• Bioorganic Chemistry and the Origins of Chemical Biology
• 56 min
  1. Biomimetic catalysis

  • Prof. Ronald Breslow
• 50 min
  2. Bioorganic studies of vision

  • Prof. Koji Nakanishi
• 48 min
  3. Perspectives on biological catalysis

  • Prof. Stephen Benkovic
• Nucleic Acids and Drug/Nucleic Acid Interactions
• 41 min
  4. The importance of nucleotide size in the chemistry and biology of DNA

  • Prof. Eric Kool
• 27 min
  5. Site-specifically modified ribosomal RNAs

  • Prof. Christine Chow
• 26 min
  6. Creation of tools for the investigation of oxidative damage to nucleic acids

  • Dr. Mel Bedi
• 48 min
  7. Drug-DNA interactions of the mitomycins

  • Prof. Maria Tomasz
• Protein Function and Cellular Signaling
• 41 min
  8. Chemical synthesis of proteins

  • Prof. Lei Liu
• 55 min
  9. Visualizing and manipulating phosphoinositide and phospholipid signaling

  • Prof. Glenn Prestwich
• 86 min
  10. Phosphoserine/threonine binding domains: molecular integrators of protein kinase signaling in cell cycle control and cancer

  • Dr. Michael Yaffe
• 59 min
  11. Polydactyl zinc finger proteins: software and hardware for genomes

  • Prof. Carlos Barbas
• Peptides, Small-Molecules and Chemical Diversity
• 41 min
  12. Chemical synthesis of peptides and peptide libraries

  • Prof. Victor Hruby
• Proteomics: The Study of Biomolecules and Interactions
• 46 min
  13. Quantitative proteomics

  • Prof. Ruedi Aebersold
• Archived Lectures *These may not cover the latest advances in the field
• 51 min
  14. Chemical protein synthesis: total synthesis of proteins for biological research

  • Prof. Stephen Kent
• 57 min
  15. Solid phase peptide synthesis

  • Prof. Stephen Kent
• 39 min
  16. Mapping small molecule binding sites with phage display technology

  • Dr. Lee Makowski
• 32 min
  17. Tagged library for chemical genetics

  • Dr. Young-Tae Chang
• 30 min
  18. Covalently constrained alpha-helices

  • Dr. Paramjit Arora
• 34 min
  19. SICLOPPS: genetic system for production of backbone cyclized peptides

  • Dr. Sergey Savinov
• 35 min
  20. Probing protein-protein interactions with peptide libraries and arrays

  • Dr. Zhou Songyang

Printable Handouts

PDF

Navigable Slide Index

1. Introduction
2. Outline of talk
3. Mitomycin properties
4. Mode of action
5. Mitomycin C is inactive in its quinone form
6. Basis of the reductive activation of mitomycins
7. The mitomycin "reductive activation cascade"
8. Leuco-aziridinomitosene may decay by reoxidation
9. O2 inhibits the first step of reductive activation
10. Concept of bioreductive anticancer drugs: Sartorelli
11. Reaction products of mitomycins with DNA
12. Isolation of reaction products of mitomycin C
13. Isolation of a fourth adduct
14. Structures of the adducts
15. Sequence recognition in the first alkylation step
16. Mechanism of the CG*CG recognition selectivity
17. Proof of the proposed minor groove alignment
18. Molecular recognition of DNA sequence
19. CpG or GpC cross-links?
20. Orientation of the intermediate monoadduct
21. Molecular evolution
22. Mitomycin C selectively recognizes 5-methyl CpG
23. Why does MC alkylate preferentially guanines?
24. 5-fluoro-C substitution has opposite effect
25. Further evidence of the hypothesis
26. Significance of special recognition of 5-methyl C*G
27. DNA adducts formed in vivo
28. Major metabolic fate of MC: reduction to 2,7-DAM
29. 2,7-DAM adducts in MC- & 2,7-DAM-treated cells
30. Models of minor and major groove monoadducts
31. Biological activity of 2,7-DAM and its DNA adducts
32. Large array of different adducts
33. Structure-function relationships of DNA adducts
34. Individual adducts selective introduction in the cell
35. The dG-2,7-DAM 5 adduct is not mutagenic
36. Neither adduct 1a nor adduct 5 is mutagenic
37. What is the basis for the different cytotoxicities?
38. Differential blockage of replication?
39. MC monoadduct blocks Klenow DNA polymerase
40. T-7 exo- polymerase by-passes 2,7-DAM
41. MC monoadduct blocks T-7 exo- DNA polymerase
42. Single nucleotide incorporation
43. Conclusions from in vitro primer extension study
44. Other studies of mitomycins in our laboratory
45. References

Topics Covered

• The mitomycins: structures, properties, early research of the molecular basis of biological activity
• Reductive activation
• Chemistry of the interactions with DNA: DNA adducts, cross-linking of DNA
• Molecular recognition of DNA
• Metabolic chemistry
• Structure/activity relationships of the DNA adducts

Links

Series:

• Chemical Biology

Categories:

• Biochemistry
• Cancer
• Cell Biology

Therapeutic Areas:

• Oncology

Talk Citation

Publication History

• Published on August 14, 2008

Financial Disclosures

• Prof. Maria Tomasz has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.