Meriolins (3-(Pyrimidin-4-yl)-7-azaindoles): Synthesis, Kinase Inhibitory Activity, Cellular Effects, and Structure of a CDK2/Cyclin A/Meriolin Complex

Abstract

We report the synthesis and biological characterization of 3-(pyrimidin-4-yl)-7-azaindoles (meriolins), a chemical hybrid between the natural products meridianins and variolins, derived from marine organisms. Meriolins display potent inhibitory activities toward cyclin-dependent kinases (CDKs) and, to a lesser extent, other kinases (GSK-3, DYRK1A). The crystal structures of 1e (meriolin 5) and variolin B (Bettayeb, K.; Tirado, O. M.; Marionneau-Lambert, S.; Ferandin, Y.; Lozach, O.; Morris, J.; Mateo-Lozano, S.; Drückes, P.; Schächtele, C.; Kubbutat, M.; Liger, F.; Marquet, B.; Joseph, B.; Echalier, A.; Endicott, J.; Notario, V.; Meijer, L. Cancer Res. 2007, 67, 8325-8334) in complex with CDK2/cyclin A reveal that the two inhibitors are orientated in very different ways inside the ATP-binding pocket of the kinase. A structure-activity relationship provides further insight into the molecular mechanism of action of this family of kinase inhibitors. Meriolins are also potent antiproliferative and proapoptotic agents in cells cultured either as monolayers or in spheroids. Proapoptotic efficacy of meriolins correlates best with their CDK2 and CDK9 inhibitory activity. Meriolins thus constitute a promising class of pharmacological agents to be further evaluated against the numerous human diseases that imply abnormal regulation of CDKs including cancers, neurodegenerative disorders, and polycystic kidney disease.

Recent Advances in the Design, Synthesis, and Biological Evaluation of Selective DYRK1A Inhibitors: A New Avenue for a Disease Modifying Treatment of Alzheimer’s?

“…Table 3, and significant antiproliferative effects were observed in various cancer cell lines, likely due to inhibition of multiple cell cycle kinases targets. 81 No reports have been found detailing the activity of these molecules in DYRK1A cellular phosphorylation assays, which may represent an opportunity for further study.…”

Synthesis, kinase inhibitory potencies and in vitro antiproliferative activity of isoindigo and 7′-azaisoindigo derivatives substituted by Sonogashira cross-coupling

“…Taxotere was used as a positive control at a drug concentration of 2.5 × 10 −10 M with 46% of HL60 cell growth inhibition and 32% of K562 cell growth inhibition. In vitro kinase inhibitory potencies of compounds 3-7, 10, 11, 13-15 were evaluated toward CDK5/p25, GSK3, CK1 and DyrK1A as already described in the literature [11] by Laurent Meijer's group (Station Biologique CNRS, Roscoff, France). Regarding the residual kinase activity (more than 65%) when the compounds were tested at 10 µM, none of them was particularly active toward these kinases.…”

7-Azaindole: A Versatile Scaffold for Developing Kinase Inhibitors

“…32) Echalier et al 33) reported successful design of CDK inhibitors using interactions with the ribose binding region. Meriolins, structural hybrid of two natural kinase inhibitors (meridianins and variolins), are highly potent inhibitors of CDKs.…”