No abstract

No abstract

No 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.

Symmetric paramagnetic diene 6 was prepared and proved to be a useful intermediate in 1,4-addition, cheletropic, and Diels-Alder reactions. These methods were used for the synthesis of both aromatic 10, 12 heteroaromatic 15, 23 and heterocyclic ring fused nitroxide rings 7, 14, 16, 25a, 25b. The symmetric dibromo compound 20 led to homobifunctional spin label reagents 21, 22b, 24a, 24b, 27a, 27b heterobifunctional reagents 26a, 28a and to double sensor reagents 26b, 28b.The Diels-Alder reaction is an important tool in organic chemistry for construction of six-membered rings. A great variety of carbo-and heterocyclic ring systems have been synthesized in this way. 1 The synthesis of paramagnetic asymmetric six-membered 2 and five-membered 3 (17) dienes is well documented and their Diels-Alder reactions were also reported. The challenge was the synthesis of paramagnetic symmetric pyrrolidine diene 6 which was expected to be a versatile synthetic intermediate. It is interesting to note that the synthesis of the sterically hindered amine precursor of target molecule 6 was reported 30 years ago, 4 but as far as we know the amine was not oxidized to nitroxide. Stable paramagnetic nitroxides are widely used as spin labels, 5 MRI reagents 6 or co-oxidants 7 and their pharmacological properties are also of interest. 8In this paper we report on the synthesis and reactions of a paramagnetic symmetric pyrrolidine diene 6 in the presence of a paramagnetic free radical centre. Oxidation of γ-nitro ester 1, which was synthesized by Michael addition of nitromethane to an α,β-unsaturated ester, 9 with Nmethylmorpholin-N-oxide (NMO) in the presence of tetrapropylammonium perruthenate (TPAP) resulted not only in the conversion of the nitro group to a formyl group 10 but also in the oxidation of the pyrrolidine ring to pyrroline by forming the double bond yielding the α,β-unsaturated aldehyde ester 2. We found a simpler and cheaper oxidation method with KMnO 4 in basic medium 11 which gave saturated aldehyde ester 3 and also biradical 4 as a byproduct. This can be attributed to the in situ Henry nitro condensation 12 between 1 and 3 followed by oxidation. Treatment of compound 3 with NMO/TPAP yielded 2, demonstrating that a Ley-Griffith oxidation reagent 13 was capable of introducing the double bond. Compound 3 was easily reduced with NaBH 4 in EtOH to saturated paramagnetic 1,4-diol 5a which could be converted to the diiodide 5b through mesylate. The diiodide 5b was converted to the thiol specific reversible bisthiosulfonate reagent 5c by cautious heating of compound 5b with NaSSO 2 Me in DMSO. Elimination of HI from the diiodide 5b was carried out in aqueous NaOH/EtOH solution with heating resulting in the desired diene 6 (Scheme 1).Reagents and conditions: a) NMO (1.5 equiv)/AgOAc (2 equiv)/ K 2 CO 3 (5 equiv)/TPAP (0.1 equiv)/MeCN, 40°C, 12 h (62-75%); b) KOH (1.2 equiv)/MeOH, 0°C, 30 min, then KMnO 4 (0.7 equiv)/ MgSO 4 (1 equiv)/H 2 O, 0°C, 2 h (3: 37%, 4: 59%); c) NaBH 4 (3 equiv)/EtOH, 30 min, r.t. (80%); d) i: MsCl (2.2 equ...