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Targeting procaspase-3 with WF-208, a novel PAC-1 derivative, causes selective cancer cell apoptosis.

Wang F, Liu Y, Wang L, Yang J, Zhao Y, Wang N, Cao Q, Gong P, Wu C - J. Cell. Mol. Med. (2015)

Bottom Line: Caspase-3 is a critical effector caspase in apoptosis cascade, and is often over-expressed in many cancer tissues.WF-208 also showed greater antitumour activity than PAC-1 in murine xenograft model.In conclusion, we have discovered WF-208 as a promising procaspase-3 activating compound, with higher activity and higher cell selectivity than PAC-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.

No MeSH data available.


Related in: MedlinePlus

The general structures of target compounds.
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fig01: The general structures of target compounds.

Mentions: Oxadizole, an important heterocyclic ring present in a variety of biologically active molecules, is responsible for effective anticancer treatment. A common type of oxadizole is 1,2,4-oxadizole exerts various physiological effects on organisms 21,22. Hence, in consideration of the good potent of PAC-1, we inserted a 1,2,4-oxadizole between the structures of piperazine and phenyl ring of PAC-1 as a linker to investigate the influence of the altering PAC-1 structure on anticancer effects. Moreover, various substituted phenoxymethyl moiety (X) were introduced into the terminal of PAC-1 to extend the length of carbon chain and to explore the influence of electronic and steric effects on the antitumour activity. Therefore, we designed and synthesized a series of 1,2,4-oxadiazole substituted hydrazide derivatives A (Fig.1). Because of a previous SAR study shown that the PAC-1 derivatives lacking the ortho-hydroxyl group displayed little anticancer activity in vitro23, we retained the substituted 2-hydroxyl phenyl ring moiety and introduced various substituted benzyloxy groups to get compounds B1–B12. Furthermore, to investigate the effect of a heterocylic ring for moiety YB, we replaced the phenyl group with a 1,3-benzodioxole group, and then introduced a thiazol group as a linker to obtain compounds C1 and C2 (WF-208) (Fig.1, Table1).


Targeting procaspase-3 with WF-208, a novel PAC-1 derivative, causes selective cancer cell apoptosis.

Wang F, Liu Y, Wang L, Yang J, Zhao Y, Wang N, Cao Q, Gong P, Wu C - J. Cell. Mol. Med. (2015)

The general structures of target compounds.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549042&req=5

fig01: The general structures of target compounds.
Mentions: Oxadizole, an important heterocyclic ring present in a variety of biologically active molecules, is responsible for effective anticancer treatment. A common type of oxadizole is 1,2,4-oxadizole exerts various physiological effects on organisms 21,22. Hence, in consideration of the good potent of PAC-1, we inserted a 1,2,4-oxadizole between the structures of piperazine and phenyl ring of PAC-1 as a linker to investigate the influence of the altering PAC-1 structure on anticancer effects. Moreover, various substituted phenoxymethyl moiety (X) were introduced into the terminal of PAC-1 to extend the length of carbon chain and to explore the influence of electronic and steric effects on the antitumour activity. Therefore, we designed and synthesized a series of 1,2,4-oxadiazole substituted hydrazide derivatives A (Fig.1). Because of a previous SAR study shown that the PAC-1 derivatives lacking the ortho-hydroxyl group displayed little anticancer activity in vitro23, we retained the substituted 2-hydroxyl phenyl ring moiety and introduced various substituted benzyloxy groups to get compounds B1–B12. Furthermore, to investigate the effect of a heterocylic ring for moiety YB, we replaced the phenyl group with a 1,3-benzodioxole group, and then introduced a thiazol group as a linker to obtain compounds C1 and C2 (WF-208) (Fig.1, Table1).

Bottom Line: Caspase-3 is a critical effector caspase in apoptosis cascade, and is often over-expressed in many cancer tissues.WF-208 also showed greater antitumour activity than PAC-1 in murine xenograft model.In conclusion, we have discovered WF-208 as a promising procaspase-3 activating compound, with higher activity and higher cell selectivity than PAC-1.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.

No MeSH data available.


Related in: MedlinePlus