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Synthesis and evaluation of bisbenzylidenedioxotetrahydrothiopranones as activators of endoplasmic reticulum (ER) stress signaling pathways and apoptotic cell death in acute promyelocytic leukemic cells.

Tan KL, Ali A, Du Y, Fu H, Jin HX, Chin TM, Khan M, Go ML - J. Med. Chem. (2014)

Bottom Line: Replacing the heptadienedione moiety of curcumin with a monocarbonyl cross-conjugated dienone embedded in a tetrahydrothiopyranone dioxide ring resulted in thiopyranone dioxides that were more resilient to hydrolysis and had greater growth inhibitory activities than curcumin on APL cells.Several members intercepted the degradation of misfolded N-CoR and triggered the signaling cascade in the unfolded protein response (UPR) which led to apoptotic cell death.The Michael acceptor reactivity of the scaffold may have a role in exacerbating ER stress in APL cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, National University of Singapore , 18 Science Drive 4, 117543, Republic of Singapore.

ABSTRACT
Curcumin is known to trigger ER-stress induced cell death of acute promyelocytic leukemic (APL) cells by intercepting the degradation of nuclear co-repressor (N-CoR) protein which has a key role in the pathogenesis of APL. Replacing the heptadienedione moiety of curcumin with a monocarbonyl cross-conjugated dienone embedded in a tetrahydrothiopyranone dioxide ring resulted in thiopyranone dioxides that were more resilient to hydrolysis and had greater growth inhibitory activities than curcumin on APL cells. Several members intercepted the degradation of misfolded N-CoR and triggered the signaling cascade in the unfolded protein response (UPR) which led to apoptotic cell death. Microarray analysis showed that genes involved in protein processing pathways that were germane to the activation of the UPR were preferentially up-regulated in treated APL cells, supporting the notion that the UPR was a consequential mechanistic pathway affected by thiopyranone dioxides. The Michael acceptor reactivity of the scaffold may have a role in exacerbating ER stress in APL cells.

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Replacement of the β-diketone moiety of curcumin by monocarbonylcross-conjugated dienones (monocarbonyls, cyclopentanones, cyclohexanones,thiopyranones, piperidinones). The thiopyranones 32, 34, and 39 had potent growth inhibitory activities(IC50) on NB4, an APL cell line,27 and were targeted for further modifications (shown in box) in thisreport.
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fig2: Replacement of the β-diketone moiety of curcumin by monocarbonylcross-conjugated dienones (monocarbonyls, cyclopentanones, cyclohexanones,thiopyranones, piperidinones). The thiopyranones 32, 34, and 39 had potent growth inhibitory activities(IC50) on NB4, an APL cell line,27 and were targeted for further modifications (shown in box) in thisreport.

Mentions: Acute promyelocytic leukemia(APL) is caused by the fusion protein PML-RARα that is formedby the reciprocal translocation of PML and RARα genes located at chromosomes 15 and 17.1,2 The oncogenic potential of the PML-RARα fusion protein islinked to the nuclear receptor co-repressor (N-CoR) protein,3−6 which is recruited by the fusion protein to give the N-CoR-PML-RARαcomplex. The latter represses retinoic acid responsive genes thatare essential for the maturation of promyelocytic cells, hence curtailingcell differentiation and transformation.7,8 The PML-RARαfusion protein also induces misfolding of N-CoR which leads to increasedlevels of endoplasmic reticulum (ER) stress due to the accumulationof misfolded protein.9 In an effort torestore ER homeostasis, cells activate the unfolded protein response(UPR) which entails temporarily shutting down protein translationand up-regulating ER folding and quality control mechanisms.10,11 In APL cells, this is achieved in part by protease-mediated andER-associated degradation (ERAD) of misfolded N-CoR.12−14 If ER stress persists, the UPR shifts to a prodeath mode in an effortto eliminate cells harboring deleterious malfolded proteins.10,11,15 Curcumin, the active substanceof the spice turmeric (Curcuma longa), was reportedto block the protease- and proteasomal-mediated degradation of N-CoR.16 The resulting build-up of misfolded N-CoR amplifiedER stress and caused the UPR to switch from a prosurvival to a proapoptoticmode. ER stress-induced apoptosis is increasingly viewed as an attractiveand novel signaling target for anticancer therapies,11,17 and the ability of curcumin to sensitize APL16 and other malignant cells18−21 to apoptosis underscores itsanticancer potential. There are however several shortcomings to curcuminthat has limited its therapeutic usefulness, notably its modest potency,intrinsic instability, and limited bioavailability.22,23 Various strategies have been proposed to address these limitationssuch as engaging novel formulations to enhance delivery of curcumin22,24 and modifying the curcumin scaffold to improve pharmacokinetic andpotency end points.25,26 Some examples are provided inFigure 1. We had previously investigated theAPL growth inhibitory activity of compounds derived by replacing theconjugated β-diketone moiety of curcumin with a monocarbonylcross-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(IC50 = 0.3–1 μM) than curcumin (IC50 = 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, switchingof the latter to pyridine, and replacement of the thiopyranone ringwith thiopyranone 1,1-dioxide (Figure 2). Hereinwe describe the synthesis and growth inhibitory properties of thesecompounds on APL cells, the hydrolytic stabilities of selected members,and in view of their structural connection to curcumin, the involvementof ER stress-induced apoptosis in the mechanistic pathways of potentmembers. In addition, the effects of a representative potent member(41) on the expression of genes involved in ER proteinprocessing and on selected proteins/transcription factors that mediatethe response to ER stress in the UPR signaling pathway were examinedfor mechanistic insight.


Synthesis and evaluation of bisbenzylidenedioxotetrahydrothiopranones as activators of endoplasmic reticulum (ER) stress signaling pathways and apoptotic cell death in acute promyelocytic leukemic cells.

Tan KL, Ali A, Du Y, Fu H, Jin HX, Chin TM, Khan M, Go ML - J. Med. Chem. (2014)

Replacement of the β-diketone moiety of curcumin by monocarbonylcross-conjugated dienones (monocarbonyls, cyclopentanones, cyclohexanones,thiopyranones, piperidinones). The thiopyranones 32, 34, and 39 had potent growth inhibitory activities(IC50) on NB4, an APL cell line,27 and were targeted for further modifications (shown in box) in thisreport.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216202&req=5

fig2: Replacement of the β-diketone moiety of curcumin by monocarbonylcross-conjugated dienones (monocarbonyls, cyclopentanones, cyclohexanones,thiopyranones, piperidinones). The thiopyranones 32, 34, and 39 had potent growth inhibitory activities(IC50) on NB4, an APL cell line,27 and were targeted for further modifications (shown in box) in thisreport.
Mentions: Acute promyelocytic leukemia(APL) is caused by the fusion protein PML-RARα that is formedby the reciprocal translocation of PML and RARα genes located at chromosomes 15 and 17.1,2 The oncogenic potential of the PML-RARα fusion protein islinked to the nuclear receptor co-repressor (N-CoR) protein,3−6 which is recruited by the fusion protein to give the N-CoR-PML-RARαcomplex. The latter represses retinoic acid responsive genes thatare essential for the maturation of promyelocytic cells, hence curtailingcell differentiation and transformation.7,8 The PML-RARαfusion protein also induces misfolding of N-CoR which leads to increasedlevels of endoplasmic reticulum (ER) stress due to the accumulationof misfolded protein.9 In an effort torestore ER homeostasis, cells activate the unfolded protein response(UPR) which entails temporarily shutting down protein translationand up-regulating ER folding and quality control mechanisms.10,11 In APL cells, this is achieved in part by protease-mediated andER-associated degradation (ERAD) of misfolded N-CoR.12−14 If ER stress persists, the UPR shifts to a prodeath mode in an effortto eliminate cells harboring deleterious malfolded proteins.10,11,15 Curcumin, the active substanceof the spice turmeric (Curcuma longa), was reportedto block the protease- and proteasomal-mediated degradation of N-CoR.16 The resulting build-up of misfolded N-CoR amplifiedER stress and caused the UPR to switch from a prosurvival to a proapoptoticmode. ER stress-induced apoptosis is increasingly viewed as an attractiveand novel signaling target for anticancer therapies,11,17 and the ability of curcumin to sensitize APL16 and other malignant cells18−21 to apoptosis underscores itsanticancer potential. There are however several shortcomings to curcuminthat has limited its therapeutic usefulness, notably its modest potency,intrinsic instability, and limited bioavailability.22,23 Various strategies have been proposed to address these limitationssuch as engaging novel formulations to enhance delivery of curcumin22,24 and modifying the curcumin scaffold to improve pharmacokinetic andpotency end points.25,26 Some examples are provided inFigure 1. We had previously investigated theAPL growth inhibitory activity of compounds derived by replacing theconjugated β-diketone moiety of curcumin with a monocarbonylcross-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(IC50 = 0.3–1 μM) than curcumin (IC50 = 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, switchingof the latter to pyridine, and replacement of the thiopyranone ringwith thiopyranone 1,1-dioxide (Figure 2). Hereinwe describe the synthesis and growth inhibitory properties of thesecompounds on APL cells, the hydrolytic stabilities of selected members,and in view of their structural connection to curcumin, the involvementof ER stress-induced apoptosis in the mechanistic pathways of potentmembers. In addition, the effects of a representative potent member(41) on the expression of genes involved in ER proteinprocessing and on selected proteins/transcription factors that mediatethe response to ER stress in the UPR signaling pathway were examinedfor mechanistic insight.

Bottom Line: Replacing the heptadienedione moiety of curcumin with a monocarbonyl cross-conjugated dienone embedded in a tetrahydrothiopyranone dioxide ring resulted in thiopyranone dioxides that were more resilient to hydrolysis and had greater growth inhibitory activities than curcumin on APL cells.Several members intercepted the degradation of misfolded N-CoR and triggered the signaling cascade in the unfolded protein response (UPR) which led to apoptotic cell death.The Michael acceptor reactivity of the scaffold may have a role in exacerbating ER stress in APL cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, National University of Singapore , 18 Science Drive 4, 117543, Republic of Singapore.

ABSTRACT
Curcumin is known to trigger ER-stress induced cell death of acute promyelocytic leukemic (APL) cells by intercepting the degradation of nuclear co-repressor (N-CoR) protein which has a key role in the pathogenesis of APL. Replacing the heptadienedione moiety of curcumin with a monocarbonyl cross-conjugated dienone embedded in a tetrahydrothiopyranone dioxide ring resulted in thiopyranone dioxides that were more resilient to hydrolysis and had greater growth inhibitory activities than curcumin on APL cells. Several members intercepted the degradation of misfolded N-CoR and triggered the signaling cascade in the unfolded protein response (UPR) which led to apoptotic cell death. Microarray analysis showed that genes involved in protein processing pathways that were germane to the activation of the UPR were preferentially up-regulated in treated APL cells, supporting the notion that the UPR was a consequential mechanistic pathway affected by thiopyranone dioxides. The Michael acceptor reactivity of the scaffold may have a role in exacerbating ER stress in APL cells.

Show MeSH
Related in: MedlinePlus