Planta Med 2014; 80 - P1L39
DOI: 10.1055/s-0034-1394696

Towards the first SAR study on the Securinega alkaloids

E Chirkin 1, W Atkatlian 1, S Michel 1, FH Porée 1
  • 1Laboratoire de Pharmacognosie UMR CNRS 8638, Université Paris Descartes, 4 Avenue de l'Observatoire, F-75006, Paris France

Securinega alkaloids are an intriguing class of secondary metabolites, comprising about 30 members, isolated from plants belonging to the Securinega (Flueggea), Phyllanthus, Breynia and Margaritaria genera, Phyllanthaceae family.[1] They possess a unique tetracyclic structure featuring a strained α,β-unsaturated γ-lactone. The securinine-type (e.g. securinine 1, virosecurinine 2, phyllanthidine 3) is based on the six-membered piperidine A ring, and the norsecurinine-type (e.g. norsecurinine 4) derives from pyrrolidine. Interestingly, almost all the possible stereoisomers are naturally occurring (e.g. securinine 1, virosecurinine 2), but in different plants.

Fig 1: Securinine 1, virosecurinine 2, phyllanthidine 3, norsecurinine 4.

Schema 1: Semi-synthetic structural modifications on virosecurinine
Reagents and conditions: a) MeMgBr. THF, 0 °C to r.t. (45%) b) nBuLi, THF. -78 °C to r.t. (42%) c) H2, PdC, EtOH (73%) d) mCPBA, MeOH, 0 °C, then xylene, reflux (67% over 2 steps) c) KCN, MeOH, reflux (52%).

Schema 2: Compounds obtained by Lewis acid promoted conjugate hetero-Michael addition.

The antitumor, antimalarial, antibacterial and GABA-ergic activities of these compounds are reported. [2 – 4] However, to date no structure-activity relationship (SAR) has been described. Therefore, the first series of synthetic derivatives of virosecurinine (2) for a SAR study was prepared.

Acknowledgements: This work was supported by Université Paris Descartes and CNRS. We thank the Association Lapervenchelif for the travel grant to attend GA 2014. We are also grateful to Dr. Christophe Velours (CNRS Gif/Yvette) for his technical assistance in ECD spectra recording.

Keywords: Securinega, alkaloid, GABAA receptor antagonist, Michael addition

References:

[1] Snieckus V. The Alkaloids. New-York: Academic Press; 1973, 12: 425 – 506.

[2] Xu L, Zhang JT. Neuroprotection by D-securinine against neurotoxicity induced by beta-amyloid (25 – 35). Neurol Res 2004; 26: 792 – 796.

[3] Lubick K, Radke M, Jutila M. Securinine, a GABAA receptor antagonist, enhances macrophage clearance of phase II C. burnetii: comparison with TLR agonists. Leukocyte Biol 2007; 82: 1062 – 1069.

[4] Weenen H, Nkunya MHH, Bray DH, Mwasumbi LB, Kinabo LS, Kilimali VAEB, Wijnberg JBPA. Antimalarial compounds containing an a,b-unsaturated carbonyl moiety from Tanzanian medicinal plants. Planta Med 1990; 56: 371 – 373.