CHEM-E8130 Medicinal Chemistry

Transcription

1 CEM-E8130 Medicinal Chemistry Lecture 9: RA/DA Mimicry & Interference Jan Deska Laboratory of rganic Chemistry

2 DA & RA structurally rather low level of diversity o o o four nucleobases (compared to 21 amino acids in protein targets) ribose and deoxyribose as core monophosphate as linker between the units but almost unlimited capacity to store and trensfer genetic information 2 (deoxy)ribose (deoxy)ribose (deoxy)ribose deoxyribose ribose bases: adenine guanine cytosine thymine (only DA) uracil (only RA)

3 DA: secondary structure P 3' P 3' P 3' 2 5' 3' specific base pairing 5' G-C pair (3 -bonds) P 2 5' 3' 5' P 2 5' 3' 5' P A-T pair (2 -bonds)

4 DA: secondary structure 10 Å major groove 22 Å 12 Å minor groove

5 DA: tertiary structure to accomodate the enormous length of DA inside the cell, the double helix undergoes complex twisting and wrapping around proteins

6 RA multiple functions and shapes messenger RA (mra) transfer RA (tra)

7 Biological Function of ligonucleotides cell division helicase DA replication during mitosis (prophase) topisomerase DA primase ancy, Brown, ature Education 2008, 1, 101. DA polymerase

8 Biological Function of ligonucleotides protein synthesis information transfered from DA to mra mra programs the ribosome to synthesize polypeptides ancy, Brown, ature Education 2008, 1, 101.

9 Biological Function of ligonucleotides protein synthesis information transfered from DA to mra mra programs the ribosome to synthesize polypeptides complementary pairs between mra attract tra that brings in the encoded amino acid ancy, Brown, ature Education 2008, 1, 101.

10 Biological Function of ligonucleotides protein synthesis three nucleobases encode for one amino acid tra mra tra-anticodon / mra pairing ancy, Brown, ature Education 2008, 1, 101.

11 DA binding drugs direct binding to DA blocks reading prevents DA replication cytostatic effect inhibits cell division and leads to apoptosis (anti-cancer) prevents transcription no production of harmful proteins (derived from viral infections or genetic diseases) covalent DA binders coordinative DA binders DA intercalators

12 DA alkylation Mustard gas and similar chemical warfare agents act via DA alkylation S mustard gas mechlorethamine (nitrogen lost) mode of action: crosslinking between nucleobases (inter-strand and intra-strand)

13 DA alkylation Mustard gas and similar chemical warfare agents act via DA alkylation S mustard gas mechlorethamine (nitrogen lost) mode of action: crosslinking between nucleobases (inter-strand and intra-strand)

14 DA alkylation Mustard gas and similar chemical warfare agents act via DA alkylation S mustard gas mechlorethamine (nitrogen lost) modern variations with less brutal activity highest impact on cells with high nucleobase turnover (against leukemia) P P metabolic activation via oxidative ring cleavage (against leukemia, brain cancer and lymphoma)

15 rganometallic DA b i n d e r s square-planar platinum complexes crosslink DA 3 Pt 3 cisplatin 3 Pt 3 carboplatin broadly applied in treatment of all kinds of cancer P 5' 3' 3 P 5' 3 Pt 5' 2 3' 2 2 5'

16 DA intercalators planar extended aromatic systems of the anthracycline-type widen the helix by fitting between two base pairs R Me R = : doxorubicin : daunomycin broadly applied in treatment of all kinds of cancer

17 Minor groove binders pyrrol- and imidazole-based polyamides bind strongly to the minor groove oechst dye to stain cell nuclei in cell imaging

18 Minor groove binders pyrrol- and imidazole-based polyamides bind strongly to the minor groove oechst dye to stain cell nuclei in cell imaging 2 netropsin (from Streptomyces sp) 2 in clinical trials as antibiotic

19 Minor groove binders pyrrol- and imidazole-based polyamides bind strongly to the minor groove 3 hairpin polyamides bind with much higher affinity due to double occupancy of the minor groove Kielkopf, White, Szewczyk, Turner, Baird, Dervan, Rees, Science 1998, 282,

20 R A silen cing Interference with messenger RA can switch off genes short pieces of double-stranded RA bind to their complementary mra and suppress the protein production related to the targeted gene dicer enzymes reduces double-stranded RA to nucleotide sequence no read-out by ribosome possible sira mra Andrew Z. Fire Craig C. Mello obel prize in Physiology or Medicine 2006

21 Antisense therapy Interference with messenger RA can switch off genes specific designed oligonucleotides with "anti-sense" to the target mra sira/mra hybrid recognized by Rase for degradation challenges: use of unnatural analogues to avoid degradation by nucleases during transport (e.g. thio- or amidate-analogues of the phosphate linker) use of lipid vesicles, nanoparticles or viruses to facilitate sira-infection of the cell sira mra

22 Antimetabolites Fake nucleotides lead to defective DA or interrupt replication by DA polymerase often as mode of action in antiviral treatment P P P 3 3 azidotymidine (AZT) against IV/AIDS after phosphorylation, AZT is accepted by DA polymerase as monomer 3 acts as chain terminating group: no phosphate bridge possible additionally inhibitor of viral reverse transcriptase

23 Antimetabolites Fake nucleotides lead to defective DA or interrupt replication by DA polymerase improved selectivity by "Trojan horse" approach only by viral kinase P P P aciclovir (against erpes simplex) activation as triphosphate not observed with "normal" kinases only virus-infected cells unlock the destructive nucleotide unit

24 Inhibitors of nucleoside biosynthesis Thymidine originates from deoxyuridine 2 3 P thymidylate synthase 2 3 P S Enz Enz-S "C 3 + " conjugate addition of thymidylate synthese cysteine activates the uracil C-methylation of the reactive enol yields thymidine phosphate 2 3 P C 3 thymidine monophosphate

25 Inhibitors of nucleoside biosynthesis 5-Fluorouracil blocks thymidine synthesis F P F thymidylate synthase P F S Enz thiol aduct binds irreversible to the folate cofactor (methylating agent) 5-FU or Adrucil as common chemotherapeutic agent in breats, anal, stomach, pancreatic and skin cancer

26 Inhibitors of nucleoside biosynthesis Trojan horse path to 5-fluorouracil Capecitabine as prodrug of 5-FU requires multiple activation steps, some of them rather specific for tumor cells F F F capecitabine treatment of colorectal and breast cancer F