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. 2008 Dec 10;130(49):16521-3.
doi: 10.1021/ja806593w.

An additional spirocyclization for duocarmycin SA

Karen S MacMillan  1 , Dale L Boger
Affiliations

An additional spirocyclization for duocarmycin SA

Karen S MacMillan et al. J Am Chem Soc. .

Abstract

A unique alternative to the p-spirocyclization for activation of compounds containing the duocarmycin SA alkylation subunit was established involving indole NH deprotonation and subsequent cyclopropane formation. The structural characterization of an alternative spirocyclization product, and the establishment of its relative reactivity, intrinsic reaction regioselectivity, biological activity, and DNA alkylation properties (selectivity, rate, and efficiency) including the isolation, characterization, and quantitation of its adenine N3 adduct, are disclosed.

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Figures

Figure 1
Figure 1
A) Natural products. B) Alternate spirocyclization pathway.
Figure 2
Figure 2
Rates of solvolysis and solvolysis pH rate profile for 4.
Figure 3
Figure 3
Plot of −log IC50 (L1210, cytotoxic activity) versus log ksolv (pH 3) that includes the natural products and a representative related compound illustrating the direct correlation between stability and biological potency and highlighting Nature’s potential steps in the optimization of this class of DNA alkylating agents.
See this image and copyright information in PMC

References

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