Camptothecins are DNA topoisomerase I inhibitors that have recently emerged as a prominent class of anticancer agent.1-3 Topotecan and CPT-11 are watersoluble analogues of the natural product camptothecin and in 1996 were the first two members within the family to gain FDA approval (topotecan as second-line therapy for advanced epithelial ovarian cancer and CPT-11 as first-line therapy for colon cancer). Other camptothecin congeners currently under clinical evaluation include Lurtotecan (GI147211), 9-aminocamptothecin, and DX-8951f, all of which display improved water solubility over camptothecin, and 9-nitrocamptothecin, which is a lipophilic analogue. Although widely used, camptothecins are known to undergo relatively rapid hydrolysis in the bloodstream resulting in a marked loss of therapeutic potential. It is the key R-hydroxy-δlactone pharmacophore within the clinically relevant camptothecins that undergoes facile acyl cleavage at physiological pH4 to yield a biologically inactive5-7 carboxylate form. In this report we describe the rational design and total synthesis of highly lipophilic A,B,Ering-modified camptothecins that are the most bloodstable camptothecins displaying intrinsic anticancer activity yet to be identified.