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

Abstract

Several series of compounds containing the 1,4-dioxo-2-butenyl moiety have been prepared as candidate cytotoxins, including the methyl N-arylmaleamates, methyl N-arylfumaramates, and N-arylmaleimides. In addition, the N-arylisomaleimides were synthesized which are the structural isomers of N-arylmaleimides. These compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 cells. Methyl N-arylfumaramates showed the highest cytotoxic potencies and, in particular, methyl N-(3,4-dichlorophenyl)fumaramate is six times more potent than melphalan towards L1210 cells and is equipotent with this drug in the Molt 4/C8 assay. Electrophilicity of compounds under investigation was demonstrated by carrying out thiolation using model benzyl mercaptan on representative compounds. Methyl N-(3,4-dichlorophenyl)fumaramate and methyl N-(4-chlorophenyl)maleamate inhibited human N-myristoyltransferase, a possible molecular target, in high micromolar range. QSAR and molecular modeling revealed some correlations between different structural features of a number of the molecules and cytotoxic potencies. Methyl N-arylfumaramates were well tolerated in mice in comparison to the analogs in other series of compounds tested. The data obtained in this investigation affords guidelines for preparing new series of molecules with greater potencies.

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

“…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]. 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].…”

“…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]. 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].…”

Synthesis of fluorescent drug molecules for competitive binding assay based on molecularly imprinted polymers

“…As a spacer, succinic anhydride (SA) is oen used to connect amines or alcohols by ester or amide bond. 15,16 SA produces a four-carbon chain between the two molecules through two step reactions. [17][18][19] SA is a good choice in the labelling of drug molecules.…”

Complexes of selected transition metal ions with 4-oxo-4-{[3-(trifluoromethyl)phenyl]amino}but-2-enoic acid: Synthesis, structure and magnetic properties

“…Transaminase form a group of enzymes that catalyze the transfer of the amino group (ANH 2 ) of an amino acid to a carbonyl compound, commonly an a-keto acid. The maleinic acid derivatives reveal the potent cytotoxicity towards leukemic cells [14,15]. They also show a strong antifungal activity [16] or they may act as inhibitors against aldose reductase [17].…”