Synthesis and evaluation of some lipidic aminoalcohols and diamines as immunomodulators Esther del Olmo, a, * Alvaro Plaza, b Antonio Muro, b, * Antonio R. Martı ´nez-Ferna ´ndez, c Juan J. Nogal-Ruiz, c Jose ´ L. Lo ´ pez-Pe ´rez a and Arturo San Feliciano a a Departamento de Quı ´mica Farmace ´utica, Facultad de Farmacia, CIETUS, Universidad de Salamanca, 37007 Salamanca, Spain b Laboratorio de Parasitologı ´a, Facultad de Farmacia, CIETUS, Universidad de Salamanca, 37007 Salamanca, Spain c Departamento de Parasitologı ´a, Facultad de Farmacia, Universidad Complutense, 47007 Madrid, Spain Received 13 July 2006; revised 25 August 2006; accepted 28 August 2006 Available online 26 September 2006 Abstract—Lymphoproliferation inhibition and cytotoxicity of a number of lipidic aminoacids, aminoalcohols and diamines were evaluated as a preliminary screening to select potential immunomodulators. The four most potent/less toxic compounds were sub- mitted to delayed hypersensibility (DTH) assays to define the best to be evaluated further Graft-vs-Host, NO production and other immunoevaluation (CD4 + , CD45, CD8, CD11b, I-Ek, and NK cells) assays, to establish their immunomodulation potential for being further considered as auxiliary agents for vaccination against some parasitic infections. Compounds 5d, 6d, 6f, 7a, and 9a, fairly inhibited the lymphoproliferation (71.6–79.5%, at 3.2–2.4 nM), while the aminoalcohol derivative 6f and the diamine 7a gave the most promising results in the DTH assays. Diamine derivative 8b induced nitrite production on normal macrophages, whereas compounds 6f and 7a induced nitrite production on LPS pre-stimulated macrophages. These two last compounds have been selected to follow in vivo vaccination assays. Ó 2006 Elsevier Ltd. All rights reserved. Immunosuppressants play important clinical roles in organ transplantation and in the treatment of autoim- mune diseases such as rheumatoid arthritis, psoriasis and systemic lupus erythematosus. Cyclosporin A (CsA) 1 and tacrolimus (FK506) 2 have made great con- tributions to the prevention of acute rejection in hu- man organ transplantation. Both drugs have similar mechanisms of action and proved their immunosup- pressant activity by inhibiting the production of inter- leukin-2 (IL-2) in antigen-stimulated helper T-cells, 3–5 but they also have severe side effects, 6 such as a high cytotoxicity and renal and liver toxicities. Therefore, less toxic drugs for the prevention of graft rejection are needed. ISP-1 (myriocin, thermozymocidin) was isolated in 1989 from the culture broth of Isaria sinclairii by Fuj- ita et al. 7 These authors also described the ISP-1 immu- nosuppressant activity, 8 that was nearly five times more potent than that of CsA, with lower toxicity. They also worked on the identification of the minimal structure requirements for the activity and concluded that a 2-al- kyl-2-aminoethanol moiety was needed. 9 They also optimised the alkyl chain length, the functions and their locations on the alkyl chain to develop compound FTY720 (IC 50 6.1 nM), as the best drug candidate. 10 In the course of these studies, compound OA-12 displayed an intermedium immunosuppressant activity (IC 50 98.3 nM), nearly seven times lesser potent than CsA in the allogeneic mouse mixed lymphocyte reaction (MLR) assay. 11 Our research group has been working on lipidic ethy- lenediamine and b-aminoalcohol derivatives displaying different biochemical, pharmacological and antimicrobi- al properties. 12–16 The close structural relationship between the above-mentioned drugs and compound OA-12 with some related compounds prepared by us suggested their evaluation as immunomodulators through lymphoproliferation inhibition, delayed hyper- sensitivity and other studies. 0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2006.08.113 Keywords: Synthesis; Evaluation; Lipidic aminoalcohols; Lipidic dia- mines; Immunomodulators. * Corresponding authors. Fax: +34 923294515; e-mail: olmo@usal.es Bioorganic & Medicinal Chemistry Letters 16 (2006) 6091–6095