Design, synthesis and bioevaluation of novel maleamic amino acid ester conjugates of 3,5-bisarylmethylene-4-piperidones as cytostatic agents

Curcumin-inspired cytotoxic 3,5-bis(arylmethylene)-1-(N-(ortho-substituted aryl)maleamoyl)-4-piperidones: A novel group of topoisomerase II alpha inhibitors

“…[22] Briefly, the energy of the molecular structure of the compound was minimized using Merck Molecular Force Field (MMFF94). Atomic charges were obtained using extended Hückel method.…”

“…Notably, the analogs from series 5-10 contain additional enone moiety in their side chains bearing for interaction with auxiliary binding domain [20] and/or protein thiolation [25,28]. We have identified human topoisomerase IIα as a potential molecular target for 3,5-bisarylmethylene-4-piperidone derivatives [22]. This thiol-rich enzyme is essential for sustained cell proliferation [29][30][31].…”

“…It was observed in these investigations [15][16][17][18] that compounds retaining the oxygenation pattern similar to that of curcumin were found to be more active in terms of their anticancer and antioxidant potency in-vitro compared to the other analogs. Simultaneously, we have also studied a large number of diarylpentanoids (Series 4-10, Figure 1) [19][20][21][22][23][24], which may be viewed as simplified analogs of diarylheptanoid curcumin. Curcumin as well as its analogs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10) contain α,β-unsaturated carbonyl group(s) and therefore are Michael acceptors with selective affinity for protein thiols as opposed to O/N-based nuclephiles found on genetic materials [25,28].…”

“…Continuous efforts in our lab are focused on analogs of curcumin in attempts to develop molecules with superior pharmacodynamic and pharmacokinetic profile than those of curcumin [15][16][17][18][19][20][21][22][23][24][25][26][27]. Among our previous research, we have prepared and studied curcumin analogs where the diarylheptanoid skeleton of curcumin was retained (Series 1- Fig.…”

Derivatives of aryl amines containing the cytotoxic 1,4-dioxo-2-butenyl pharmacophore

“…A number of studies report that protein thiolation plays an important role in biochemical processes. Some representative examples of this phenomenon include inhibition of human cytomegalovirus protease, 16 inhibition of Ref-1, a therapeutic target for asthma, 17 inactivation of cysteine proteases, 18 blockade of platelet-derived growth factor BB-stimulated Akt phosphorylation, 19 catalytic inhibition of human topoisomerase-2 alpha, an established target for the development of anticancer agents, 20,21 etc. This encouraged us the study the reactivity of representative compounds in each of the series 1 – 5 and 9 towards a model thiol, benzyl mercaptan, under simulated physiological conditions These experiments were undertaken in order to evaluate whether the compounds in these series are in fact thiol alkylators and, if so, to determine the locus of thiolation.…”