Solid‐Phase Multicomponent Synthesis of 3‐Substituted Isoindolinones Generates New Cell‐Penetrating Probes as Drug Carriers

• Published in: ChemMedChem Vol. 15; no. 10; pp. 833 - 838
• Main Authors: Massarano, Tlalit, Mazir, Alexandra, Lavi, Ronit, Byk, Gerardo
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 19.05.2020; Wiley Subscription Services, Inc
• Subjects: Aldehydes; Amides; Apoptosis; Cell death; cell penetrating probe; Chemical synthesis; Chemistry, Medicinal; Drug carriers; Drug delivery; flow cytometry; Fluorescence; Life Sciences & Biomedicine; Modularity; multicomponent reactions; Optimization; Peptides; Pharmacology & Pharmacy; Probes; Science & Technology; Solid phases; staurosporine; Substitutes; multicomponent reactions; staurosporine; ASYMMETRIC-SYNTHESIS; PROTEIN; cell penetrating probe; ONE-POT SYNTHESIS; PROAPOPTOTIC PEPTIDE; CHEMISTRY; flow cytometry; EFFICIENT
• DOI: 10.1002/cmdc.201900656
• ISSN: 1860-7179

A modular solid‐phase multicomponent reaction for the synthesis of 3‐substituted isoindolinone derivatives has been carried out. A mixture of a chiral β‐keto lactam, an aldehyde, an isocyanide and a dienophile react to produce chiral 3‐substituted isoindolinones in one pot. Modularity was accomplished by using solid supported aldehydes and dienophiles. Optimization was achieved by using microwave as the source of energy. The reaction was also performed on a biologically relevant well‐known programed cell death‐inducing peptide D(KLAKLAK)2 on solid phase. The molecules show significant fluorescence with large Stokes shifts and fast cell penetration. The chimeric peptides can be tracked under a microscope thus proving the potential of the probes as cell sensors. They were efficiently internalized compared to unlabeled peptide, with a concomitant induction of programed cell death, thereby proving their potential as drug carriers. A solid start: A microwave‐mediated, multicomponent reaction on solid support gives good yields of complex 3‐substituted isoindolinones. The products displayed significant fluorescence with excellent Stokes shifts. We also demonstrated fast cell penetration of some of these nontoxic compounds and their conjugates with biologically active molecules, showing them to be attractive molecular probes for cell sensing or as carriers for cell‐penetration applications.