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

Article abstract of DOI:10.1021/ja00097a006

The synthesis of (+)- and ent-(-)-CBI-TMI (3), a key analog of the naturally occurring potent antitumor antibiotics duocarmycin SA (1) and duocarmycin A (2), is disclosed and was facilitated by the development of a general and direct chromatographic resolution of the advanced synthetic intermediate 13 on a preparative Diacel Chiralcel OD HPLC column. The DNA alkylation properties and the cytotoxic activity of (+)- and (-)-CBI-TMI (3) are detailed in conjunction with a comparative study of a key series of duocarmycin SA and A analogs. (+)-CBI-TMI proved to be an effective DNA alkylating agent which exhibited a selectivity and efficiency of DNA alkylation that are not distinguishable from those of (+)-duocarmycin SA (1), and it was found to be an exceptionally potent cytotoxic agent (IC₅₀ = 30 pM, L1210). The comparative examination of the natural enantiomers of duocarmycin SA, duocarmycin A (2), CBI-TMI (3), and CI-TMI (4) revealed that the agents follow a predictable linear relationship between solvolytic chemical stability and cytotoxic activity which spans 3-4 orders of magnitude for the series of agents examined. In contrast, ent-(-)-CBI-TMI, unlike ent-(-)-duocarmycin SA, exhibited less effective DNA alkylation properties (100x) and it proved to be a relatively nonpotent cytotokic agent (100x). These latter observations are consistent with expectations based on recent models advanced which suggest that the distinguishing behavior of such unnatural enantiomers is the result of destabilizing steric interactions surrounding the duocarmycin C7 center.