Relationship of chemical structures of anthraquinones with their effects on the suppression of immune responses.

A series of 37 anthraquinones were evaluated for their ability to inhibit the induction of cytolytic T-lymphocytes in a mixed lymphocyte culture system, useful as a preliminary screen for immunosuppressive agents. These compounds were also tested for their ability to prevent the production of antibody in mice. It was demonstrated that 1,4-bis [(2-aminoethyl)amino]-5, 8-dihydroxy-9,10-anthracenedione dihydrochloride (AEAD, 2) derived from mitoxantrone (MX, 1) by removing hydroxyethyl groups from both side chains was extremely active in depressing immune responses in vitro and in vivo. Four additional anthraquinones related to AEAD were also identified to share similar suppressive activity. They include a Schiff base, 1,4-dihydroxy-5,8-bis[[2-[(3-pyridinylmethylene)amino]ethyl]amino] -9,10-anthracenedione; a dimer with N-terminals methylated, 1,1-[ethylenebis (iminoethyleneimino)]-bis [5,8-dihydroxy-4-[(2-methylamino-ethyl)amino] anthraquinone tetrahydrochloride; an oxazolidine, 1,4-dihydroxy-5,8-bis [[2-(2-propyl-3-oxazolidinyl)ethyl]amino] anthraquinone; and its polymeric oxazolidine, poly [5,8-dihydroxy-1,4-anthraquinonyleneiminoethylene-3,2-oxazolidine- diyltrimethylene-2,3-oxazolidinediylethyleneimino]. These compounds may warrant further consideration as candidates for the treatment of refractory autoimmune diseases and in organ transplantation.