Summary of Lecture III

IV-Oxidation of amides

• Oxidative carbon- nitrogen cleavage.

1. Oxidative dealkylation of N- substituted amide.

diazepam..............................................desmethyldiazepam
parent drug..................................................active metabolite

Chlorpropamide...........................carbinplamid

Hyopglycemic..................................Intermediate

2. Cyclic amides or lactams will undergo hydroxylation of carbon α to the nitrogen leading to ring opening.

3. Aromatic amides will undergo N- Hydroxylation (minor extent) giving chemically reactive
metabolites (Toxic).

Acetaminophen...........N-acety- acetaminophen.......N-acetyl-imidoquinone

• N-acetylimidoquinone is electrophilic thus may react with either

1. Liver macromplecules causing liver necrosis.
2. GSH as a protection mechanism.

b-Oxidation involving Carbon-Oxygen System

• Attack only on the α-carbon atom causing dealkylation (mainly ethers) .
• Mixed function oxidases will undergo α-carbon hydroxylation giving hemiacetal or hemiketal intermediate the equivalant of carbinolamine in amines.

Hemiacetal

• If several non-equivalent methoxy groups are present only one will undergo O-dealkylated selectively.

c-Oxidation of carbon-sulfur system

• Three types of oxidative metabolic reactions.

1......Cleavage of carbon-sulfur bonds (S-Dealkylation).

similar to O- and N- dealkylation reactions (α-carbon hydroxylation} + (α-hydrogen atom).

2.......Desulfuration:
oxidative conversion of carbon-Sulfur double bonds (C=S) to carbon-oxygen double bond (C=O).

• Similar desulfuration takes place in P=S in organophosphorous insecticides.
• Mechanism is still unknown (microsomal oxidation of the C=S or C=P).

3.......Oxidation of the sulfer or S-Oxidation.

• Common metabolic pathway.
• Major metabolic pathways for several phenothiazines.

• Thioridazine (Mellaril) undergoes S-oxidation (2-methylthio group) giving the active sulfoxide metabolite mesoridazine twice as active an antipsychotic thus was synthesized and introduced in the market as sentril. Further S-oxidation will produce sulfones (-SO2-).

Oxidation of alcohols and aldehydes

non-microsomal

• Alcoholic metabolites produced by microsomal oxidation will undergo phase Π conjugation or will be oxidized. Primary alcohols will give aldehydes and secondary alcohols will give ketones.
• Catalyzed by a non-microsomal enzyme alcohol dehydrogenase in the liver and
  other tissues and requires NAD+ or NADP+ as coenzyme.
• Reversible i.e. if not immediately oxidized will be reduced to the alcohol again by
  alcohol dehydrogenase.
• Aldehyde produced from primary alcohol drug or from the deamination aliphatic amines will be further oxidized to the corresponding carboxylic acids catalyzed by aldehyde dehydrogenase enzymes e.g. aldehyde oxidase and xanthine oxidase.
• As mentioned before cyclic amines give lactam metabolites.
  
  

First oxidized by microsomal oxidation of ring carbon α- to the nitrogen giving carbinolamine intermediate then carbinolamine will be oxidized tocarbonyl moiety by non microsomal alcohol dehydrogenase.

2-Reductive reactions

i-Reduction of aldehydes and ketones:

• The aldehyde or keton may be parent drugs or metabolits (oxidative deamination of primary and secondary amines) will undergo reductive metabolic reactions.
• Reduction is not a major metabolic pathway for aldehydes since the undergo rapid oxidation to carboxylic acids.
• Ketones are not easily oxidized so they undergo reduction to secondary alcohols then are conjugated to glucuronic acid and are excreted in urine.
• The reduction is catalyzed by enzymes called aldo-keto reductases (nammely alcohol dehydrogenase) undergo bioreduction of aldehydes and ketones.
• In liver and other tissues and require NADPH as cofactor.
• The same enzyme undergoes both the oxidation and the reduction reactions e.g. alcohol dehydrogenase.
• Bioreduction of aldehydes to alcohols is not common, a known example.

• Reduction of ketones will produce asymmetric center i.e. two possible isomers ( formation of one isomer more favorable).
• The preferable production of one stereoisomer over the other is called product stereoselectivity.

ii-Reduction of azo and nitro compounds:

• Leads to formation of primary amines.
• Aromatic nitro compounds are reduced initially to the nitroso and hydroxylamine
  intermediates.

• Another example is Clonazepam reduction of the aromatic nitro group to amino.

• Performed by NADPH-dependant microsomal and nitro reductase enzymes in the liver and bacterial reducrases in intestine.
• Clonazepam and nitrazepam are metabolized extensively by reduction of the nitro group to give the 7-amino metabolite in human.

• Most famous example is metabolic redcution of azo drugs e.g. sulphamidochyrosidine (prontosil) to give sulfanilamide (liver). This lead to discovery of sulfonamides as antibacterial. (structures before).
• Bacterial reductase in the intestine also undergo reduction of nitro compounds ehich are excreted in the bile.
• Bacterial reductases also contributeto the reduction of azo drugs (poorly absorbed) e.g. sulfasalazine (in ulcerative colitis) (poorly absorbed) undergoes reductive cleavage of the azo linkage in the colon producing Sulfapyridine and 5-aminosalicylic acid in thus becomes active.
  
  

iii-Miscellaneous reductions :
1-N-oxides will givete rtiary amines

• Important reaction.
• Several tertiary amines are polar, excretable N-oxide.
• Extensive reduction reaction → delay elimination of the tertiary amine parent drug

2- Reduction of sulfoxides (limited extent)

• More common is the oxidation of sulfoxides to sulfone (i.e. the opposit reaction).
• Sulindac (anti-inflammatory) will undergo reduction to give sulfide metabolite (active and is responsible for the overall anti-inflammatory activity of the parent drug.
• Sulfone metabolite have little anti-inflammatory activity.

3-Hydrolytic reactions

1-Hydrolysis of esters:

• Catalyzed by esterasesin the liver, kidney and intestine.
• Hydrolysis is major metabolic pathway for esters (ease of hydrolysis of the ester
  linkage).
• Hydrolysis of esters will produce alcohol and acid functional groups which will undergo conjugation.
• Hydrolysis → pharmacologically active metabolites.

• P-chlorophenoxyisobutyric acid is a major metabolite and is responsible for hypolipidimic effect of the drug.
• The ease of hydrolysis of esters and the presence of estrases in many tissues and plasma leds to the use of ester derivatives as prodrugs to overcome side effects (bitter taste, poor absorption, and poor solubility irritation at site of injection).
• Once inside is biotransformed to the active drugs.
• A famous example is the antibiotic chloramphenicol ( bitter taste).
• Palmitate ester will mask the taste in pediatric preparations.
• Upon oral administration intestinal estrases and lipases will undergo hydrolyis liberating active chloramphenicol.

2-Hydrolysis of amides:

• Microsomal amidases and deacylases will produce carboxylic acid + amine metabolites.
• Hydrolyis of amides is slowler than ester hydrolysis.

Hydrolysis of procainamide is much slower than procain (ester) (cannot be administered orally).

• Another example is the hydrolysis of the amide linkage in.

• Another example is indomethacine.