Document Detail

Total synthesis and evaluation of iso-duocarmycin SA and iso-yatakemycin.
MedLine Citation:
PMID:  19154178     Owner:  NLM     Status:  MEDLINE    
The total synthesis and evaluation of iso-duocarmycin SA (5) and iso-yatakemycin (6), representing key analogues of the corresponding natural products incorporating an isomeric alkylation subunit, are detailed. This pyrrole isomer of the natural alkylation subunit displayed an enhanced reaction regioselectivity and a 2-fold diminished stability. Although still exceptionally potent, the iso-duocarmycin SA derivatives and natural product analogues exhibited a corresponding approximate 3-5-fold reduction in cytotoxic activity [L1210 IC(50) for (+)-iso-duocarmycin SA = 50 pM and for (+)-iso-yatakemycin = 15 pM] consistent with their placement on a parabolic relationship correlating activity with reactivity. The DNA alkylation selectivity of the resulting key natural product analogues was unaltered by the structure modification in spite of the minor-groove presentation of a potential H-bond donor. Additionally, a unique ortho-spirocyclization with such derivatives was explored via the preparation, characterization, and evaluation of 34 that is incapable of the more conventional para-spirocyclization. Although 34 proved sufficiently stable for isolation and characterization, it displayed little stability in protic solvents (t(1/2) = 0.19 h at pH 3, t(1/2) = 0.20 h at pH 7), a pH-independent (H(+) independent) solvolysis rate profile at pH 3/4-7, and a much reduced cytotoxic potency, but a DNA alkylation selectivity and efficiency comparable to those of duocarmycin SA and iso-duocarmycin SA. The implications of these observations on the source of the DNA alkylation selectivity and catalysis for this class of natural products are discussed.
Karen S MacMillan; Trihn Nguyen; Inkyu Hwang; Dale L Boger
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  131     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-21     Completed Date:  2009-03-10     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1187-94     Citation Subset:  IM    
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MeSH Terms
Biological Products / chemistry
Cell Line, Tumor
Cell Survival / drug effects
DNA / chemistry
Indoles / chemical synthesis*,  chemistry,  toxicity
Molecular Structure
Pyrroles / chemical synthesis*,  chemistry,  toxicity
Structure-Activity Relationship
Grant Support
CA41986/CA/NCI NIH HHS; R01 CA041986/CA/NCI NIH HHS; R01 CA041986-22/CA/NCI NIH HHS
Reg. No./Substance:
0/Biological Products; 0/Indoles; 0/Pyrroles; 0/yatakemycin; 130288-24-3/duocarmycin SA; 9007-49-2/DNA

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