SYNTHESIS AND EVALUATION OF ABORTED AND EXTENDED CC-1065 FUNCTIONAL ANALOGS - (+)-CPI-PDE-I1, AND (-)-CPI-PDE-I1, (+)-CPI-PDE-I1, AND (-)-CPI-CDPI1, AND (+/-)-CPI-PDE-I1, (+)-CPI-PDE-I1, AND (-)-CPI-CDPI3 - PREPARATION OF KEY PARTIAL STRUCTURES AND DEFINITION OF AN ADDITIONAL FUNCTIONAL-ROLE OF THE CC-1065 CENTRAL AND RIGHT-HAND SUBUNITS

Full details of the incorporation of (±)-(lR⋆)-8, (-)-(1S)-8, and (+)-(1R)-8 into the total syntheses of the aborted and extended CC-1065 functional analogues (+)-and (-)-CPI-PDE-I1 [(+)-and (-)-1], (+)-and (-)-CPI-CDPI1 [(+)-and (-)-3], and (±)-, (+)-, and (-)-CPI-CDPI3 [(±)-, (+)-, and (-)-5] are described. Comparative DNA binding studies of the agents versus (+)-.N-BOC-CPI (6), (-t-)-N-acetyl-CPI (7), (+)-CC-1065 (2), and (+)-/(-)-CPI-CDPI2 (4) are presented in efforts to establish the structural and functional features of CC-1065 responsible for its sequence-selective B-DNA minor groove association and the resulting potent cytotoxic activity. The results of the comparative study suggest that the agents noncovalent binding contributes to the DNA covalent alkylation selectivity and stabilizes the DNA-agent covalent complex formation. It is suggested that it is the simple event of DNA covalent complex stabilization that potentiates the cytotoxic activity of the agents. © 1990, American Chemical Society. All rights reserved.