Curcumin Analogues with Potent and Selective Anti‐proliferative Activity on Acute Promyelocytic Leukemia: Involvement of Accumulated Misfolded Nuclear Receptor Co‐repressor (N‐CoR) Protein as a Basis for Selective Activity

Abstract

Curcumin arrests the proliferation of acute promyelocytic leukemia (APL) cells by stabilizing the misfolded nuclear receptor co-repressor (N-CoR) protein, thereby sensitizing APL cells to apoptosis induced by the unfolded protein response. This phenomenon was attributed to inhibition of the proteasomal and protease-induced breakdown of misfolded N-CoR by curcumin. Curcumin is, however, a modest inhibitor and affected the viability of APL cells at micromolar concentrations. Modifying curcumin at its conjugated β-diketone linker and terminal phenyl rings yielded potent congeners with sub-micromolar growth inhibitory activities which selectively kill APL cells over non-APL leukemic and nonmalignant cells. Analogues with pronounced APL-selective anti-proliferative activities, as observed in representative dibenzylidenecyclohexanones and dibenzylidenecyclopentanones, strongly promoted the accumulation of misfolded and nonfunctional N-CoR at significantly lower concentrations than their growth inhibitory IC(50) values. These compounds also inhibited the human 20S proteasome in an enzyme-based assay, thus providing convincing support for the prevailing hypothesis that impeding the degradation of N-CoR is a key mechanistic event contributing to APL cell death.

Synthesis and Evaluation of Bisbenzylidenedioxotetrahydrothiopranones as Activators of Endoplasmic Reticulum (ER) Stress Signaling Pathways and Apoptotic Cell Death in Acute Promyelocytic Leukemic Cells

“…As shown in Figure 2, these groups were present in the earlier hits 32 , 34 , and 39 . 27 Second, asymmetric substitution of the phenyl rings was explored with the above-mentioned groups. Third, the phenyl rings were replaced by pyridines, motivated in part by the good results observed for several cyclohexanones 27 and piperidinones 28 which had similar phenyl-to-pyridine substitution.…”

“…Also included in Table 1 are previously determined IC 50 values of selected thiopyranones, cyclohexanones, and piperidinones. 27 …”

“…The thiopyranones 32 , 34 , and 39 had potent growth inhibitory activities (IC 50 ) on NB4, an APL cell line, 27 and were targeted for further modifications (shown in box) in this report.…”

“…We had previously investigated the APL growth inhibitory activity of compounds derived by replacing the conjugated β-diketone moiety of curcumin with a monocarbonyl cross-conjugated dienone that was either unmodified (“monocarbonyls”) or embedded in carbocyclic (“cyclopentanones”, “cyclohexanones”) or heterocyclic (“thiopyranones”, “piperidinones”) rings (Figure 2). 27 Several compounds bearing the tetrahydrothiopyran ring (“thiopyranones”) were found to arrest APL cell proliferation at lower concentrations (IC 50 = 0.3–1 μM) than curcumin (IC 50 = 5.5 μM). To further explore the potential of this scaffold, additional structural modifications were investigated in this report, namely, asymmetrical substitution of the terminal phenyl rings, switching of the latter to pyridine, and replacement of the thiopyranone ring with thiopyranone 1,1-dioxide (Figure 2).…”

Ceramide generation during curcumin-induced apoptosis is controlled by crosstalk among Bcl-2, Bcl-xL, caspases and glutathione

“…Such studies have shown, e.g., that curcumin induces apoptotic death of human leukemia cells including HL-60 cells and their multidrug-resistant derivatives [8,9,41,42]. We have found that the pro-apoptotic activity of curcumin involves accumulation of ceramide in these cells.…”