Part I. The combretastatins. Part II. Synthesis of the antineoplastic agent resverastatin. Part III. Stereospecific synthesis of dolaproine

Combretastatins A-1 and A-4, the principal antineoplastic constituents isolated from Combretum caffrum in the late 1980s, exhibit potent antitumor and antimitotic activity. Extensive structure-activity relationship (SAR) studies previously reported for combretastatin A-4 have provided understanding into its biological mechanism of action and have furthered its clinical application. A water-soluble prodrug of combretastatin A-4 is currently undergoing clinical trials in the United States and Europe. Phenstatin, a benzophenone analogue of combretastatin A-4, displays potent anticancer activity, and the benzophenone derivative of combretastatin A-1 was synthesized. The benzophenone, designated hydroxyphenstatin, exhibits slightly greater antimitotic and antitumor activity when compared to combretastatin A-1.;Resveratrol is a phytoalexin found in grapes and other sources that received great attention as of late. A structure-activity relationship study was conducted and a series of stilbene and benzophenone derivatives of resveratrol were synthesized. A trimethoxystilbene derivative of resveratrol displays antineoplastic activity 1000 times greater. A hydroxyl derivative, designated resverastatin, was converted to the sodium phosphate prodrug in order to increase its water-solubility.;Dolastatin 10 is one of the most potent anticancer drugs ever tested. This pentapeptide presents many challenges to the synthetic chemist because of its nine chiral centers. Dolaproine, a novel beta-methoxy-gamma-amino acid, constitutes the most complex unit of dolastatin 10. This amino acid was stereospecifically synthesized utilizing a cobalt-triphenylphosphine complex. The improved synthesis will aid in the supply of this remarkable natural product for further clinical evaluation.