Purine

purine heterocyclic chemistry

1. ORGANIC CHEMISTRY HRTEROCYCLIC CHEMISTRY PURINE unit-4 M.PHARM Pharmaceutical chemistry (1 ST SEM )

2. PURINE Purines are anticancer, antiviral in action. They are used in rheumatoid arthritis, ulcerative colitis etc. some purines are shown below.

3. PURINE ACYCLOVIR NAME OF THE DRUG( TRADE NAME ): Zovirax-400mg oral tablet (GSK) ACTIVE CONSTITUENT : Acyclovir (guanine analogue ) COMMON NAME: Acyclo -G IUPAC NAME : 2-amino-9-(2-hydroxyethoxymethyl)-1H-purin-6-one CHEMICAL FORMULA : C8H11N5O3 MOL. WT.: 225.2g/ mol ENANTIOMERIC/RACEMIC: No chiral carbon is present (achiral) OPTICAL ACTIVITY: unspecified DOSE: 400mg / 12 hr (For genital herpes),800mg/4hr(For HSV) MELTING POINT: 256.5 C PURITY: 100% (95-105% as per IP) ASSAY: U.V (I.P. 2007,Vol.2, pg 70) MOA: Acyclovir convert to acyclovir triphosphate by the action of thymidine kinase. Acyclovir triphosphate can be incorporated into viral DNA and viral growth is inhibited

4. PURINE SAR: Removal of –OH by L- valyl ester can increase 10 times bioavailability ( Valacyclovir ) Addition of –CH2 in side chain increases safety profile( Gancyclovir ) Removal of carbonyl group by –NH2 at 6 th position can increase water solubility but decreases metabolism and absorption ( Desciclovir ) Addition of 3,5-dichlorobenzyl to –NH2 group at 2, will increase activity against HSV(Herpes Simplex Virus). USES: Used for treatment of HSV(Herpes Simplex Virus) and chickenpox. ACYCLOVIR Gancyclovir Acyclovir

5. PURINE ACYCLOVIR Hexamethyldisilazane is used to protect the amino and keto group of guanine SYNTHESIS

6. PURINE 6-MERCAPTOPURINE NAME OF THE DRUG( TRADE NAME ): 6-Mercaptopurine( Zydus cadila healthcare limited( biogen ) ACTIVE CONSTITUENT : 6-mercaptopurine (6-MP) , Purine analogue COMMON NAME: 6-MP IUPAC NAME : 3,7-dihydropurine-6-thione CHEMICAL FORMULA: C5H4N4S,H2O MOL. WT.: 170.2 g/ mol ENANTIOMERIC/RACEMIC : No chiral carbon is present (achiral) OPTICAL ACTIVITY: Unspecified DOSE: 1.5mg/kg daily(50mg tablets) for leukemia MELTING POINT: 313 C PURITY: 100%(90-100% I.P.) ASSAY: U.V.(specific absorbance 1165 at 325nm) (I.P. 2007,Vol.2, pg 737)

7. PURINE MOA: The hypoxanthine-guanine phosphoribosyl transferase enzyme (HPRT) processes 6-MP to thio -IMP ( Thio-iminophosphate ), which is then converted to thio -XMP( Thio xanthine monophosphate) and thio -GMP. Subsequent metabolism of thio -GMP by kinases and reductases yields thio-dGTP ( thio-deoxy Guanosine triphosphate) which is incorporated into replicating DNA strands and triggers the DNA mismatch-repair machinery, leading to cell cycle arrest and apoptosis. SAR: Substitution at 6 th position with hydrophobic group will lead to increased activity. Substitution at 6 th position with carbon chain upto 15-16 will increase activity but after that it decreases activity. Thione group is essential for activity. USES: Used for treatment of acute lymphatic leukemia, Ulcerative colitis and Crohn’s disease. 6-MERCAPTOPURINE

8. PURINE 6-MERCAPTOPURINE SYNTHESIS

9. PURINE TENOFOVIR DISOPROXIL FUMARATE NAME OF THE DRUG( TRADE NAME ): Tenvir 300mg tablets ( cipla ) ACTIVE CONSTITUENT : Prodrug , Converts to tenofovir COMMON NAME: Tenofovir Disoproxil Fumarate IUPAC NAME : [[( 2 R )-1-(6-aminopurin-9-yl)propan-2-yl] oxymethyl -(propan-2-yloxycarbonyloxymethoxy) phosphoryl ] oxymethyl propan-2-yl carbonate;but-2-enedioic acid CHEMICAL FORMULA: C23H34N5O14P MOL. WT.: 635.5g/ mol ENANTIOMERIC/RACEMIC : R(absolute stereochemistry) OPTICAL ACTIVITY: Unspecified DOSE: 300mg/day( for HIV) MELTING POINT: 113-115 C PURITY: 100%(90-100%) ASSAY: Liquid chromatography( I.P. 2007, Vol. 3,pg.1158) MOA: Tenofovir   diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5'- triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir   diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ

10. PURINE SAR: Removal of –CH3 will form adefovir disoproxil which is less potent USES: Anti-HIV, anti- hepetitis -B TENOFOVIR DISOPROXIL FUMARATE

11. PURINE TINOFOVIR DISOPROXIL FUMARATE SYNTHESIS Adenine or 6-amino purine 9-(2-Hydroxypropyl) adenine Diethyl P-toluene Sulfonyloxy Methyl Phosphonate (DESMP) Tinofovir Disoproxil Fumarate Tenofovir

12. PURINE VALACYCLOVIR NAME OF THE DRUG( TRADE NAME ): Valcivir (1000 and 500 mg) cipla ACTIVE CONSTITUENT : Prodrug , converts to acyclovir COMMON NAME: Valacyclovir IUPAC NAME : 2-[(2-amino-6-oxo-1H-purin-9-yl) methoxy ]ethyl (2S)- 2-amino-3-methylbutanoate;hydrochloride CHEMICAL FORMULA: C13H21ClN6O4 MOL. WT.: 360.8g/ mol ENANTIOMERIC/RACEMIC : S(absolute stereochemistry) OPTICAL ACTIVITY: unspecified DOSE: For cold sores-2000 milligrams (mg) every 12 hours for one day. For genital herpes 1 st outbreak: Adults—1000 milligrams (mg) two times a day for ten days MELTING POINT: 170-172 C PURITY: 100%(90-110%) as per USP ASSAY: Liquid chromatogtaphy ( USP Revision Bulletin Official May 1, 2012)

13. PURINE VALACYCLOVIR MOA : Valacyclovir  is converted to acyclovir, which is converted to its triphosphate form, acyclovir triphosphate (ACV-TP). ACV-TP competitively inhibits viral DNA polymerase, incorporates into and terminates the growing viral DNA chain, and inactivates of the viral DNA polymerase USES: For herpes simplex, varicella zoster, cytomegalovirus infections

14. PURINE VALACYCLOVIR SYNTHESIS Acyclovir N- benzyloxy carbonyl-L- valine DCC (N,N′- Dicyclohexylcarbodiimide ), DMAP (N,N-Dimethylpyridin-4-amine), and DMF( Dimethyl formamide ) Benzyloxy carbonyl valacyclovir Valacyclovir hydrochloride

15. PURINE AZATHIOPRINE NAME OF THE DRUG( TRADE NAME ): Imuran 25mg/50mg/75 mg(GSK) ACTIVE CONSTITUENT : thiopurine COMMON NAME: AZA IUPAC NAME : 6-(3-methyl-5-nitroimidazol-4-yl)sulfanyl-7H-purine CHEMICAL FORMULA: C9H7N7O2S MOL. WT.: 277.263 g/ mol ENANTIOMERIC/RACEMIC : Achiral OPTICAL ACTIVITY: Unspecified DOSE: Initial dose: 3 to 5 mg/kg orally once a day, beginning at the time of transplant Maintenance dose: 1 to 3 mg/kg orally once a day MELTING POINT: 243.5 °C PURITY: 100%(93-107%) ASSAY: Liquid chromatography(USP 28- NF24, Pg-226) 1 2 3 4 5

16. PURINE AZATHIOPRINE MOA: i. Azathioprine inhibits the synthesis of purine in the cell. ii. This will further leads to the inhibition of synthesis of DNA and RNA. iii . Azathioprine also interacts with cellular metabolism and results in the inhibition of mitosis SAR : Substitution at 6 th position with hydrophobic group will lead to increased activity. Substitution at 6 th position with carbon chain upto 15-16 will increase activity but after that it decreases activity. Thione group is essential for activity. USES: Immunosuppressive medication. It is used in rheumatoid arthritis, granulomatosis with polyangiitis , Crohn's disease, ulcerative colitis, systemic lupus erythematosus , and in kidney transplants to prevent rejection.

17. PURINE AZATHIOPRINE SYNTHESIS

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