Structure-Based Design of Potent, Conformationally Constrained Smac Mimetics

Abstract

Intermolecular electron transfer (ET) between the free phenothiazine donor (PH) and its cation radical (PH*+) proceeds via the [1:1] precursor complex (PH)(2)*+ which is transiently observed for the first time by its diagnostic (charge-resonance) absorption band in the near-IR region. Similar intervalence (optical) transitions are also observed in mixed-valence cation radicals with the generic representation: P(br)P*+, in which two phenothiazine redox centers are interlinked by p-phenylene, o-xylylene, and o-phenylene (br) bridges. Mulliken-Hush analysis of the intervalence (charge-resonance) bands afford reliable values of the electronic coupling element H(IV) based on the separation parameters for (P/P*+) centers estimated from some X-ray structures of the intermolecular (PH)(2)*+ and the intramolecular P(br)P*+ systems. The values of H(IV), together with the reorganization energies lambda derived from the intervalence transitions, yield activation barriers DeltaG(ET)() and first-order rate constants k(ET) for electron-transfer based on the Marcus-Hush (two-state) formalism. Such theoretically based values of the intrinsic barrier and ET rate constants agree with the experimental activation barrier (E(a)) and the self-exchange rate constant (k(SE)) independently determined by ESR line broadening measurements. This convergence validates the use of the two-state model to adequately evaluate the critical electronic coupling elements between (P/P*+) redox centers in both (a) intermolecular ET via the precursor complex and (b) intramolecular ET within bridged mixed-valence cation radicals. Important to intermolecular ET mechanism is the intervention of the strongly coupled precursor complex since it leads to electron-transfer rates of self-exchange that are 2 orders of magnitude faster (and activation barrier that is substantially lower) than otherwise predicted solely on the basis of Marcus reorganization energy.

SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events

“…A number of studies have demonstrated that SMAC and SMAC mimetics potentiate apoptosis induced by anticancer agents, including chemotherapeutic drugs and irradiation, in human cancer cells (Fulda et al, 2002;Arnt and Kaufmann, 2003;Giagkousiklidis et al, 2005;Zhao et al, 2006). Efforts have also been made to develop improved SMAC mimetic agents (Li et al, 2004;Sun et al, 2004). However, the precise function of SMAC in promoting apoptosis induced by anticancer agents was unclear.…”

Design, Synthesis, and Characterization of a Potent, Nonpeptide, Cell-Permeable, Bivalent Smac Mimetic That Concurrently Targets Both the BIR2 and BIR3 Domains in XIAP

“…[21][22][23] Using this approach, we have designed compound 1 (SM-122) as a conformationally constrained, Smac AVPI mimetic containing a [8,5] bicyclic system ( Figure 2) and evaluated its binding affinities to XIAP BIR2 and BIR3 proteins. To facilitate the investigation of the molecular mechanism of action for Smac mimetics, we have also designed a biotinylated analogue of SM-122 (2, named BL-SM-122, Figure 2).…”

Targeting XIAP for the treatment of malignancy

“…Tripeptide BIR 3 inhibitors with unnatural amino acids have also been identified by Sun et al 61,62 who modified a series of SMAC-pseudomimics and tested their binding to the BIR 3 domain of XIAP by NMR. Binding of peptides to BIR 3 was confirmed by a fluorescent polarization assay.…”