Targeting Cancer Stem Cells with Small Molecules

Abstract

Cancers arise as a result of physiological imbalances and subsequent uncontrolled cell division. Cancer initiation requires a set of biochemical alterations, including some occurring at the genetic and epigenetic levels. Thus, tumors are heterogeneous in nature making it challenging to selectively target different cancer cells by means of small molecule intervention. The paradigm of cancer stem cells (CSCs) describes subpopulations of cells with high selfrenewal and tumor-seeding capacity. These cells, typically refractory to conventional therapies, can give rise to relapse after treatment. Combinatorial strategies, including drugs that selectively target this population of cells, have emerged in recent years. Here, we review how discovery-basedunbiased -screening approaches [1] have helped identify small molecules that specifically target CSCs. We also highlight biological pathways characteristic of CSCs that can potentially be selectively targeted in a hypothesis-driven manner by small molecules. We describe molecules that effectively target CSCs and emphasize what is known about their biological modes of action. The diversity and complexity of biochemical processes that CSCs may be addicted to, raises the question of how selective targeting of these pathways can be achieved. This challenge may be addressed by the continuing production of structurally complex and diverse small molecules using target and diversity-oriented synthesis approaches.[2]

Synthesis and Anticancer Activity of Tertiary Amides of Salinomycin and Their C20‐oxo Analogues

“…Significant peaks are reported within the overlapping~2.00-0.50 ppm region of the 1 H NMR spectra. 13 C NMR spectra are reported in chemical shifts downfield from TMS using the respective residual solvent peak as internal standard (CDCl 3 δ 77.16 ppm). Line broadening parameters were 0.5 or 1.0 Hz, while the error of chemical shift value was 0.1 ppm.…”

“…The reaction mixture was further warmed to room temperature and stirred for additional 48 h. After that, the solvent was evaporated under reduced pressure, and the residue was suspended in CH 2 Cl 2 and filtered off. Purification of the filtrate on silica gel using the 13 13 General procedure for preparation of novel C20-oxo analogues of salinomycin tertiary amides (analogues 3 b-13 b, except 10 b). To a stirred solution of the corresponding SAL tertiary amide 3 a-13 a (1.0 equiv.)…”

“…The filtrate was concentrated under reduced pressure. Purification of the filtrate on silica gel using the 13 13 ppm. 13…”

“…Emerging more recently as novel anticancer agents of natural origin are select polyether ionophores, such as salinomycin . Salinomycin ( SAL , 1 , Scheme ), isolated from Streptomyces albus , exhibits a broad spectrum of bioactivity .…”

“…[10] Emerging more recently as novel anticancer agents of natural origin are select polyether ionophores, such as salinomycin. [11][12][13][14] Salinomycin (SAL, 1, Scheme 1), isolated from Streptomyces albus, [15] exhibits a broad spectrum of bioactivity. [16,17] SAL is commercially used as a food additive and a growth promoter due to its potent coccidiostatic and antibacterial properties.…”