Course synthesis of active site directed oncolytic agents

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1977

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Abstract

A unique approach in obtaining new synthetic anticancer compounds involves the chelation of trace metals associated with cancer cells. Several α-(N)-heterocyclic carboxaldehyde thiosemicarbazones (HCT), with the potential to form coordination compounds with certain transition metals inhibit the growth of a number of transplanted rodent neoplasms, spontaneous lymphomas of dogs, and DNA viruses of the Herpes family. Several researchers have investigated the structure activity relationship of HCT compounds and found the activity was best with 5-amino-1-formyl-thiosemicarbazone isoquinoline. The objective of this investigation was to explore the principle of active site-directed drug design. This principle has been utilized to develop very potent drugs, for example dilantin and amino sugars like 2-amino-3-ß-D-glucose, which have been used as a carrier of nitrogen mustard. Applying this principle, an attempt has been made to generate a model antitumor agent which would be more potent and be delivered more specifically to the site of action than previously existing antitumor agents. Hence, one of the most active chelators in clinical trial, 5-amino-1-formylisoquinoline thiosemicarbazone was modified by attaching at position five one of the essential amino acids as a carrier, preferably L-phenylalanine. The synthesis of other thiosemicarbazone analogs were also attempted.

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