Presentation is loading. Please wait.

Presentation is loading. Please wait.

Patrick: An Introduction to Medicinal Chemistry 6e

Similar presentations


Presentation on theme: "Patrick: An Introduction to Medicinal Chemistry 6e"— Presentation transcript:

1 Patrick: An Introduction to Medicinal Chemistry 6e
Chapter 9 DRUGS TARGETING NUCLEIC ACIDS DNA & RNA modified

2 1. DRUGS ACTING ON DNA Intercalating agents Topoisomerase poisons Alkylating agents Metallating agents Chain cutters Chain terminators Control of gene transcription

3 1. DRUGS ACTING ON DNA 1.1 Intercalating agents Mechanism of action
Contain planar aromatic or heteroaromatic ring systems Planar systems slip between the layers of nucleic acid pairs and disrupt the shape of the helix Preference is often shown for the minor or major groove Intercalation prevents replication and transcription Intercalation can inhibit topoisomerases

4 1. DRUGS ACTING ON DNA 1.1 Intercalating agents
Proflavine Planar tricyclic system The amino substituents are protonated and charged Used as a topical antibacterial agent in the second world war Targets bacterial DNA Too toxic for systemic use Prflavine structure not shown

5 Sugar phosphate backbone
1. DRUGS ACTING ON DNA 1.1 Intercalating agents Example - Proflavine Proflavine T DNA DOUBLE HELIX A G C Sugar phosphate backbone Proflavine R van der Waals interactions Ionic interactions Prflavine structure not shown

6 1. DRUGS ACTING ON DNA 1.1 Intercalating agents
Examples - anticancer agents Planar rings Doxorubicin (Adriamycin) Dactinomycin Doxorubicin (Adriamycin) Dactinomycin Planar rings Doxorubicin (Adriamycin) Dactinomycin Planar rings Doxorubicin (Adriamycin) Dactinomycin Extra binding to sugar phosphate backbone by cyclic peptides Extra binding to sugar phosphate backbone by NH3

7 1. DRUGS ACTING ON DNA 1.1 Intercalating agents Notes on dactinomycin
Intercalates via minor groove of DNA double helix Prevents unwinding of DNA double helix Blocks transcription by blocking DNA-dependent RNA polymerase Notes on doxorubicin Intercalates via the major groove of DNA double helix Blocks the action of topoisomerase II by stabilising the DNA-enzyme complex Acts as a topoisomerase poison

8 1. DRUGS ACTING ON DNA 1.1 Intercalating agents Examples - Bleomycins
Primary amine Primary amide Bithiazole intercalating region Pyrimidine ring Primary amine Imidazole ring Structure refreshed B l e o m y c i n A 2 R = N H C S M ( ) +

9 1. DRUGS ACTING ON DNA 1.1 Intercalating agents Notes on bleomycins
Used as anticancer agents Intercalate DNA by means of bithiazole ring system Ferrous ion then chelated by nitrogens of the primary amines, amide, and pyrimidine ring Reaction with oxygen results in a ferric ion and reactive oxygen species Results in radical formation and chain cutting Bleomycin prevents DNA ligase from repairing damage modified

10 1. DRUGS ACTING ON DNA 1.2 Topoisomerase poisons - non-intercalating
Examples Etoposide Teniposide Notes on etoposide and teniposide Stabilise the complex between DNA and topoisomerase enzymes Used as anticancer agents Also cause chain cutting

11 1. DRUGS ACTING ON DNA 1.2 Topoisomerase poisons - non-intercalating
Examples - Camptothecin Lactone ring Notes Stabilises complex between DNA and topoisomerase I Single-strand breaks accumulate in the chain Irreversible double-strand breaks occur during transcription Semi-synthetic analogues used as anticancer agents Structure refreshed

12 1. DRUGS ACTING ON DNA 1.2 Topoisomerase poisons - non-intercalating
Examples - Quinolones and fluoroquinilones Nalidixic acid Ciprofloxacin Notes Synthetic agents used as antibacterial agents Stabilise complex between bacterial DNA and topoisomerases Binding site for agents revealed once DNA strands are ‘nicked’ Modified Both structures refreshed

13 1. DRUGS ACTING ON DNA 1.2 Topoisomerase poisons - non-intercalating
Examples - Quinolones and fluoroquinilones Topoisomerase enzyme Region binding to DNA Region binding to enzyme Stacking domain modified Fluoroquinolones Four drug molecules are stacked in the bound complex Bound to DNA and enzyme by hydrogen and ionic bonds

14 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Notes
Contain highly electrophilic groups Form covalent bonds to nucleophilic groups in DNA (e.g. 7-N of guanine) Prevent replication and transcription Useful anticancer agents Toxic side effects (e.g. alkylation of proteins) Can cause interstrand and intrastrand crosslinking if two electrophilic groups present Alkylation of nucleic acid bases can result in miscoding

15 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Crosslinking
Intrastrand crosslinking Interstrand crosslinking

16 1. DRUGS ACTING ON DNA 1.3 Alkylating agents
Nucleophilic groups on nucleic acid bases Nucleophilic groups Cytosine Guanine Adenine Nucleophilic groups

17 Miscoding resulting from alkylated nucleic acid bases
1. DRUGS ACTING ON DNA 1.3 Alkylating agents Cytosine Guanine Normal base pairing Miscoding resulting from alkylated nucleic acid bases Structures refreshed Guanine prefers keto tautomer Abnormal base pairing. Alkylated guanine prefers enol tautomer

18 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Example Notes
Chlormethine (nitrogen mustard) Notes Used medicinally in 1942 Causes intrastrand and interstrand cross-linking Prevents replication Mono-alkylation of guanine also possible Analogues with better properties have been prepared

19 1. DRUGS ACTING ON DNA 1.3 Alkylating agents
Chlormethine - mechanism of action Chlormethine Aziridine ion Mofified Second set of curly rrows redrawn Crosslinked DNA

20 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Example - Nitrosoureas
Lomustine Carmustine Mechanism of action Decompose in body to form an alkylating agent and a carbamoylating agent Bottom diagram redone + Isocyanate (carbamoyating agent Alkylating agent

21 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Example - Nitrosoureas
Akylation Cross linking Isocyanate Protein-Lys-NH2 Carbamoylation Protein-Lys-NH Notes Alkylating agent causes interstrand crosslinking Crosslinking between G-G or G-C Carbamoylating agent reacts with lysine residues on proteins May inactivate DNA repair enzymes Diagrams copied from chapter 21

22 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Mechanism Busulfan
Synthetic agent used as anticancer agent Causes interstrand crosslinking Mechanism Guanine -MeSO3- All structures copied from chapter 21 First part of sequence recopied -MeSO3-

23 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Mechanism Dacarbazine
Prodrug activated by demethylation in liver Decomposes to form a methyldiazonium ion Alkylates guanine groups Mechanism Cyt P-450 Liver -CH2O Dacarbazine and two intermediates refreshed N CH3

24 1. DRUGS ACTING ON DNA 1.3 Alkylating agents Example - Mitomycin C
Notes Prodrug activated in the body to form an alkylating agent One of the most toxic anticancer drugs in clinical use

25 .. .. Reduction -MeOH Mitomycin C H2N-DNA -H + H2N-DNA Ring opening
Alkylating agent Modified Copied from chapter 21 Last two sets of curly arrows redrawn -CO2 -NH3 Crosslinked DNA

26 1. DRUGS ACTING ON DNA 1.4 Metallating agents Cisplatin Notes
Neutral inactive molecule acting as a prodrug Platinum covalently linked to chloro substituents Ammonia molecules act as ligands Activated in cells with low chloride ion concentration Chloro substituents replaced with neutral water ligands Produces positively charged species DNA + H2O Cisplatin 2+

27 1. DRUGS ACTING ON DNA 1.4 Metallating agents Cisplatin
Binds to DNA in regions rich in guanine units Intrastrand links rather than interstrand Localised unwinding of DNA double helix Inhibits transcription

28 1. DRUGS ACTING ON DNA 1.5 Chain cutters Intercalating agent
Bleomycin Used vs skin cancer BLEOMYCIN A R = NHCH2CH2CH2SMe2 BLEOMYCIN B R = NHCH2CH2CH2CH2NHC(NH2)=NH modifued Intercalating agent Abstracts H from DNA to generate radicals Radicals react with oxygen resulting in chain cutting Bleomycin also inhibits repair enzymes

29 1. DRUGS ACTING ON DNA 1.5 Chain cutters Generates DNA diradical
Calicheamicin g1I Antitumour agent Enediyne system Structure refreshed Generates DNA diradical DNA diradical reacts with oxygen Results in chain cutting

30 1. DRUGS ACTING ON DNA 1.5 Chain cutters Mechanism . DNA . Michael
addition Cycloaromatisation DNA . DNA . (Diradical) Modifed Last structure refreshed O2 Oxidative cleavage

31 1. DRUGS ACTING ON DNA 1.6 Chain terminators Notes
Enzymes in vivo Azidothymidine (AZT) (Zidovudine;Retrovir) Chain terminating group modified Notes Azidothymidine is a prodrug used in the treatment of HIV AZT is phosphorylated to a triphosphate in the body Triphosphate has two mechanisms of action - inhibits a viral enzyme (reverse transcriptase) - is added to growing DNA chain and acts as a chain terminator

32 1. DRUGS ACTING ON DNA 1.6 Chain terminators
Aciclovir (Zovirax) Famciclovir (Famvir) Chain terminating group Chain terminating group Prodrugs used as antiviral agents Same mechanisms of action as AZT Used vs herpes simplex and shingles

33 1. DRUGS ACTING ON DNA 1.6 Chain terminators a) Normal replication A T
3 ' D N t e m p l a r o w i n g c h GPPP redone

34 1. DRUGS ACTING ON DNA 1.6 Chain terminators b) Chain termination A T
3 ' D N t e m p l a r o w i n g c h Chain termination DrugPPP redone

35 1. DRUGS ACTING ON DNA 1.7 Control of gene transcription Notes
Design of synthetic molecules capable of controlling gene transcription Molecules capable of recognising and binding to specific base pairs Hairpin polyamides containing heterocyclic rings are capable of binding to the minor groove Binding involves amide groups and heterocycles Particular patterns of heterocyclic rings allow recognition of particular base pairs Capable of inhibiting transcription Designed to bind to regulatory element of a gene modified

36 1. DRUGS ACTING ON DNA Py Im Hp DNA and molecule refreshed

37 2. DRUGS ACTING ON rRNA Antibiotics Streptomycin Chloramphenicol
Rifamycins Chloramphenicol (vs typhoid) Erythromycin Chlortetracycline (Aureomycin)

38 3. DRUGS ACTING ON mRNA Antisense Therapy Protein synthesis Antisense
molecule Protein synthesis m-RNA Antisense molecule m-RNA Bottom interactions refreshed

39 3. DRUGS ACTING ON mRNA Antisense Therapy Advantages
Same effect as an enzyme inhibitor or receptor antagonist Highly specific where the oligonucleotide is 17 nucleotides or more Smaller dose levels required compared to inhibitors or antagonists Potentially less side effects Disadvantages ‘Exposed’ sections of mRNA must be targeted Instability and polarity of oligonucleotides (pharmacokinetics) Short lifetime of oligonucleotides and poor absorption across cell membranes

40 3. DRUGS ACTING ON mRNA Micro-RNA (miRNA)
Short segments of double stranded RNA Recognised by enzyme complex RISC to produce single stranded RNA (siRNA) in the form of a guide strand Guide strand remains bound to RISC and also binds to a complementary region of mRNA mRNA is then cleaved by the enzyme complex AllRisc structurerefreshed Duplex Passenger strand Guide strand m-RNA

41 3. DRUGS ACTING ON mRNA Micro-RNA (miRNA) Advantages
siRNAs have potential to be used in gene therapy Greater efficiency in silencing mRNA than conventional antisense therapy One siRNA could lead to cleavage of several mRNA molecules Problems siRNAs need to be metabolically stable Need to reach target cells Need to enter target cells


Download ppt "Patrick: An Introduction to Medicinal Chemistry 6e"

Similar presentations


Ads by Google