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

Abstract 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 IC 50 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.