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, N-acylpiperidines, 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 macromolecular 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.

Fig. 1

The design of 3,5-bis(benzylidene)-4-piperidones as candidate antineoplastic agents.

Fig. 2

The postulated interactions of N-acyl-3,5-bis(benzylidene)-4-piperidones at binding sites.

Fig. 3

Overlap of models of 31 (R¹ = R² = H), 32 and 33. The four atoms which are superimposed are indicated with an asterisk.

Scheme 1

The sequential alkylations of cellular thiols by compounds containing the 1,5-diaryl-3-oxo-1,4-pentadienyl group.

Scheme 2

Conversion of the 3,5-bis(benzylidene)-4-piperidones 5 and 6 into the N-acylated products 7-10.

Scheme 3

Formation of the N-acyl products 15-19 from series 14.

Scheme 4

Synthesis of 20-23 from 14a.