1109 JPP 2005, 57: 1109–1115 ß 2005 The Authors Received January 7, 2005 Accepted March 1, 2005 DOI 10.1211/jpp.57.9.0006 ISSN 0022-3573 Dipartimento di Scienze Farmaceutiche, Universita ` di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy A. L. Piccinelli, F. De Simone, L. Rastrelli Department of Cellular and Molecular Medicine-Infectious Diseases, St George’s Hospital Medical School, Cranmer Terrace, Tooting, London SW17 0RE, UK N. Mahmood Centro de Investigaciones en Productos Naturales (CIPRONA), Universidad de Costa Rica, 2060 San Jose ´ , Costa Rica G. Mora Escuela de Ciencias Ambientales, Facultad de Ciencias de la Tierra y el Mar, Universidad Nacional, Heredia, Costa Rica L. Poveda Correspondence: L. Rastrelli, Dipartimento di Scienze Farmaceutiche, Universita ` di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy. E-mail: rastrelli@unisa.it Anti-HIV activity of dibenzylbutyrolactone-type lignans from Phenax species endemic in Costa Rica A. L. Piccinelli, N. Mahmood, G. Mora, L. Poveda, F. De Simone and L. Rastrelli Abstract Previously, we isolated two new dibenzylbutyrolactone-type lignans, named phenaxolactones 1 and 2, from the leaves of Phenax angustifolius Wedd. (Urticaceae). In this investigation three new dibenzylbutyrolactone lignans (phenaxolactones 3–5), together with phenaxolactone 1, and fla- vones vitexin (6), isovitexin (7), were isolated from Phenax rugosus Wedd. leaves collected in Santa Ana, Costa Rica. The structures were elucidated using 1D and 2D NMR spectroscopy as well as mass spectrometry. Phenaxolactones 1–5 and flavones 6 and 7 were evaluated for their inhibitory activity against HIV-1 MN in infected C8166 cells. The most promising compound was phenaxolactone 1 with an EC50 value of 3.0 M, no cytotoxicity at 112 M and a therapeutic index value of 37.3. Introduction HIV-AIDS is a major cause of mortality and due to the potential for development of resistance to existing therapies, discovery of new therapeutic agents is crucial. Investigations into the molecular processes of HIV infection have led to the identifica- tion of a number of macromolecular targets for drug design, such as HIV-1 reverse transcriptase, protease, and integrase enzyme, and regulatory proteins. Other targets include proteins that are involved in virus attachment and fusion. The viral surface protein gp120 interacts with the cellular receptor CD4 (Dalgleish et al 1984). This causes a change in the conformation of gp120 (Wyatt et al 1998), which binds to a second cellular receptor of the family of chemokine receptors (LaBranche et al 2001), allowing the HIV protein gp41 to penetrate the cell membrane, leading to membrane fusion (Yachou & Sekaly 1999). We report the isolation and structure elucidation of the new dibenzylbutyrolactone- type lignans from plants and their inhibitory activities against HIV-infection in cell cultures. Phenax is a genus of the family Urticaceae consisting of aproximately12 species, which are very well distributed throughout Tropical America, although some of them have become naturalized in the Asian tropics (Burger 1977). The individuals are shrubs or herbs and, occasionally, small trees. These species grow wild in Costa Rica and have been used traditionally as insecticidal agents (Rastrelli et al 1998). Previously, we isolated two new dibenzylbutyrolactone-type lignans, named phenaxolactones 1 and 2, from the leaves of Phenax angustifolius Wedd. (Urticaceae) (Rastrelli et al 2001). In this investigation three new dibenzylbutyrolactone lignans named phenaxolactones 3– 5, together with phenaxolactone 1 and flavones vitexin (6) and isovitexin (7), have been isolated from Phenax rugosus Wedd. leaves collected in Santa Ana, Costa Rica. Lignans are found in the roots, stems, bark, fruit and seeds of many plant species and are derived from dimerization of phenylpropanoid units at the central carbons of their side chains. Lignans of the podophyllotoxin and dibenzylbutyrolactone series have received considerable interest recently as antiviral agents. There have been several modes of antiviral activity associated with lignans: tubulin binding (inhibition of tubulin polymerization interferes with the formation of the cellular cytoskeleton and with some critical viral processes), reverse transcriptase inhibition, integrase inhibition Downloaded from https://academic.oup.com/jpp/article/57/9/1109/6147498 by guest on 12 January 2023