Research paper Structure-based design, synthesis and antitumoral evaluation of enulosides Jonh A.M. Santos a, b , Cosme S. Santos a, b , Claudia L.A. Almeida a, b , Thiago D.S. Silva c , Jo ~ ao R. Freitas Filho a , Gardenia C.G. Milit ~ ao c , Teresinha G. da Silva d , Carlos H.B. da Cruz b , Juliano C.R. Freitas a, e, ** , Paulo H. Menezes b, * a Departamento de Química, Universidade Federal Rural de Pernambuco, Rua Dom Manoel de Medeiros s/n, 52171-900, Recife, PE, Brazil b Departamento de Química, Universidade Federal de Pernambuco, Av. Jornalista Anibal Fernandes s/n, 50670-901, Recife, PE, Brazil c Departamento de Fisiologia e Farmacologia, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego,1235, 50670-901, Recife, PE, Brazil d Departamento de Antibi oticos, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego,1235, 50670-901, Recife, PE, Brazil e Centro de Educaç~ ao e Saúde, Universidade Federal de Campina Grande, Acesso Professora Maria Anita Furtado Coelho, s/n, 58175-000, Cuit e, PB, Brazil article info Article history: Received 5 November 2016 Received in revised form 13 January 2017 Accepted 21 January 2017 Available online 24 January 2017 Keywords: Pseudoglycosides Enulosides Antitumoral CRM-1 abstract Enulosides, carbohydrate derivatives containing an a,b-unsaturated carbonyl unit, were designed and obtained in high yields and isomeric purity. All synthesized compounds exhibited antitumoral activity in micromolar range against four tested tumor cells lines, being the best results observed for HL-60 cells. These compounds open new possibilities to prepare an array of more active, site-specific or selective antitumor agents. 2016 Elsevier Ltd. All rights reserved. © 2017 Elsevier Masson SAS. All rights reserved. 1. Introduction Several natural products that have an a,b-unsaturated d-lactone as structural motif are known to exhibit various biological activities [1e3]. Among these, leptomycin B, a natural product first isolated from Streptomyces sp. ATS1287 [4] has a prominent position (Fig. 1). The cellular target of leptomycin B, a nuclear export inhibitor, has been identified as CRM1, an evolutionarily conserved receptor for the nuclear export signal of proteins [5]. Leptomycin B and parent compounds can act as a Michael-type acceptor for biological nucleophiles, in special the sulfhydryl groups of cysteines. Specif- ically, the region containing Cys-529 from CRM1 forms a pocket into which leptomycin B is readily incorporated, just like an enzy- meesubstrate interaction [6]. However, the clinical development of leptomycin B was subsequently discontinued due to the significant toxicity observed [7]. Despite of the presence of an a,b-unsaturated d-lactone motif in several natural products with biological activity, few reports of naturally occurring enone-containing sugars (enulosides) are described. Examples are Microthecin [8], and Ascopyrone P [9], both exhibiting antibacterial activity (Fig. 2). The general strategy for the synthesis of enulosides is based on the use of glycals as starting materials [10] and they are versatile building blocks that can be used in a variety of transformations [11]. One example is the synthesis of enantiopure 2,4-disubstituted 6- hydroxy-1,6-dihydro-2H-pyridin-3-ones using an aza- Achmatowicz type chemistry [12]. From the pharmacological point of view, some synthetic enu- losides exhibited activity against Mycobacterium tuberculosis H37Rv [13], and they can also act as glycosidase inhibitors [14]. Moreover, they exhibited excellent in vitro activities against different Gram- positive, Gram-negative as well as resistant bacterial strains and fungi [15]. Synthetic enolosides containing hydrophobic chains also exhibited antifungal and antibacterial activities and a preliminary screening indicated that some of the synthesized compounds exhibited low toxicity to eukaryotic cells [16]. * Corresponding author. ** Corresponding author. Departamento de Química, Universidade Federal Rural de Pernambuco, Rua Dom Manoel de Medeiros s/n, 52171-900, Recife, PE, Brazil. E-mail addresses: julianocrufino@yahoo.com.br (J.C.R. Freitas), paulo.menezes@ pq.cnpq.br (P.H. Menezes). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2017.01.036 0223-5234/© 2017 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 128 (2017) 192e201