CBI-TMI - SYNTHESIS AND EVALUATION OF A KEY ANALOG OF THE DUOCARMYCINS - VALIDATION OF A DIRECT RELATIONSHIP BETWEEN CHEMICAL SOLVOLYTIC STABILITY AND CYTOTOXIC POTENCY AND CONFIRMATION OF THE STRUCTURAL FEATURES RESPONSIBLE FOR THE DISTINGUISHING BEHAVIOR OF ENANTIOMERIC PAIRS OF AGENTS

The synthesis of (+)- and ent-(-)-CBI-TMI (3), a key analog of the nat urally occurring potent antitumor antibiotics duocarmycin SA (1) and d uocarmycin A (2), is disclosed and was facilitated by the development of a general and direct chromatographic resolution of the advanced syn thetic intermediate 13 on a preparative Diacel Chiralcel OD HPLC colum n. The DNA alkylation properties and the cytotoxic activity of (+)- an d (-)-CBI-TMI (3) are detailed in conjunction with a comparative study of a key series of duocarmycin SA and A analogs. (+)-CBI-TMI proved t o be an effective DNA alkylating agent which exhibited a selectivity a nd efficiency of DNA alkylation that are not distinguishable from thos e of (+)-duocarmycin SA (1), and it was found to be an exceptionally p otent cytotoxic agent (IC50 = 30 PM, L1210). The comparative examinati on of the natural enantiomers of duocarmycin SA (1), duocarmycin A (2) , CBI-TMI (3), and CI-TMI (4) revealed that the agents follow a predic table linear relationship between solvolytic chemical stability and cy totoxic activity which spans 3-4 orders of magnitude for the series of agents examined. In contrast, ent-(-)-CBI-TMI, unlike ent-(-)-duocarm ycin SA, exhibited less effective DNA alkylation properties (100X) and it proved to be a relatively nonpotent cytotoxic agent (100X). These latter observations are consistent with expectations based on recent m odels advanced which suggest that the distinguishing behavior of such unnatural enantiomers is the result of destabilizing steric interactio ns surrounding the duocarmycin C7 center.