Shijie Yao

Comprehensive ab initio quantum mechanical and molecular orbital (MO) analysis of cisplatin: Structure, bonding, charge density, and vibrational frequencies

We carried out an extensive series of ab initio quantum mechanical (QM) calculations using pure effective core potential (ECP) and hybrid Hartree–Fock (HF)/ECP basis sets, including various electron correlation treatments up to the MP4 level on cis‐diamminedichloroplatinum(II), cisplatin, an important anticancer drug. The optimized geometric parameters and vibrational frequencies of cisplatin were compared with the experimental values, and the effects of varying basis sets and correlation (MP level) treatments on the geometric parameters and vibrational frequencies were analyzed. We also present a detailed description of the bonding in cisplatin using qualitative MO analysis to characterize the key intramolecular interactions in cisplatin. The calculated molecular electrostatic potential (MEP), and the electrostatic potential (ESP) charges for cisplatin were used to identify regions of electrophilic and nucleophilic character. The charge density and the Laplacian of charge density of cisplatin were calculated to determine its bonding relationships. Using basis set performance, we identified two hybrid basis sets (HF/6‐311G* and MP2/6‐311G*) as basis sets of choice for studying cisplatins molecular properties. Furthermore, we recommend a hybrid ECP/HF approach with electron correlation for the most accurate physicochemical and electronic description of cisplatin and related compounds. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 365–382, 1999

Small changes in cationic substituents of diphenylfuran derivatives have major effects on the binding affinity and the binding mode with RNA helical duplexes

The interactions of dicationic, 2-4, and tetracationic, 5-7, diphenylfuran analogs of 1 (furamidine) with RNA have been analyzed by thermal melting, spectroscopic, viscometric, kinetic and molecular-modeling techniques. The results of these studies indicate that most of the furan derivatives bind to RNA duplexes by intercalation in contrast to their minor-groove binding mode in AT sequences of DNA, but similar to their binding mode in GC rich regions of DNA. The highest affinity for RNA is found for an imidazoline dication, 2. With some substituents which inhibit formation of a strong intercalation complex, the results suggest a non-intercalative type of binding occurs. The non-intercalative binding probably occurs through a complex with the furan derivative bound in the narrow, deep major groove of A-form RNA helices.

Stabilization of the Karenitecin® lactone by alpha-1 acid glycoprotein.

PurposeCamptothecins contain a lactone ring that is necessary for antitumor activity, and hydrolysis of the lactone ring yields an inactive carboxylate species. Human serum albumin (HSA) and alpha-1 acid glycoprotein (AGP) are clinically significant plasma proteins thought to have important roles in camptothecin lactone stability. Herein, we examined the effect(s) of HSA and AGP on the lactone stability of Karenitecin, a novel, highly lipophilic camptothecin analog, currently at the phase 3 clinical testing stage.MethodsAn AGP-immobilized protein column was used to develop HPLC methods to evaluate the effect(s) of physiologically relevant HSA and AGP concentrations on the lactone/carboxylate ratio and hydrolysis kinetics of Karenitecin, camptothecin (CPT), and topotecan (TPT).ResultsPhysiologically relevant concentrations of HSA and AGP substantially slowed Karenitecin lactone hydrolysis. AGP was notably more effective at protecting the Karenitecin lactone from hydrolysis than HSA was in promoting hydrolysis. Additionally, AGP reversed the hydrolysis of partially hydrolyzed Karenitecin lactone. In contrast, HSA and AGP had minimal effects on hydrolysis of the TPT lactone, while the AGP/HSA solutions dramatically accelerated hydrolysis of the CPT lactone.ConclusionAGP strongly enhances the lactone stability of Karenitecin. Since Karenitecin is highly protein-bound in human plasma and exhibits greater lactone stability, relative to other camptothecins, in patient plasma samples, this newly identified role of AGP in promoting lactone stability may have important implications for the design of more effective anticancer agents within the Karentecin™ and camptothecin classes.