Diversity-oriented synthesis and cytotoxic screening of fused dihydropyrazin-2(1H)-ones through a Ugi 4-CR/deprotection/Heck sequence

Highlights

• Diversity-Oriented Synthesis of fused dihydropyrazin-2(1H)-ones is reported.

• Three-step Ugi 4-CR/deprotection/Heck synthetic sequence.

• Activity against the prostate cancer cell line PC-3 was observed.

• 21 structurally diverse fused-dihydropyrazin-2(1H)-ones.

Abstract

An expedited approach to the synthesis of fused-dihydropyrazin-2(1H)-ones from Ugi dimethylacetamide adducts is presented. The protocol relies on the formation of a C–N bond between the primary amide and the transitory oxocarbenium ion formed under acidic conditions, and then the construction of a fused-pyrazinone system after an intramolecular C(sp2)-C(sp2) Heck coupling. The methodology was able to generate 21 structurally diverse poly aza-heterocycles, a collection which was screened for its cytotoxicity in prostate, breast and lung cancer cell lines. The best activity was observed against the prostate cancer cell line PC-3 for two compounds with IC50 values of 23.6 and 20.9 μM, respectively.

Introduction

Dihydropyrazin-2(1H)-one (II) is a key structural motif commonly incorporated in drug design and medicinal chemistry programs in the quest for new biologically relevant molecules [1]. This 1,4-diazaheterocycle in its reduced (I) and oxidized (III) variants also are widely distributed in nature [2] (see Fig. 1). For example, dibromophakellstatin (1), a cytotoxic tetracyclic fused-piperazin-2-one alkaloid, was isolated from the marine sponge Phakellia mauritiana [3], while (−)-agelastatin A (2) was isolated from the deep water marine sponge Agelas dendromorpha. This later oroidin alkaloid has demonstrated a significant cytotoxicity against several human cancer cell lines (IC₅₀ values ranging from 0.097 to 0.703 μM) [4]. Aspergillic acid (3) is another antibiotic and antifungal agent that is derived from certain strains of the fungus Aspergillus flavus [5]. Another important class of alkaloids containing the same heterocyclic core are the bis-indole pyrazinones, as exemplified by dragmacidin D (4), with activity against Parkinson’s and Alzheimer’s diseases [6]. Furthermore, the hexahydropyrazino[2,1-a]isoquinolin-4-one praziquantel (5) is the most widely used anthelmintic drug [7]. Thus, as a consequence of their impressive activities, several methodologies have been devised for the preparation of the 2-pyrazinone core (in all its oxidized forms), which is commonly obtained from different 1,2-amino/carbonyl difunctionalized substrates [8]. In this context, we have recently described a multicomponent approach for the rapid preparation of a series of pyrazinones with remarkable anti-inflammatory effects (6 showed IC₅₀ in TPA = 0.46 μmol/ear) [9]

Among the various isocyanide-based multicomponent processes, the Ugi reaction (Ugi-4CR) has gained enormous attention in modern synthetic organic chemistry because - when it is combined with further transformations - this reaction allows the construction of collections of molecules with high structural diversity and atom economy, in few synthetic steps from simple starting materials [10].

In this respect, the use of 2-aminoacetaldehyde dimethyl acetal (11) in the initial four-component input set was crucial for the synthesis of the dihydropyrazin-2(1H)-one ring, such as in the case of the approaches proposed by Cheng [11], Silvani [12] and Chauhan [13], under acidic conditions. Besides, to develop practical entries for the synthesis of fused dihydropyrazin-2(1H)-ones, we have previously described the preparation of methylpyrazino[2,1-a]isoindoles 9 through a 6-exo cycloisomerization of propargyl-containing Ugi adducts, in which a transient allenamide (Scheme 1, A) was anticipated to be generated, to afford the dihydropyrazinone core 8 (R⁴ = Me). Subsequently acid treatment to equilibrate the regioisomeric mixture of endo/exo alkene and further C–C bond formation with Heck reaction conditions led to the construction of the desired tricyclic compounds (9) (Scheme 1) [14]. Unfortunately, only aliphatic aldehydes afforded good yields of the product. Aromatic aldehydes gave the corresponding dihydropyrrole nuclei [15], or the decomposition of the starting material. Thus, as an extension of this previously reported protocol, herein we describe the diversity-oriented synthesis of fused-dihydropyrazin-2(1H)-ones 9 through a Ugi-4CR/deprotection/Heck synthetic sequence (Scheme 1). In this study, the 2-aminoacetaldehyde dimethylacetal (instead of the propargyl amine used in the previously work) was used in the Ugi reaction and both aliphatic and aromatic aldehydes were incorporated as well as homoaromatic and heteroaromatic carboxylic acids (10). To complement the study, preliminary cytotoxic activities of the synthetized molecules were investigated in several cancer cell lines.