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Objectives: A number of drugs target DNA and RNA. At the end of the lecture, the student will be aware of the classes of low-molecular weight drugs that target DNA and RNA, including specific examples. In addition, knowledge of the forces important for the binding strength and specificity of those drugs will be presented.
Conformational flexibility
DNA intercalators
CH3O NHSO2CH3
NH
NH2
NH2
Proflavin
Amsacrine
Distamycin A
NH2
N CH3
C NH O N O CH3
C NH NH
C NH NH N CH3 NH O
C
NH CH2 CH2 NH2+ NH2
Netropsin
C
N CH3 NH CH2 CH2 NH2+ NH2
O NH2
O CH3 CH3
Actinomycin D (Dactinomycin)
Alkylating Agents
i) Wide variety of alkylations of DNA/RNA possible N7 of Gua or Ade (also N2 and N3 atoms) Both SN1 and SN2 mechanisms ii) Many alkylating agents are mutagenic and/or carcinogenic iii) Also react with other biomolecules iv) Generally block synthesis of DNA v) Both monofunctional and bifunctional alkylating agents are known. Some bifunctional agents can crosslink DNA strands.
RX RX + Y
O Benzo(a)pyrene Epoxide Hydroxylase H2O cyt P450 NADPH O2 OH OH Carcinogen DNA O N N DNA HN N OH NH OH
OH
OH OH
Nitrogen Mustards
Cl CH2CH2 S Cl CH2CH2 Cl CH2CH2 Cl CH2CH2 N R
3' Gua
CH3
Cl
CH2CH2
.. N
CH3
Cl
CH2CH2
N (+)
Cl
PO4
Gua 3'
5'
NH3 Pt NH3
G PO4G
C PO4C
NH3 Pt NH3
G PO4A
C PO4T
G PO4N PO4G
C PO4N PO4C
O HOCH2
OH
OH
OH
deoxycytidine
Gemcitibine 2'-2'-difluorodeoxycytidine
Possible mechanisms i) termination of DNA strand synthesis ii) incorporation into genome
G-G-C-C-A-G-A C-C-G-G-U-C-U
46
NH2 NH2
NH2
IC50 = 0.9 uM
OH
NH2
IC50 = 1.3 uM
N N N NH
IC50 = 10 uM
NH
O2 N
NH
Ribosome
http://www.molgen.mpg.de/~ag_ribo/ag_franceschi/
Protein/RNA complex that synthesizes proteins (translation) Some antibiotics target the ribosome
erythromycins tetracyclines aminoglycosides