Methylsulfanylpyridine based diheteroaryl isocombretastatin analogs as potent anti-proliferative agents

Abstract

The microtubules of the eukaryotic cells are hollow dynamic tubes formed by polymerization and depolymerization of αβ-tubulin heterodimers, referred to as tubulin. This dynamic equilibrium is essential for their functioning and the aim of microtubule-targeting agents or MTAs, acting as anti-tumor and anti-parasitic drugs[1]. MTAs bind to tubulin in at least seven structurally characterized binding sites, some of them favoring (microtubule-stabilizing agents or MSAs) and some of them opposing polymerization (microtubule destabilizing agents or MDAs)[2]. The combretastatins are a family of natural products that bind to the colchicine domain of tubulin, located at the interface between the αβ-tubulin heterodimers. Binding of combretastatins to the colchicine site hampers the curved to straight transition of tubulin dimers necessary for polymerization, and therefore they behave as MDAs[3]. MDAs inhibition of tubulin polymerization is especially patent in the highly dynamic mitotic microtubules and, therefore, they arrest cells at the metaphase to anaphase transition, which results in an enhanced population of cells in the G2/M phases of the cell cycle, and a late apoptosis onset of cancer cells[4]. Furthermore, combretastatins act as vascular disrupting agents or VDAs, causing a rapid collapse of the tumor neo-vasculature in vivo and tumor death[5]. The phosphate prodrug of combretastatin A-4 (CA4P, fosbretabulin) as fosbretabulin tromethamine (Fig. 1) has been granted the orphan drug designation for the treatment of ovarian adenocarcinoma, gastroenteropancreatic and neuroendocrine cancers, and anaplastic thyroid cancer, and the combretastatin A-1 diphosphate prodrug Oxi 4503 (Fig. 1) for the treatment of relapsed/refractory Acute Myeloid Leukemia (AML) in combination with cytarabine[6].