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An efficient synthesis in 10 steps and overall yields up to 27% of NEtXaa(4)-cyclosporin A derivatives (Xaa = Leu, Val, Ile, Thr) starting from cyclosporin A is described. Biological activities of the new analogues show promising results for the design of cyclosporin derivatives exhibiting non-immunosuppressive and anti-HIV activity. (C) 2000 Elsevier Science Ltd. All rights reserved.