Synthesis of Thalidomide Analogues and Their Potential in Cancer Treatment

Abstract

Thalidomide has been used as an effective treatment for multiple myeloma. It is suggested that thalidomide exert its effects via immunomodulation and anti-angiogenesis. Many thalidomide analogues have been developed in order to reduce its adverse effect of teratogenicity and to improve its efficacy or potency.

In this study, I have synthesised two novel thalidomide analogues 3-[(1R)-1-hydroxy-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione (compound 3) and 3-[(1S)-1-hydroxy-1-methyl-3-oxo-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione (compound 4), along with two other phthalimides 2-(2,6-dioxopiperidin-3-yl)-phthalimidine (EM-12) (compound 2) and 2-(1-Chloromethyl-2,6-dioxopiperidin-3-yl)phthalimidine (compound 5). The novelty has been confirmed by Scifinder Scholar search. The biological activities of the novel compounds have been tested and compared with thalidomide.

Compounds 3, 4 and 5 significantly increased TNF-α inhibition rate in lipopolysaccharide-induced human white blood cells compared with thalidomide. Compound 2 showed similar TNF-α inhibition rate as thalidomide. For anti-angiogenic effects, all analogues except compound 5 exhibited inhibition in a dose-dependent manner. Compound 3 and 4 generated significantly higher inhibitory effect compared with thalidomide.

For anti-proliferative effects, compound 2, 3 and 4 showed no statistical difference compared with thalidomide treatment. Compound 5 showed significant tumour cell growth inhibition with arresting cell cycle in S and G2-M phase, as analysed by flow cytometer.

In conclusion, two novel thalidomide analogues compound 3 and 4 have been successfully synthesised and they possess significantly higher biological activities as compared with the parent compound thalidomide. It is possible to add other chemical groups to those four synthesised compounds to obtain more analogues which may possess better biological activities.