Structure-Activity Relationships of closo- and nido-Carborane Erlotinib Analogs: Lipophilicity as a Key Modulator of...

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 R_M⁰ and theoretically via fragment-based logP calculations (flogP) using Hansch-Fujita hydrophobic parameters π of some substituents and the experimentally determined logD_{n-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 carbon-bound protons. Results: For the series of carboranes, the R_M⁰ discretely correlated to the flogP. Neither R_M⁰ nor flogP correlated with the electronic characteristics of the carboranes. From the correlation between R_M⁰ 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 EGFR-inhibitory activities, providing new insights into their structure-activity relationships.