Rational design, synthesis, and evaluation of key analogues of CC-1065 and the duocarmycins.
The design, synthesis, and evaluation of a predictably more potent analogue of CC-1065 entailing the substitution replacement of a single skeleton atom in the alkylation subunit are disclosed and were conducted on the basis of design principles that emerged from a fundamental parabolic relationship between chemical 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 the MeCPI alkylation subunit found in CC-1065 and slightly more stable than even the DSA alkylation subunit found in duocarmycin SA, placing it at the point of optimally balanced stability and reactivity for this class of antitumor agents. Their incorporation into the key analogues of the natural products provided derivatives that surpassed the potency of MeCPI derivatives (3-10-fold), matching or slightly exceeding the potency of the corresponding DSA derivatives, consistent with projections made on the basis of the parabolic relationship. Notable of these, MeCTI-TMI proved to be as potent as or slightly more potent than the natural product duocarmycin SA (DSA-TMI, IC50 = 5 vs 8 pM), and MeCTI-PDE2 proved to be 3-fold more potent than the natural product CC-1065 (MeCPI-PDE2, IC50 = 7 vs 20 pM). Both exhibited efficiencies of DNA alkylation that correlate with this enhanced potency without impacting the intrinsic selectivity characteristic of this class of antitumor agents.
Tichenor
Mark S
MS
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
MacMillan
Karen S
KS
Stover
James S
JS
Wolkenberg
Scott E
SE
Pavani
Maria G
MG
Zanella
Lorenzo
L
Zaid
Abdel N
AN
Spalluto
Gianpiero
G
Rayl
Thomas J
TJ
Hwang
Inkyu
I
Baraldi
Pier Giovanni
PG
Boger
Dale L
DL
D000478:Alkylation; D000818:Animals; D000977:Antiparasitic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000737:chemistry; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015195:Drug Design; D000080890:Duocarmycins; D007211:Indoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D007274:Injections, Intraperitoneal; D051379:Mice; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D011758:Pyrroles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
D000977:Antiparasitic Agents; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; C066098:duocarmycin SA; C018782:CC 1065; D004247:DNA