New Steric Hindrance Approach Employing the Hybrid Ligand 2-Aminomethylpiperidine for Diminishing Dynamic Motion Problems of Platinum Anticancer Drug Adducts Containing Guanine Derivatives

A fundamental problem obscuring the role of the ammine and primary amine groups in the activity of clinically
used Pt anticancer drugs is the dynamic character of the adducts with DNA and DNA constituents. Dynamic
motion is slower in analogues containing only secondary or tertiary amines, but such agents are not used clinically.
Recently we found that enclosing the N center within a piperidine (pip) ring greatly reduces dynamic motion. In
this work, we test the hypothesis that a diamine with only one pip ring, 2-aminomethylpiperidine (pipen), would
slow dynamic motion enough for insightful study of adducts with one site (cis to the primary amine) closely
reflecting the coordination environment of clinically used drugs. Racemic pipen was prepared and resolved by
improved methods. PtCl2(pipen) synthesized with the pipen enantiomer having an R configuration of the asymmetric
carbon (determined on the basis of the [α]D sign) has the S stereochemistry at the N asymmetric center. In the
adduct (S,R)-pipenPt(5‘-GMP)2, restricted rotation of the two nonequivalent N7-coordinated 5‘-GMP's about the
Pt−N7 bonds potentially could lead to two head-to-tail (ΛHT and ΔHT) and two head-to-head (HH1 and HH2)
atropisomers. However, 1D and 2D NOESY NMR data at pH ∼ 3 indicated the dominance of the two HT
atropisomers in a ΛHT:ΔHT ratio of 2:1. Deprotonation of the phosphate group (pH 7) further stabilized the
ΛHT form, and the CD signal had the shape characteristic of a ΛHT form with a positive peak at ∼280 nm.
However, at pH 9.5, where the 5‘-GMP N1H was largely deprotonated, the NMR spectrum and the ∼280 nm CD
peak both revealed that the ΛHT form had decreased. When the pH was jumped down to 6.9, the NMR signals
of the ΛHT form and the ∼280 nm CD peak increased with a half-time of ∼3 min. Thus, the pip ring lengthens
the atropisomerization time from seconds for ethylenediaminePt(5‘-GMP)2 to minutes for (S,R)-pipenPt(5‘-GMP)2.
This pH jump experiment indicates that the signs of the CD signal are opposite for the ΛHT and ΔHT forms.
Changes with pH in both the relative abundance and shifts of the H8 signals of the ΛHT and ΔHT forms correlated
with an increase in hydrogen bonding by the phosphate group of the 5‘-GMP cis to the primary amine. The
hydrogen bonding changes the 5‘-GMP base tilt and hence the H8 chemical shift. Such information is not obtainable
on 5‘-GMP adducts of clinically used anticancer drugs.