Slow-reacting substances and their structural elucidation

For more than forty years since their discovery, the structure of a group of closely related materials known collectively as slow-reacting substances has been unknown. These substances are released from a variety of tissues in response to immunological or non-immunological stimulation. A slow-reacting substance is believed to be implicated in hypersensitivity reactions such as asthma; in order to fully understand its bronchoconstrictor role, the structural elucidation of these materials has been a necessary (albeit difficult) task. Studies on both immunologically generated slow-reacting substance of anaphylaxis (SRS-A) and other slow-reacting substances (SRSs) have indicated a precursor role for arachidonic acid in their biosynthesis; this, coupled with enzymic and chemical activity destruction data, gave an insight into the structure of these moieties. In order to define the structure of these materials homogeneous SRS-A was required; a purification scheme was developed relying on the high resolution separative capability of reverse-phase high pressure liquid chromatography, resulting in extensively purified SRS-A. It was then possible to demonstrate that SRS-A possessed a characteristic ultraviolet spectrum, allowing us for the first time to define a major structural moiety in the molecule (conjugated triene). To complement studies on, and to act as a model for the more pathologically relevant SRS-A, a slow-reacting substance was produced from rat basophilic leukaemia (RBL-1) cells. The structure of this biologically active species has been determined by mass spectrometric examination of the intact molecule as a derivative, together with analytical protein chemical studies, and shown to be the novel peptidolipid 5-hydroxy-6-cysteinylglycinyl-7,9,11,14-eicosatetraenoic acid.