Camptothecin analogs with bulky, hydrophobic substituents at the 7-position via a Grignard reaction |
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Authors: | Manikumar Govindarajan Wadkins Randy M Bearss David Von Hoff Daniel D Wani Mansukhlal C Wall Monroe E |
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Affiliation: | Research Triangle Institute, 3040 Cornwallis Road, Research Triangle Park, NC 27709, USA. |
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Abstract: | By developing a new synthetic procedure for introduction of side chains onto the camptothecin ring system, we were able to achieve the preparation of a number of analogs bearing bulky, hydrophobic groups directly attached to the 7-position. These include 7-tert-butylcamptothecin, 7-benzylcamptothecin and the corresponding 10,11-methylenedioxycamptothecins. This method involves the reaction of an appropriate orthoaminobenzonitrile with various Grignard reagents to give the corresponding orthoaminoketones. Friedlander condensation of the latter with the key tricyclic ketone leads to 7-substituted camptothecin analogs. We report the activity of these compounds as topoisomerase I poisons and their ability to inhibit growth of selected tumor cell lines. |
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