Synthesis, Biological and In Silico Evaluation of Pure Nucleobase-Containing Spiro (Indane-Isoxazolidine) Derivatives as Potential Inhibitors of MDM2–p53 Interaction

Abstract

Nucleobase-containing isoxazolidines spiro-bonded to an indane core have been synthesized in very good yields by regio- and diastereoselective 1,3-dipolar cycloaddition starting from indanyl nitrones and N-vinylnucleobases by using environmentally benign microwave technology. The contemporary presence of various structural groups that are individually active scaffolds of different typology of drugs, has directed us to speculate that these compounds may act as inhibitors of MDM2–p53 interaction. Therefore, both computational calculations and antiproliferative screening against A549 human lung adenocarcinoma cells and human SH-SY5Y neuroblastoma cells were carried out to support this hypothesis.

Heterocycles by Consecutive Multicomponent Syntheses via Catalytically Generated Alkynoyl Intermediates

“…This palladium-catalyzed sequence retains from high catalyst loadings and from copper complexes enabling a broad substituent pattern for 29 examples embedding electron-rich and electron-poor (hetero)aryls, allyl and alkyl groups in good to excellent yields (Scheme 3) [38]. The straightforward Sonogashira coupling of aryl iodides 6 with ethyl propiolate (7) provides 12 examples of aryl propiolates 2 with multi-faceted substituents in up to 97% yield (Scheme 4). By applicating a syringe pump, this access compensated the inherent propensity of ethyl propiolate to undergo oligomerization under basic conditions as well as the reduced alkyne reactivity [39].…”

“…Heterocyclic systems are ubiquitous both in natural products and applied chemistry and thus their MCR synthesis makes them predestined targets. Alongside their use in life sciences [6][7][8], heterocycles are increasingly applied in molecular electronics [9] and photonics [10][11][12], e.g., as organic field effect transistors (OFETs) [13], in organic lightemitting diodes (OLEDs) [14,15] and in dye-sensitized solar cells (DSSCs) [16]. Particularly, MCR accesses to fluorophores [17] by virtue of transition metal catalysis [18] or via the intermediacy of alkynoyl derivatives [19] aroused growing attention over the past years.…”

Recent Advances of Pd/C-Catalyzed Reactions

“…The coupling reactions were taken place between solid aryl halides 89 and solid arylboronic acids 90, in the presence of solid 10% Pd/C and Cs 2 CO 3 or K 2 CO 3 , under absolute solid-phase conditions, and afforded moderate to excellent yield for most substrates (Scheme 15). Moreover, solvent free synthesis in the solid state is a valid approach to obtain biologically active heterocycle rings in ecofriendly way [50]. In addition, this group studied a solvent-free Pd/C-catalyzed heteroaryl coupling reaction between 2-bromopyridine 92 and p-methoxyphenylboronic acid 93 (Scheme 16).…”

Recent Developments on 1,3-Dipolar Cycloaddition Reactions by Catalysis in Green Solvents

“…Spirooxindole derivatives have a privileged hetereocyclic core that confers them substantial biological activity, such as antimicrobial, anticancer, inhibitorial of MDM2-p53 interaction, and so on [24][25][26]. In 2015, an efficient, simple, and rapid one-pot synthesis of dispirooxindolo-pyrrolidines 8a-f and 9a-f via a three-component 1,3-dipolar cycloaddition in ionic liquid media was proposed from Arumugam et al (Scheme 1) [27].…”