A Fundamental
Relationship between Hydrophobic Properties
and Biological Activity for the Duocarmycin Class of DNA-Alkylating
Antitumor Drugs: Hydrophobic-Binding-Driven Bonding
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Abstract
Two systematic series of increasingly
hydrophilic derivatives of
duocarmycin SA that feature the incorporation of ethylene glycol units
(<i>n</i> = 1–5) into the methoxy substituents of
the trimethoxyindole subunit are described. These derivatives exhibit
progressively increasing water solubility along with progressive decreases
in cell growth inhibitory activity and DNA alkylation efficiency with
the incremental ethylene glycol unit incorporations. Linear relationships
of cLogP with −log IC<sub>50</sub> for cell growth inhibition
and −log AE (AE = cell-free DNA alkylation efficiency)
were observed, with the cLogP values spanning the productive range
of 2.5–0.49 and the −log IC<sub>50</sub> values
spanning the range of 11.2–6.4, representing IC<sub>50</sub> values that vary by a factor of 10<sup>5</sup> (0.008 to 370 nM).
The results quantify the fundamental role played by the hydrophobic
character of the compound in the expression of the biological activity
of members in this class (driving the intrinsically reversible DNA
alkylation reaction) and define the stunning magnitude of its effect
