A Fundamental Relationship between Hydrophobic Properties and Biological Activity for the Duocarmycin Class of DNA-Alkylating Antitumor Drugs: Hydrophobic-Binding-Driven Bonding

Abstract

Two systematic series of increasingly hydrophilic derivatives of duocarmycin SA are described that feature the incorporation of ethylene glycol units (n = 1–5) into the methoxy substituents of the trimethoxyindole subunit. 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. A linear relationship between cLogP and –logIC50 for cell growth inhibition and –logAE (AE = cell free DNA alkylation efficiency) is observed where cLogP values span the productive range of 2.5–0.49 and –logIC50 values span the range of 11.2–6.4, representing IC50 values covering a 105 range (0.008 to 370 nM). The results quantify a fundamental role the compound hydrophobic character plays 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.

A Novel Depurination Methodology to Assess DNA Alkylation of Chloro-Bis-Seco-Cyclopropylbenzoindoles Allowed for Comparison of Minor-Groove Reactivity

“…The lower extent of di-alkylation with compound 5 also correlated with a .20-fold lower in vitro activity compared with compounds 3 and 4 ( Table 1). The similar IC 50 values of compounds 3 and 4 and much higher IC 50 of compound 5 were also somewhat in line with a previous finding that smaller and more hydrophobic duocarmycins exerted more potent cytotoxicity (Wolfe et al, 2013).…”

The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry–Biology Interface

“…145–151 We demonstrated and quantified the fundamental role the hydrophobic character of the compounds plays in the expression of the biological activity, driving the intrinsically reversible DNA alkylation reaction, and defined the stunning magnitude of its effect (hydrophobic binding-driven-bonding). 152 In collaboration with Walter Chazin, we provided high-resolution NMR-derived structures of the natural products and their unnatural enantiomers bound to DNA (Figure 9), 153–155 and established that they are subject to an exquisite “target-based activation”. 156 In the course of these studies, we introduced a convenient M13-derived alternative to 32 P-end-labeling of restriction fragments for DNA cleavage studies.…”

Simple Nonionic Omnisoluble Tetraphenylporphyrin for Relative Referencing of Singlet Oxygen Quantum Yield

“…Tetrakis(3,4,5-trimethoxyphenyl)porphyrin was prepared according to the method of Adler et al 22 (after Albery et al 23 ) and purified according to Barnett et al 24 The purified porphyrin was treated with BBr3 effective for the preparation of TEG12PH2 than preparing the corresponding benzaldehyde followed by acid catalyzed condensation with pyrrole due to the low yields generally obtained for the triple O-alkylation of 3,4,5-trihydroxybenzaldehyde using tosylates. 28 Using our procedure, it is possible to prepare large multigram batches of TEG12PH2. It was found convenient to use TEGTs also as solvent in the O-alkylation procedure with excess of that reagent being recycled following completion of the reaction.…”