Efficient Synthesis of Conformationally Restricted Apoptosis Inhibitors Bearing a Triazole Moiety

Abstract

Apoptosis is a biological process relevant to different human diseases that is regulated through protein-protein interactions and complex formation. Peptidomimetic compounds based on linear peptoids and cyclic analogues with different ring sizes have been previously reported as potent apoptotic inhibitors. Among them, the presence of cis/trans conformers of an exocyclic tertiary amide bond in slow exchange has been characterized. This information encouraged us to perform an isosteric replacement of the amide bond by a 1,2,3-triazole moiety, in which different substitution patterns would mimic different amide rotamers. The syntheses of these restricted analogues have been carried out through an Ugi multicomponent reaction followed by an intramolecular cyclization. The unexpected formation of a β-lactam scaffold prompted us to study the course of the intramolecular cyclization of the Ugi adducts. In order to modulate this cyclization, a small library of compounds bearing both heterocyclic scaffolds has been synthesized and their activities as apoptosis inhibitors have been evaluated.

Regioselective Synthesis of a Family of β‐Lactams Bearing a Triazole Moiety as Potential Apoptosis Inhibitors

“…The best inhibitors of the 15 b-lactam library were 3aA and 3aB,w hich meanst hat the diphenylpropyl group at R 3 is crucial for the biological ac-tivity.T hese trends were in agreement with previous results obtained with other generations of apoptosis inhibitors. [10] Noticeably,t hese two new derivatives 3aA and 3aB displayed an improved aqueous solubility,w ith the concomitant drugability advantages.…”

“…The final ring-closure reactiong ave the corresponding b-lactamsi nh igh yields. [18] In the present work, we took advantage of the Ugi-4CC approach and the versatility of the subsequent intramolecular cyclization,w hich affords two different compounds (six-or four-membered rings) depending on the reactionc onditions and the substitution patterns,t op repare al ibrary of 15 blactam derivatives with total regioselectivity.C onsidering that the 2,4-dichlorophenetyl moiety at R 1 was crucial for the biological activity, [10] we also envisioned the introduction of different substituents at R 2 andR 3 with the aim of enhancing the bioavailability and, therefore, the activity of these b-lactams as apoptosis inhibitors.…”

“…Biological evaluation of ap reliminary collection of conformationally constrained cyclic compounds bearing an exocyclic 2,4-triazole moiety,r evealed compounds 1 and 2a,b oth bearing the b-lactam scaffold, as the mostp otent apoptosis inhibitors tested in an in vitro assay (Scheme 1B). [10] Moreover, two essential substituents for the activity were identified:d iphenylpropyla tR 3 and 2,4-dichlorophenetyl at R 1 .H owever, 1 and 2a showed to be highly hydrophobic molecules, which could lead to undesired side effects, unspecific toxicity,a nd non-optimal pharmacokinetics in furthers tages of drug development. With Apoptosis is ab iological process important to severalh uman diseases;i ti ss trongly regulated throughp rotein-protein interactions and complex formation.W ep reviously reported the synthesis of apoptosis inhibitors bearing an exocyclic triazole amide isoster by using an Ugi four-component coupling reaction (Ugi-4CC), followed by ab ase-promoted intramolecular cyclization.D epending on the substitution patternsa nd the reaction conditions, this cyclization forms the six-or four-membered ring.…”

“…Biological evaluation of a preliminary collection of conformationally constrained cyclic compounds bearing an exocyclic 2,4‐triazole moiety, revealed compounds 1 and 2 a , both bearing the β‐lactam scaffold, as the most potent apoptosis inhibitors tested in an in vitro assay (Scheme B) . Moreover, two essential substituents for the activity were identified: diphenylpropyl at R 3 and 2,4‐dichlorophenetyl at R 1 .…”

“…We previously reportedt he synthesis of conformationally restricted apoptosis inhibitors bearing an exocyclic triazole moiety by using an Ugi four-component coupling reaction (Ugi-4CC), followed by ab ase-promoted intramolecular cyclization. [10] The cyclization led to the corresponding six-membered ring (2,5-diketopiperazine, DKP) or four-membered ring, as the intramolecular alkylation reaction can occur either through the nitrogen or the a-carbon atom of the secondary amide formed duringt he Ugi-4CC (Scheme 1A). The ratio between the DKP and the b-lactam products depended on the relative acidity of the NH and a-CH hydrogen atoms,w hich were clearly affected by the substitution pattern in the triazole ring or in the amide nitrogen atom.…”