Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients

Abstract

Breast cancer is considered as a leading cancer type with the secondary highest possibility of brain metastasis. Most research in breast cancer is currently directed into the mortality of brain metastatic breast cancer. However, there is no effective treatment or anticancer therapeutics specifically for this cancer type. Hence, development of effective and novel anticancer therapeutic drugs/APIs to inhibit HDAC and mTOR, playing very important role on modulating breast cancer progression is an increasing demand. In this study, the structure-activity relationship and in silico modeling of a series of prodigiosin and 1,10-phenanthroline derivatives as highly potent anticancer therapeutic drugs/APIs against mTOR and HDAC enzymes have been investigated. Compared to the natural product Ps, 20 of the highly potent ligands, especially 2a, 6b, 13 and 13a, have exhibited very promising binding energies ranging from –9.4 to –7.1 kcal/mol and inhibition constants ranging from 225 to 569 nM against HDAC1 and/or mTOR enzymes. Ligands 2a, 5, 6b, 7b and 13 in particular show effective dual action against both enzymes. The findings from the in silico modeling studies have also been supported with MD simulations and ADMET study with Lipinski’s rule of five, providing outstanding therapeutic potential for the breast cancer brain metastasis.