Structural studies of immunomodulators. Part 2: Crystal structure and conformation of azimexon (BM 12.531) an immunostimulant and an anti-tumor drug.
Azimexon [2-cyanaziridinyl-2-carbamoyl-aziridinyl-1-propane] is a derivative of 2-cyanaziridine. Azimexon is an immunostimulant which shows therapeutic effects in tumor models and experimental infections in mice in vitro, enhances T lymphocyte transformation in vitro and increases phagocytosis of latex particles by mouse peritoneal cells. In cancer patients it increases blood active T rosettes, increases T4/T8 ratio and is used in the treatment of melanomas. The crystal structure analysis of azimexon has been undertaken to study the conformation of the molecule in the solid state as a first step in the investigation of a possible structure-function relationship of immunomodulators. Crystals of azimexon are triclinic, space group P1, with a = 6.342(2), b = 6.804(1), c = 13.106(2) A, alpha = 75.17(1), beta = 89.17(2), gamma = 83.26(2) degrees, V = 542.8 A3, Z = 2, D0 = 1.18 g cm-3 and Dc = 1.189 g cm-3. The structure was solved using CAD-4 data by multisolution techniques and refined to a final R value of 0.057. There are two independent molecules in the asymmetric unit with very different conformations relating the two aziridine rings in the molecule. The mean lengths of C-N and C-C in the aziridine rings are 1.461 and 1.494 A and the configuration of the ring nitrogen is pyramidal. The mean C-C-N and C-N-C bond angles in the ring are 59.2 and 60.6 degrees respectively. The two molecules, which differ significantly in the relative orientation of their aziridine rings, are linked by hydrogen bonding involving the amino group of one molecule as the donor and the cyano nitrogen and carbamoyl oxygen of the other molecule as the acceptor. There are a number of C-H...O and C-H...N interactions in the structure. The mode of action of azimexon is unknown. It has been suggested that azimexon may alkylate DNA. The knowledge of the three-dimensional structure should facilitate distance geometry calculations that would determine which modes of crosslinking would be possible. The end-to-end distances between the two ends of the molecule is 9.0 A which is of the same order as the intrastrand distances in the DNA double helix. The present structural work of azimexon strongly indicates that azimexon crosslinks with DNA using its two reactive groups at its ends. Further study is necessary in order to determine which modes of crosslinking would be possible.
Srikrishnan
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Department of Biophysics, Roswell Park Cancer Institute, Buffalo, New York 14263.
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D001388:Aziridines; D055598:Chemical Phenomena; D002621:Chemistry; D003461:Crystallography
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D001388:Aziridines; C016866:azimexon