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.

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

Arrigoni, Federico;Prpic, Helena;Zambra, Marco;Gazzola, Silvia
;
Piarulli, Umberto
2024-01-01

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 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.
2024
2024
https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejoc.202400915
Antitumor Agents; Carboline; Drug Delivery; Protein-Protein Interactions
Arrigoni, Federico; Prpic, Helena; Ferrari, Ana; Zambra, Marco; Roscilli, Giuseppe; Gazzola, Silvia; Piarulli, Umberto
File in questo prodotto:
File Dimensione Formato  
Eur J Org Chem - 2024 - Arrigoni - Design Synthesis and Preliminary In‐Vitro Activity of 6‐Hydroxyalkyl ‐Carboline.pdf

accesso aperto

Tipologia: Versione Editoriale (PDF)
Licenza: Creative commons
Dimensione 1.9 MB
Formato Adobe PDF
1.9 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2187953
 Attenzione

L'Ateneo sottopone a validazione solo i file PDF allegati

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact