Rational Design, Synthesis, and Evaluation of Key Analogues of CC-1065 and the Duocarmycins

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• 作者：Mark S. Tichenor ; Karen S. MacMillan ; James S. Stover ; Scott E. Wolkenberg ; Maria G. Pavani ; Lorenzo Zanella ; Abdel N. Zaid ; Gianpiero Spalluto ; Thomas J. Rayl ; Inkyu Hwang ; Pier Giovanni Baraldi ; Dale
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：November 14, 2007
• 年：2007
• 卷：129
• 期：45
• 页码：14092 - 14099
• 全文大小：718K
• 年卷期：v.129,no.45(November 14, 2007)
• ISSN：1520-5126

文摘

The design, synthesis, and evaluation of a predictably more potent analogue of CC-1065 entailingthe substitution replacement of a single skeleton atom in the alkylation subunit are disclosed and wereconducted on the basis of design principles that emerged from a fundamental parabolic relationship betweenchemical reactivity and cytotoxic potency. Consistent with projections, the 7-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one (MeCTI) alkylation subunit and its isomer 6-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[2,3-e]indol-4-one (iso-MeCTI) were found to be 5-6 times more stable than theMeCPI alkylation subunit found in CC-1065 and slightly more stable than even the DSA alkylation subunitfound in duocarmycin SA, placing it at the point of optimally balanced stability and reactivity for this classof antitumor agents. Their incorporation into the key analogues of the natural products provided derivativesthat surpassed the potency of MeCPI derivatives (3-10-fold), matching or slightly exceeding the potencyof the corresponding DSA derivatives, consistent with projections made on the basis of the parabolicrelationship. Notable of these, MeCTI-TMI proved to be as potent as or slightly more potent than the naturalproduct duocarmycin SA (DSA-TMI, IC₅₀ = 5 vs 8 pM), and MeCTI-PDE₂ proved to be 3-fold more potentthan the natural product CC-1065 (MeCPI-PDE₂, IC₅₀ = 7 vs 20 pM). Both exhibited efficiencies of DNAalkylation that correlate with this enhanced potency without impacting the intrinsic selectivity characteristicof this class of antitumor agents.