Structure-activity relationships of closo- and nido-carborane Erlotinib analogs: lipophilicity as a key modulator of anti-glioma activity

Abstract

Background/Objectives: To enhance the anti-glioma activity of erlotinib, we previously developed a series of carborane-based analogs exploiting the concept of three-dimensional bioisosterism. These carboranes generally exhibited improved cytotoxicity against glioma cell lines compared with the parent compound erlotinib and additionally showed varying degrees of EGFR inhibition. Given the well-described influence of lipophilicity on pharmacological properties, we aimed to determine this parameter for the new analogs and explore its correlations with biological behaviors. Methods: Lipophilicity was assessed experimentally, through chromatographic procedure, in terms of RM0 and theoretically via fragment-based logP calculations (flogP) using Hansch–Fujita hydrophobic parameters π of some substituents and the experimentally determined logDn-octanol/buffer(7.4) of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline. Additionally, the electronic properties of the carborane clusters were considered using the NMR chemical shifts of cluster carbonbound protons. Results: For the series of carboranes, the RM0 discretely correlated to the flogP. Neither RM0 nor flogP correlated with the electronic characteristics of the carboranes. From the correlation between RM0 and flogP, it was possible to estimate the π value for a nido-carboranyl substituent. Cytotoxicities, against glioma cells, exhibited a parabolic dependence on lipophilicity, finding optimal flogP for each cellular system. Some tendencies were observed between EGFR inhibition and flogP, requiring more hydrophilic compounds for optimal wild-type EGFR inhibition or a specific flogP for mutant EGFR inhibition. It was observed that the electronic features of the boron cluster also influenced both biological activities studied. Conclusions: Unlike our previous reports, which focused on the synthesis and biological evaluation of carborane-erlotinib analogs, this study establishes for the first time the correlation of lipophilicity and electronic features with cytotoxic and EGFRinhibitory activities, providing new insights into their structure–activity relationships.