Design, Synthesis and Preliminary In‐Vitro Activity of 6‐Hydroxyalkyl β‐Carboline Derivatives for the Development of Drug Conjugates Targeting MDM2

The mouse-double-minute-2 (MDM2) protein, the main downregulator of the tumor suppressor p53 protein, represents a promising target for the development of novel anticancer therapies. However, the lack of selectivity and poor effectiveness in tumors bearing mutated-p53 impaired the approval of several MDM2 inhibitors for the market. In this context, the possibility of generating drug-conjugates within a MDM2 inhibitor is a growing research area aimed to overcome these drawbacks. Considering the promising MDM2 inhibition by the β-carboline-based 1, in this work we explored the introduction of a new functionalization on it for a future conjugation while preserving its anticancer properties. Based on preliminary docking studies, we synthesized derivatives 2 a–d having linear hydroxyalkyl chains with different lengths at the 6-position of the β-carboline core, which effectively preserved the submicromolar IC50 on wild-type-p53-U87MG glioblastoma cell line observed with 1. Candidates 2 a, d showed the functionalization was tolerated with respect of bioactivity also on mutated-p53-U138MG glioblastoma cell line, and their hydroxyl groups proved to be easily accessible when coupled to 4-pentynoic-N,N’-dimethylethylenediamine affording derivatives 10 a, d with high yields. In summary, our results led to generating novel 6-hydroxyalkyl-β-carboline compounds displaying a suitable hydroxyl-site useful to improve the efficacy and/or the tumor specificity of 1 through conjugation strategies.