The objective of this project is to develop a series of water soluble conjugates of isothiocyanates as a novel type of prodrug with site specificity and less toxicity against bladder and colon cancer. The approach to the design of prodrugs is based on the observation that when isothiocyanates were administered to animals or humans, their corresponding conjugates appeared as principal urinary metabolites. In addition, the bulky, highly hydrophilic conjugates, when orally administered, will reduce the systemic toxicity by covering the highly reactive isothiocyanate group until they reach the target tissues and release the parent drugs.
The specific aims are: (1) to synthesize a series of phenylalkyl isothio- cyanates and their corresponding conjugates, (2) to determine the induction of detoxifying enzyme activity by these compounds in the mouse target tissues, (3) to determine and compare the partition coefficients of conjugates and parent compounds, (4) to analyze the concentration of these compounds in the gastrointestinal tract, colon, and urinary bladder after oral administration, (5) to evaluate the inhibition of colon aberrant crypts formation by the conjugates, and (6) to establish the structure-activity relationship and to select leads for further development in the phase II study.
| Zheng, G Q (1994) Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med 60:54-7 |
