﻤﺔ اﻟﺒﯿﻮﻟﻮﺟﯿﺔ‬.‫اﻟﻔﺴﻔﺮة ھﻲ إﺿﺎﻓﺔ ﻣﺠﻤﻮﻋﺔ ﻓﺴﻔﻮرﯾﻞ إﻟﻰ ﺟﺰيء‬ ‫اﻟﺘﻔﺎﻋﻞ ﺣﯿﻮﯾﺎ ﻟﻠﺘﺨﺰﯾﻦ اﻟﺨﻠﻮي وﻧﻘﻞ اﻟﻄﺎﻗﺔ اﻟﺤﺮة ﺑﺎﺳﺘ...

PRODRUGS 5TH CLASS, 1 ST SEMESTER 2024-2025 Dr. Rafid Mohammed Lec:5 ‫ ﯾﻌﺪ ھﺬا‬، ‫ ﻓﻲ اﻷﻧﻈﻤﺔ اﻟﺒﯿﻮﻟﻮﺟﯿﺔ‬.‫اﻟﻔﺴﻔﺮة ھﻲ إﺿﺎﻓﺔ ﻣﺠﻤﻮﻋﺔ ﻓﺴﻔﻮرﯾﻞ إﻟﻰ ﺟﺰيء‬ ‫اﻟﺘﻔﺎﻋﻞ ﺣﯿﻮﯾﺎ ﻟﻠﺘﺨﺰﯾﻦ اﻟﺨﻠﻮي وﻧﻘﻞ اﻟﻄﺎﻗﺔ اﻟﺤﺮة ﺑﺎﺳﺘﺨﺪام ﺟﺰﯾﺌﺎت ﺣﺎﻣﻠﺔ ﻟﻠﻄﺎﻗﺔ‬. Phosphorylation  Phosphorylation is the addition of a phosphoryl (PO3) group to a molecule. In biological systems, this reaction is vital for the cellular storage and transfer of free energy using energy carrier molecules.  Phosphorylation is used to produce high-energy phosphodiester bonds such as those present in ATP and GTP. The body then typically uses these molecules to phosphorylate other molecules and, in the process of doing so, activates these molecules. ATP structure Phosphorylation  Phosphorylation introduces a leaving group, which can be displaced by an incoming nucleophile. This is seen, for example, in the synthesis of DNA and RNA, in which nucleotides are added to the 3' end of a growing chain of DNA or RNA as shown in the following scheme: phosphodiester bonds  Antiviral agents  Phosphorylation is commonly required for the bioactivation of antiviral agents. These agents are commonly nucleosides, which must be converted to the nucleotides to have activity. Antiviral agents  Most often, antiviral agents disrupt the synthesis or function of DNA or RNA, which is generally accomplished by conversion to the triphosphate.  Since normal cells are less involved in the synthesis of DNA and RNA, compounds have been sought that would be converted to the triphosphates, (active form), in greater amounts in infected cells than in normal cells. ‫ﻧﻈﺮا ﻷن اﻟﺨﻼﯾﺎ اﻟﻄﺒﯿﻌﯿﺔ أﻗﻞ ﻣﺸﺎرﻛﺔ ﻓﻲ ﺗﺨﻠﯿﻖ اﻟﺤﻤﺾ اﻟﻨﻮوي‬ ‫ ﻓﻘﺪ ﺗﻢ اﻟﺒﺤﺚ ﻋﻦ ﻣﺮﻛﺒﺎت ﯾﻤﻜﻦ ﺗﺤﻮﯾﻠﮭﺎ‬، ‫واﻟﺤﻤﺾ اﻟﻨﻮوي اﻟﺮﯾﺒﻲ‬ ‫ ﺑﻜﻤﯿﺎت أﻛﺒﺮ ﻓﻲ اﻟﺨﻼﯾﺎ‬، )‫ (اﻟﺸﻜﻞ اﻟﻨﺸﻂ‬، ‫إﻟﻰ ﺛﻼﺛﻲ اﻟﻔﻮﺳﻔﺎت‬ ‫اﻟﻤﺼﺎﺑﺔ ﻣﻘﺎرﻧﺔ ﺑﺎﻟﺨﻼﯾﺎ اﻟﻄﺒﯿﻌﯿﺔ‬.  Idoxuridine  Therefore, nucleosides that have higher affinity for the viral kinase enzymes than the mammalian kinases are desirable and have greater selective toxicity.  This can be seen in the prodrug idoxuridine, which was the first agent to show clinical effectiveness against viruses as shown in the following scheme:  The nucleoside enters the cell, where it is phosphorylated. ‫ ﺣﯿﺚ ﯾﺘﻢ ﻓﺴﻔﺮﺗﮫ‬، ‫ﯾﺪﺧﻞ اﻟﻨﻮﻛﻠﯿﻮزﯾﺪ اﻟﺨﻠﯿﺔ‬  In virally infected cells, this phosphorylation is accomplished preferentially by viral thymidine kinase, because the idoxuridine is a better substrate for the viral enzyme than for the corresponding mammalian enzyme. ‫ ﯾﺘﻢ ﺗﻨﺸﯿﻂ اﻟﺪواء إﻟﻰ ﺣﺪ ﻛﺒﯿﺮ ﻓﻲ اﻟﺨﻼﯾﺎ اﻟﻤﺼﺎﺑﺔ ﺑﻔﯿﺮوس‬، ‫ﻟﺬﻟﻚ‬ Idoxuridine ‫ ﻋﻠﻰ اﻟﺮﻏﻢ ﻣﻦ أن ھﺬه اﻻﻧﺘﻘﺎﺋﯿﺔ‬، ‫وﯾﺤﻘﻖ ﺑﻌﺾ اﻟﺴﻤﯿﺔ اﻻﻧﺘﻘﺎﺋﯿﺔ‬ ‫ وھﻨﺎك ﺳﻤﯿﺔ ﻛﺒﯿﺮة ﻟﻠﺨﻼﯾﺎ اﻟﻄﺒﯿﻌﯿﺔ‬، ‫ﻣﻨﺨﻔﻀﺔ إﻟﻰ ﺣﺪ ﻣﺎ‬.  Therefore, the drug is activated to a greater extent in the virally infected cells and achieves some selective toxicity, although this selectivity is rather low, and there is significant toxicity to normal cells.  Once the drug has been phosphorylated to the triphosphate stage, it can inhibit DNA synthesis in a number of ways, including: 1-Inhibition of viral DNA polymerase. 2-Incorporation into DNA, which results in incorrect base pairing that, disrupts the ability of DNA to function as a template for DNA and RNA synthesis. Advantages of the prodrug idoxuridine  Achieves some selective toxicity.  Increased cell penetration.  The prodrug can easily enter the cell via active transport mechanisms, whereas the active nucleotides are unable to use this process and are too polar to cross the membrane via passive diffusion. CHEMICAL DELIVERY SYSTEMS:  The knowledge gained from drug metabolism and prodrug studies may be used to target a drug to its site of action.  Site-specific chemical delivery requires that the prodrug reaches the target site and that the enzymatic or chemical process exists at the target site for conversion of the prodrug to the active drug. Many factors are involved in the relative success of site-specific drug delivery including: ‫ﻣﺪى ﻧﻀﺢ اﻟﺠﮭﺎز اﻟﻤﺴﺘﮭﺪف ؛‬  Extent of target organ perfusion; since high metabolic activity occurs in highly perfused tissues such as liver and kidney, delivery to these organs has a natural advantage. ‫ﻣﻌﺪل ﺗﺤﻮﯾﻞ اﻟﺪواء اﻷوﻟﻲ‬  Rate of conversion of prodrug to active drug in both target and non target sites; On arrival at the target site, the prodrug should be selectively converted to drug relative to its rate of conversion at non target sites.  Input/output rates of prodrug and drug from the target sites. It is highly desirable to have the active drug, once formed, migrate from the target site at a slow rate. ، ‫ ﺑﻤﺠﺮد ﺗﻜﻮﯾﻨﮫ‬، ‫ﻣﻦ اﻟﻤﺮﻏﻮب ﻓﯿﮫ ﻟﻠﻐﺎﯾﺔ أن ﯾﮭﺎﺟﺮ اﻟﺪواء اﻟﻨﺸﻂ‬ ‫ﻣﻦ اﻟﻤﻮﻗﻊ اﻟﻤﺴﺘﮭﺪف ﺑﻤﻌﺪل ﺑﻄﻲء‬. Aims of site-specific drug delivery: 1- Increased therapeutic effectiveness. 2- Limited side effects. Other chemical drug delivery  Many carrier systems have been evaluated for drug delivery, including:  Proteins, Polysaccharides, liposomes, emulsions, cellular carriers (erythrocytes and leukocytes), Magnetic control targeting, and implanted mechanical pumps. What is the Basic Goal?  Protect a non-specific biological environment from a drug  Protect a drug from a non-specific biological environment  Especially evaluated for drugs with a narrow therapeutic window especially anti-cancer agents ‫ﯾﺘﻢ ﺗﻘﯿﯿﻤﮫ ﺑﺸﻜﻞ ﺧﺎص ﻟﻸدوﯾﺔ ذات اﻟﻨﺎﻓﺬة اﻟﻌﻼﺟﯿﺔ اﻟﻀﯿﻘﺔ‬ ‫ﺧﺎﺻﺔ اﻟﻌﻮاﻣﻞ اﻟﻤﻀﺎدة ﻟﻠﺴﺮطﺎن‬  General notes:  Site-specific drug delivery has been evaluated extensively for drugs with narrow therapeutic windows, such as many of the anticancer drugs.  The target sites include cancer cells, GI tract, kidney and urinary tract, bacterial cells, viral material, ocular tissue, and the blood—brain barrier. Examples of site-specific drug delivery:  The prodrug methenamine can be considered a site-specific chemical delivery system for the urinary tract antiseptic agent formaldehyde.  The low pH of the urine promotes the hydrolysis of methenamine to formaldehyde, the active antibacterial agent.  The rate of hydrolysis increases with increased acidity (decreased pH), and this can be promoted by administration of urinary pH-lowering agents or by diet. The pH of the plasma is buffered to about 7.4, and the rate of hydrolysis is low, preventing systemic toxicity from formaldehyde. Methenamine Idoxuridine  The antiviral drugs, such as idoxuridine these drugs serve as substrates for phosphorylating enzymes found in viruses, and the phosphorylated species is the active antiviral agent.  The active phosphorylated species is incorporated into viral DNA, disrupting viral replication and, thus, producing the antiviral effect. ‫ ﻣﻤﺎ ﯾﻌﻄﻞ ﺗﻜﺎﺛﺮ‬، ‫ﯾﺘﻢ دﻣﺞ اﻷﻧﻮاع اﻟﻤﻔﺴﻔﺮة اﻟﻨﺸﻄﺔ ﻓﻲ اﻟﺤﻤﺾ اﻟﻨﻮوي اﻟﻔﯿﺮوﺳﻲ‬ ‫ وﺑﺎﻟﺘﺎﻟﻲ ﯾﻨﺘﺞ ﻋﻨﮫ ﺗﺄﺛﯿﺮ ﻣﻀﺎد ﻟﻠﻔﯿﺮوﺳﺎت‬، ‫اﻟﻔﯿﺮوس‬ ‫ إﺧﺮاج ﻣﻨﺎﺳﺒﺔ ﻟﺨﺼﻮﺻﯿﺔ اﻟﻤﻮﻗﻊ‬/ ‫ﺗﺸﯿﺮ اﻟﺨﺼﺎﺋﺺ اﻟﻔﯿﺰﯾﺎﺋﯿﺔ واﻟﻜﯿﻤﯿﺎﺋﯿﺔ اﻟﻨﺴﺒﯿﺔ ﻟﻠﺪواء اﻷوﻟﻲ وﻣﺸﺘﻘﺎﺗﮫ اﻟﻤﻔﺴﻔﺮة إﻟﻰ ﻧﺴﺒﺔ إدﺧﺎل‬.  The relative physicochemical properties of prodrug and its phosphorylated derivative suggest an appropriate input/output ratio for site specificity.  The reduces any human toxicity that might be associated with this drug is due to:  A/ phosphorylation is accomplished preferentially by viral thymidine kinase  B/ increased polarity and viral retention of the active phosphorylated species. / ‫ﯾﺘﻢ ﺗﺤﻘﯿﻖ اﻟﻔﺴﻔﺮة ﺑﺸﻜﻞ ﺗﻔﻀﯿﻠﻲ ﻋﻦ طﺮﯾﻖ ﻛﯿﻨﺎز ﺛﯿﻤﯿﺪﯾﻦ اﻟﻔﯿﺮوﺳﻲ‬ ‫زﯾﺎدة اﻟﻘﻄﺒﯿﺔ واﻻﺣﺘﻔﺎظ اﻟﻔﯿﺮوﺳﻲ ﻟﻸﻧﻮاع اﻟﻤﻔﺴﻔﺮة اﻟﻨﺸﻄﺔ‬.