Novel Tetrahydropyrido[1,2-a]isoindolone Derivatives (Valmerins): Potent Cyclin-Dependent Kinase/Glycogen Synthase Kinase 3 Inhibitors with Antiproliferative Activities and Antitumor Effects in Human Tumor Xenografts

Abstract

The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number of diverse structures have been reported to inhibit CDKs and GSK-3β in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC(50) < 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of our study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates for further development as anticancer agents.

Structural basis of valmerins as dual inhibitors of GSK3β/CDK5

“…Indeed, in recent years, a few diverse structures have been determined to inhibit the enzymatic activity of GSK3β and CDK5. In particular, the tetrahydropyrido[1,2-α]isoindolone derivatives (valmerins), acting as dual inhibitors of GSK3β/CDK5, exhibited good antiproliferative activities and antitumor effects in human tumor xenografts [16]. Of them, the most potent compound, valmerin-19 ( Fig.…”

Totalsynthese von Nosiheptid

“…In Analogie zu Verdelet et al [278] wurde der MOM-Ether 229 ( [321] Eine Lösung von 3-Hydroxypicolinsäuremethylester [278] 3-Methoxypicolinsäure (241) [322] 3-Methoxypicolinsäuremethylester [308] Alle relevanten analytischen Daten stimmen mit den veröffentlichten Werten überein. [322] N,N'-(1,2-Phenylen)bis(3'-methoxypicolinamid) (104) …”

Synthesis and fungicidal activity of N-thiazol-4-yl-salicylamides, a new family of anti-oomycete compounds

“…Bis(triphenylphosphine)palladium(II) chloride (1.3 g, 1.9 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester 24 (13.9 g, 45 mmol) and a solution of sodium carbonate (11.9 g, 0.11 mol) in 30 mL of water are consecutively added to a solution of ethyl 2-bromothiazole-4-carboxylate 23 (3,8.8 g, 37 mmol) in 200 mL of dioxane. The reaction mixture was heated to reflux for 4 h, then cooled to room temperature and evaporated in vacuo.…”

“…As the de novo synthesis of this disubstituted heterocyclic scaffold seems to be restricted to certain alkyl groups in position 2 [18][19][20] and the reduction of 2-alkyl-4-nitrothiazoles is not known, the only viable methods for the preparation of 2-alkylthiazol-4-amines were so far the Beckmann rearrangement of oximes of 2-alkylthiazol-4-ketones 21,22 and the Curtius reaction of 2-alkylthiazol-4-carboxylic acids. 23,24 Such Beckmann-type ketones are in our eyes not the most suitable building blocks and, as we wanted to avoid the application of any Curtius-type azide derivatives, we were looking for an alternative approach. In this paper, we present a completely http (3) with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, 26 both of which are commercially available.…”