Role of the 20-hydroxyl group in camptothecin binding by the topoisomeraseI-DNA binary complex

Recent findings concerning the structure of the covalent binary complex for med by DNA topisomerase I and its DNA substrate, as well as the nature of i nteractions with inhibitors that bind reversibly to this binary complex, ha ve led to two proposed models for the binding of the prototype inhibitor ca mptothecin to the DNA-topisomerase I binary complex. While these models dif fer in many regards, they both suggest the involvement of the 20-OH group o f camptothecin in a donor hydrogen bond with an enzyme side chain functiona l group. Presently, five analogues of camptothecin that differ only at C-20 have been evaluated for their ability to bind to the topoisomerase I-DNA b inary complex and thereby inhibit enzyme function. Both 20-chloro- and 20-b romocamptothecin bound as well to the enzyme-DNA binary complex as 20-amino CPT despite the absence of a substituent at C-20 capable of contributing a donor hydrogen bond.