Lecture 2: Metabolism Oxidation of Aromatic Moieties

1. Metabolic Changes of Drugs andRelated Organic CompoundsOrganic Pharmaceutical Chemistry I3rd Year Pharmacy2018-2019

2. Lecture 2: MetabolismOxidation of Aromatic Moieties • Aromatic hydroxylatio refers to the mixed-function oxidation of aromatic compounds (arenes) to their corresponding phenolic metaholites (arenols). • Almost all aromatic hydroxylation reactions are believed to proceed initially through an epoxide intermediate called an "arene oxide.“ which rearranges rapidly and spontaneously to the arenol product in most instances.

3. Oxidation of Aromatic Moieties In humans, aromatic hydroxylation is a major route of metabolism for many drugs containing phenyl groups. Important therapeutic agents such as propranolol, phenobarbital , phenyloin, phenylbutazone, atorvastatin and S(-)warfarin among others, undergo extensive aromatic oxidation. In most of the drugs just mentioned, hydroxylation occurs at the para position. Most phenolic metabolites formed from aromatic oxidation undergo further conversion to polar and water-soluble glucuronide or sulfate conjugates which are readily excreted in the urine.

4. Oxidiation of Phenytoin Show the possible routes of phenytoin metabolism

5. Oxidation ….. cont • For example. The major urinary metabolite of phenytoin found in humans is the O-glucuronide conjugate of p-hydroxyphenylbutazone. • Interestingly, the para-hydroxylated metabolite of phenylbutazone, oxyphenbutazone is pharmacologically active and has been marketed itself as an anti-inflammatory agent (Tandearil, Oxalid). • While S(-) Warfarin is metabolised by hydroxylation, R(+) enantiomer is metabolised by ketoreduction.

7. Ex: 1. Indicate the site of metabolism in the following drugs. • Diazepam • Chloropromazine • Probenecid 2. Describe the carcenoginicity of • TCDD • Benz[α] pyrene • 1,12-diethyl[α] anthracene 3. Comment on the action of inhibitors in oxidation.

8. The Inhibition of Epoxide Hydrase Epoxide hydrase inhibitors, such as cyclohexene oxide and 1,1,1-trichloropropene-2,3-oxide have been used to demonstrate the toxification role of these enzymes. The toxicities of naphtaline and bezo[α] pyrene-4,5-oxide are potentiated on addition of these inhibitors.

9. The Role of GSH S-transferases In addition to epoxide hydrase a second enzymetic reaction involves nucleophylic ring openining of the arene oxide by the sulfhydryl (SH)group present in GSH to yield the corresponding GSH adduct. Because GSH is present in all mammalian tissues, it plays important rule in the detoxoification of many chemically reactive and potentially toxic metabolites.

10. The Carcinogenic Effects of Epoxides Subsequent epoxidation of dihydrodiols generates an electrophillic epoxide that readily reacts with deoxyguanosine bases (C2 amino group) leading to genetic code alterations. Similar reactions occur with the guanosine residues of RNA.

11. Effect of Substituent on Oxidation Substituents attached to the aromatic ring may influence the ease of hydroxylation. Electron rich rings proceed faster than rings with deactivating groups as in clonidine and probenecid.

12. In compounds with two aromatic rings, hydroxylation occurs preferentially in the more electron-rich ring. For example. aromatic hydroxylation of diazepam (Valium)occurs primarily in the more activated ring to yield 4'-hydroxydiazepam. • A similar situation is seen in the 7-hydroxylation of the antipsychotic agent chlorpromazine and in the para-hydroxylation of p-chlorobiphenyl to p chlorohydroxybiphenyl.

13. The Toxicity of some Environmental Pollutants EXC: Briefly describe • benzene toxicity to mammalian systems. • The harmful effect of the environmental pollutant TCDD 3. The liver necrosis by bromobenzee

14. The Toxicity of Polycyclic Aromatic Hydrocarbons Benzol[α]pyrene is a potent carcinogenic agent. Its structure shows the hydroxlation at 7,8 and and subsequent epoxidation at 9,10 positions to form a reactive electrophile that can form covalent bonding with de0xygaunosine amine of DNA at C2. 7,10-dimethylbenz[α]anthracene oxide at position 5,6 covalently bins to guanosine residues.

15. Thank you

16. Lecture 3: Oxidation of Olefins The products of the oxidation of olefins are the epoxides. They are more stable as compared to the arene eopxides. Olefin epoxides are also affected by the epoxide hydrase and to glutathione addition. Sometimes the dihydroxy compound is the major product rather then epoxide. Several epoxides undergo GSH conjugation. Examples of olefin oxidation include that of Carbamazepine, protriptyline, cyproheptadine, and diethylstilbestrol. The styrene example indicates the formation of some glutathione adducts and other nucleophiles of RNA, DNA and proteins.

17. Oxidation of Olefins, Examples

18. Exc: (i) Show the oxidation of ; • Carbamazepine, protriptyline, cyproheptadine , styrene and diethylstilbestrol. • Show the major products of the oxidation of alcofeac and secobarbital. • Show the oxidation pathways of styrene and dimethylsttibestrol. (ii) Describe; • a. The hepatocarcinogenicity of by Aflatoxin B • b. Cellular damage by vinyl chloride, stilbene and diethylstilbestrol (DES)

19. More examples of Olefins

20. The P450 Damage Some olefins may be activated by CYP to form very active intermediates that covalently binds to the heme portion of CYP, a green pigment. Long term administration of these compounds may lead to inhibition of oxidative metabolism and potential drug interactions.

21. Oxidation at Benzylic Carbons The products of the oxidation of benzylic carbons are carbinols which are oxidized further to aldehydes or ketone and carboxylic acids. Examples are tolbutamide, tolmetin, celecoxib, 2-hydroxymethylmethaqualone, metroplol and a-hyroxymetroprolol, quinidine, hexobarbitalpenozocaine and safrole.

22. The oxidation of Allylic Carbon Δ1-THC has three allylic carbons. The major metabolite in humans is the hydroxide at 7. The steric hindrance at position 3 may limit metabolism. Quinindine and its 3-hydoxy metabolite both show antiarrhythmic activity. The 3-hydroxy metabolite of hexobarbital is susceptable to GSH as well as further oxidation to 3-oxo compound. The pharmalogically less active metabolite, (R)(-) enantiomer, is metabolized more quickly than the active form, (S)(+) EXC: Describe the metabolism of pentazocaine and the hepatocaenoginicity of safrole.

23. Safrole metabolism, Hint. • Hydroxylation at C1 • Conj by SO4 • Nu attckdisplac.

24. Oxidation at Allylic Carbon……. Cont. Hexobarbital, hydoxl at 3’ then oxo- and OG cong.