Synthesis of Novel Isothiocynates From Primary Amines
Rampy, Mark A.
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The Radio Immuno Therapy project is based on the "Magic Bullet" concept which was proposed at the beginning of the century by German scientist, Paul Ehrlich. Ehrlich theorized that future scientists would eventually be able to create drugs which would be able to act on specific diseased organs while avoiding reactions with normal healthy organs. Thus, the diseased areas could be treated by large' doses of the drug. Since the drug would only act on the diseased areas, the side effects would be minima1. Today, monoclonal antibodies are able to target cancerous cells while avoiding normal cells. This ability stems from differences between the surfaces of normal cells and of cancerous cells. In this way, tumors that are not visible or palpable may be treated. The goal of the RIT project is to utilize the monoclonal antibodies as "magic bullets" and deliver radiation to cancerous cells using an attached radioactive metal chelate. The attachment of a metal chelant is possible through thiourea formation between lysyl amines on the antibody, and an isothiocyanate present on the metal chelate. The major difficulty arises in the synthesis of the isothiocyanate on a chelant possessing an aliphatic amine. In order to further study the aliphatic chelant in vivo, it is necessary to initially form the isothiocyanate. It is also of interest to determine if characteristics of a thiourea linkage and the structure of the aliphatic or aromatic chelant would alter effectiveness in cancer treatment. Previously, chelants containing aryl amines have been easily converted into isothiocyanates. Restrictions apply to the synthesis of the aliphatic chelant due to the use of radioactive metals, and because of the multiple functionalities present on the chelant. The reactions must involve little or no cleanup and result in a high yield. Few steps must be used and the reaction must be rapid because radioactive compounds with relatively short half lives are to be used. The reactions must also be run in either an aqueous medium, or in trifluoroethanol due to the solubility characteristics of the chelate complex. The reaction conditions must also avoid all contact with metals. This also excludes the use of chromatography as a separation technique since the chelate complexes have previously been demonstrated to pick up trace metals found on the column packing. In addition, excessive heat may not be used due to the relatively fragile nature of the isothiocyanate and its susceptibility to rearrangements. Extremely acidic or basic conditions are also prohibited due to possible rearrangements of the isothiocyanate, or adverse reactions with the functionalities present on the chelate complexes.