β-Lapachone and Its Derivatives: Synthetic Strategies, Structure–Activity Relationships, Pharmacological Activities, and Computational Approaches

β-Lapachone (β-Lap) is a naturally occurring ortho-naphthoquinone found in the heartwood of Handroanthus impetiginosus and other lapacho trees. The compound has been studied extensively due to its promising anticancer potential in cancer cells with high expression of NAD(P)H:quinone oxidoreductase 1 (NQO1). Reduction of β-Lap by NQO1 leads to the formation of a highly unstable hydroquinone intermediate which undergoes oxidation in a futile redox cycle, generating excessive amounts of ROS. The resultant oxidative stress can lead to DNA damage, hyperactivation of PARP1, reduction of NAD+ and ATP levels and cell death in cancer cells. Although β-Lap exhibits promising pharmacological effects, its poor solubility in water, problems with formulation and pharmacokinetics, possible toxic effects associated with dosing and limited therapeutic window limit the clinical applications of the parent compound. Therefore, various modifications of β-Lap structure were performed using the arylamino, alkoxy, thiosemicarbazone, oxime and prodrug strategies. Computer-assisted drug design approaches such as molecular docking, electronic-structure calculation and ADMET predictions serve as additional methods of selection of promising β-Lap derivatives before synthesis and testing. The present review gives a summary of the chemistry, physicochemical properties, SAR, pharmacology, synthetic and computational approaches to β-Lap and its derivatives [1-3,6]. The review was performed on published scientific papers based on β-lapachone, structural derivatives of β-lapachone, anticancer potential, molecular docking, and computational ADMET study. β-Lapachone was taken into account as the main parent compound, and structural derivatives, including arylamino, alkoxy, oxime, thiosemicarbazone, and other groups, were discussed. The computational methods, including molecular docking, were considered for the assessment of the interaction between the ligands and their targets (proteins) involved in the process of cancer development such as NQO1 and Topoisomerase IIα. Binding interactions, docking score, hydrogen bonding, hydrophobic, and π-π interactions were studied according to the reported studies. Besides, the pharmacokinetic and toxicity properties were also evaluated through ADMET prediction to obtain better anticancer agents [1,4,6,7]