Synthesis of gamma biguanides butyric acid analogues as HDAC inhibitors and studying their cytotoxic activity

Abstract

Histone deacetylase (HDAC) inhibitors have been suggested as a new class of anticancer agents with promising effect on breast cancer. HDAC plays an important role in progression of breast cancer as it is overexpressed in the cancer cells. The study aimed at finding the HDAC inhibitory effect of three newly designed and synthesized hybrid molecules; made up of SAHA conjugated with the biguanid moiety of metformin. The molecules were amino[(E)-{amino[(4-anilino-4oxobutyl)amino] methylidene}amino] methaniminium chloride, amino[(E)-(amino{[4-(4-fluoroanilino)-4-oxobutyl] amino} methylidene) amino]methaniminium chloride, amino[(E)-(amino{[4-(4-chloroanilino)-4-oxobutyl]amino}methyli dene) amino] methaniminium chloride, (7–9 respectively). Briefly, the plausible inhibitory effect against HDAC enzymes (HDAC1, HDAC2 and HDAC3) of the above mentioned compounds was deducted in silico using a chemo-informative simulation software programs, viz; SeeSAR and Chimera programs. Then, the compounds were synthesized, purified and identified using conventional synthetic and characterization methods. After that, their cytotoxic activity was determined against breast cancer using MCF-7 cell line and the results were compared with that of each of SAHA and metformin. The results revealed an appreciable cancer growth inhibition of all the synthesized analogues (IC50 range 161–72.5 mM). This suggests that these compounds could be a promising novel class of HADC inhibitors against breast cancer.