Identification of a new series of flavopiridol-like structures as kinase inhibitors with high cytotoxic potency

Nada Ibrahim (1) , Pascal Bonnet (2) , Jean-Daniel Brion (1) , Jean-François Peyrat (1) , Jerome Bignon (3) , Hélène Levaique (3) , Béatrice Josselin (4, 5) , Thomas Robert (4, 5) , Pierre Colas (6) , Stéphane Bach (6, 4) , Samir Messaoudi (1) , Mouad Alami (1) , Abdallah Hamze (1)

1 BioCIS - Biomolécules : Conception, Isolement, Synthèse
2 ICOA - Institut de Chimie Organique et Analytique
3 ICSN - Institut de Chimie des Substances Naturelles
4 FR2424 - Fédération de recherche de Roscoff
5 SBR - Station biologique de Roscoff = Roscoff Marine Station
6 SU - Sorbonne Université

In this work, unique structure of flavopiridol analogs bearing thiosugars, amino acids and heterocyclic moieties tethered to the flavopiridol via thioether and amine bonds mainly on its C ring have been prepared. The analogs bearing thioether-benzimidazoles as substituents have demonstrated high cytotoxic activity in vitro against up to seven cancer cell lines. Their cytotoxic effects are comparable to those of flavopiridol. The most active compound (13c) found after the structure-activity relationship (SAR) showed the best antiproliferative activity and was more efficient than the reference compound. In addition, compound 13c showed significant nanomolar inhibition against CDK9 and GSK3β protein kinases.

Keywords: Favopiridol; cytotoxicity; Kinase inhibition; structure-activity relationship. Highlights

Domains: Catalysis; Medicinal Chemistry

Nada Ibrahim, Pascal Bonnet, Jean-Daniel Brion, Jean-François Peyrat, Jerome Bignon, et al.. Identification of a new series of flavopiridol-like structures as kinase inhibitors with high cytotoxic potency. European Journal of Medicinal Chemistry, 2020, 199 (31), pp.112355. ⟨10.1016/j.ejmech.2020.112355⟩. ⟨hal-03036489⟩