Synthesis of N-Substituted 3,5-Bis(arylidene)-4-piperidones with High Antitumor and Antioxidant Activity

Abstract

A series of 3,5-bis(arylidene)-4-piperidones (DAP compounds) are considered as synthetic analogs of curcumin for anticancer and anti-inflammatory properties. We performed structureactivity relationship studies by synthesizing a number of 3,5-bis(arylidene)-4-piperidones Nalkylated or acylated with nitroxides or their amine precursors as potent antioxidant moieties.Both subtituents on arylidene rings and on piperidone nitrogen (five-or six-membered, 2-or 3-or 3,4-disubstituted, isoindoline nitroxides) were varied. The anticancer efficacy of the new DAP compounds was tested by measuring their cytotoxicity to cancer cell lines A2780 (human epithelial ovarian cancer cell line) and MCF-7 (human breast cancer cell line) and to H9c2, a noncancerous (healthy) cardiac cell line. The results showed that all DAP compounds induced a significant loss of cell viability in both the human cancer cell lines tested, however only pyrroline appended nitroxides (5c, 1 5e, 7, 9) showed limited toxicity toward noncancerous cell lines. Computer docking simulations support the biological activity tested.These results suggest that antioxidant-conjugated DAPs will be useful as a safe and effective anticancer agent for cancer therapy.

Amelioration of Doxorubicin-Induced Cardiotoxicity by an Anticancer-Antioxidant Dual-Function Compound, HO-3867

“…The design of HO-3867 was intended to provide both anticancer and antioxidant properties with cell-type-dependent cytotoxicity or protection (Kaìlai et al, 2011). Many chemotherapeutic agents such as DOX act by producing free radicals, which may increase oxidative stress in normal cells (Sinha and Mimnaugh, 1990;Minotti et al, 2004).…”

“…HO-3867 was synthesized as reported previously (Selvendiran et al, 2010a;Kaìlai et al, 2011). Stock solutions (20 mM) of the compound were freshly prepared in dimethyl sulfoxide.…”

Effect of Nitroxides on Swarming Motility and Biofilm Formation, Multicellular Behaviors in Pseudomonas aeruginosa

“…Since both nitric oxide and nitroxide structures possess an unpaired electron that is delocalized over the nitrogen-oxygen bond, nitroxides represent a sterically hindered version of nitric oxide. These stable free-radical species are commonly used as potent antioxidants in biological systems (21,22). Like NO, these compounds can reduce levels of oxidative stress caused by reactive oxygen species (ROS).…”

Heteroorganic molecules and bacterial biofilms: Controlling biodeterioration of cultural heritage

“…Over the past 20 years, other novel applications have been proposed for nitroxide compounds after their antioxidant activity was demonstrated in a number of experimental models. 293,[307][308][309][310][311][312] Nitroxides are known to protect cells against 293,308,315 The ability of nitroxides to participate in all of the above pathways relies on redox transformations between three oxidation states -the nitroxide, hydroxylamine and oxoammonium derivatives. Scheme 3 shows the oxidation states of 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinoxyl (38), one of the most widely studied nitroxides in the literature.…”