1,5-Diaryl-3-oxo-1,4-pentadienes: A Case for Antineoplastics with Multiple Targets

Abstract

A number of organic molecules which contain the 1,5-diaryl-3-oxo-1,4-pentadienyl group, referred to hereafter as the dienone moiety, have antineoplastic properties. Emphasis is made on the attachment of this structural moiety to several molecular scaffolds, namely piperidines, Nacylpiperidines, cycloalkanes and 3,4-dihydro-1H-napthalenes. Many of these compounds are potent cytotoxins having micromolar and nanomolar IC 50 values towards a wide range of neoplastic and transformed cells. On occasions, greater toxicity towards neoplasms than normal cells has been demonstrated. A number of these compounds have in vivo anticancer properties and in general excellent tolerability in rodents is demonstrated. The way in which a number of physicochemical properties such as redox potentials, torsion angles, atomic charges and logP values govern cytotoxic potencies are presented. The importance of the shapes of different compounds as determined by molecular modeling in contributing to antineoplastic properties is outlined. Arguments are presented in favour of designing antineoplastics which have multiple sites of action in contrast to those bioactive molecules which have only one molecular target. A number of compounds which possess the dienone group have different modes of action some of which are chronicled in this review, such as inducing apoptosis, affecting respiration in mitochondria, inhibiting macro-molecular biosynthesis and both inhibiting and stimulating certain enzymes. Other important properties of these compounds are discussed including their anti-angiogenic, MDR-revertant and antioxidant properties. It is hoped that this eulogy of the importance of the dienone group will encourage researchers to consider incorporating this structural unit into candidate cytotoxins in the future.

A novel class of piperidones exhibit potent, selective and pro-apoptotic anti-leukemia properties

“…Therefore, the genotoxic problems associated with a number of current anticancer drugs may be avoided with the use of enones (18). In particular, the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore has been mounted on heterocyclic and cycloaliphatic scaffolds, and is considered to align at a primary binding site (19). The extent of this interaction may also be influenced by the nature of the groups placed on the piperidyl nitrogen atom (19).…”

“…In particular, the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore has been mounted on heterocyclic and cycloaliphatic scaffolds, and is considered to align at a primary binding site (19). The extent of this interaction may also be influenced by the nature of the groups placed on the piperidyl nitrogen atom (19). For example, the N-acyl group may form additional bonds with various atoms and groups in cells, thus increasing the magnitude of the interaction at the primary binding site (19).…”

“…The extent of this interaction may also be influenced by the nature of the groups placed on the piperidyl nitrogen atom (19). For example, the N-acyl group may form additional bonds with various atoms and groups in cells, thus increasing the magnitude of the interaction at the primary binding site (19). A previous study revealed that the introduction of a 3-(2-hydroxyethylthio) propionyl group (-COCH 2 CH 2 SCH 2 CH 2 OH) on the piperidyl nitrogen atom led to a series of potent cytotoxins (20), whose general structure is represented in Fig.…”

A Computational Study of Structure and Reactivity of N-Substitued-4-Piperidones Curcumin Analogues and Their Radical Anions

“…These kinds of compounds have a preferential affinity for thiols, in contrast to amino or hydroxyl groups [16]. Apparently, the central heterocyclic ring fits a primary binding site, being this interaction influenced by the nature of the substituents at the nitrogen atom [17]. The presence of 4-piperidone alkylated at the nitrogen atom, along with phenyl rings bearing a great variety of substituents, constitutes the key features of a series of monocarbonyl analogues of curcumin, whose anti-inflammatory and anti-cancer activities have been recently reported [14,15].…”

A general HPLC–UV method for the quantitative determination of curcumin analogues containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore in rat biomatrices

“…Recently, Dimmock and co-workers extended this 3-aryl-2-propenoyl group to a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore (Fig. 1) [4]. The literature refers to this pharmacophore as a curcumin analogue [5], and a substantial number of these compounds have excellent antineoplastic properties [2,[6][7][8][9][10].…”