Effects of Regioisomerism on the Antiproliferative Activity of Hydroxystearic Acids on Human Cancer Cell Lines

Abstract

A series of regioisomers of the hydroxystearic acid (HSA) was prepared, and the effect of the position of the hydroxyl group along the chain on a panel of human cancer cell lines was investigated. Among the various regioisomers, those carrying the hydroxyl at positions 5, 7, and 9 had growth inhibitor activity against various human tumor cell lines, including CaCo-2, HT29, HeLa, MCF7, PC3, and NLF cells. 10-HSA and 11-HSA showed a very weak effect. 8-HSA did not show inhibitory activity in all cell lines. The biological role of 7-HSA and 9-HSA is widely recognized, while little is known about the effects of 5-HSA. Therefore, the biological effects of 5-HSA in HeLa, HT29, MCF7, and NLF cell lines were investigated using the Livecyte’s ptychography technology, which allows correlating changes in proliferation, motility, and morphology as a function of treatment at the same time. 5-HSA not only reduces cell proliferation but also induces changes in cell displacement, directionality, and speed. It is important to characterize the biological effects of 5-HSA, this molecule being an important component of fatty acyl esters of hydroxy fatty acids (FAHFA), a class of endogenous mammalian lipids with noticeable anti-diabetic and anti-inflammatory effects.

Synthesis and Antiproliferative Insights of Lipophilic Ru(II)-Hydroxy Stearic Acid Hybrid Species

“…The first step for the preparation of the Ru(II)-HSA complexes is the synthesis of racemic 7-HSA and ( R )-9-HSA, while 12-HSA ( Figure 1 ) was purchased as commercially available. 7-HSA and ( R )-9-HSA were obtained in pure form following the synthetic procedures recently reported [ 38 , 48 ]. The following step involves the reaction of the HSAs with a stoichiometric amount of [Ru(H) 2 CO(PPh 3 ) 3 ], 1 —obtained according to slightly modified reported processes [ 49 ]—and the synthesis selectively leads to the targeted Ru(II)-HSA complexes after purification as a unique species.…”

“…Commercially available 12-HSA was purchased from Merk (Darmstad, Germany). 7-, 9-HSA were prepared by published methods [ 38 , 48 ].…”

“…In line with the crucial biological activity of hydroxy stearic acids, we recently described the effects of the hydroxyl group position along the 18-carbon chain for several HSA regioisomers [ 38 ]. Unexpectedly, the HSAs with the hydroxyl group in the odd position (5-, 7-, 9-, 11-HSA) show inhibitor activity against various human tumor cell lines, while HSAs with the -OH group in the even position (8-, 10-, 12-HSA) display reduced activity.…”

Traditional Medicinal Plants as a Source of Inspiration for Osteosarcoma Therapy

“…Chemical modifications of the plant-derived bioactive compounds can confer them improved solubility and pharmacokinetic properties. For example, Calonghi and coworkers have recently tested a series of regioisomers of the hydroxystearic acid (HSA) on different cancer cell lines, finding that positional isomers possess distinct biological activities [ 125 ]. Although osteosarcoma cells were not included in this paper, it opens a new avenue for studying how chemical modification of known natural compounds can modulate their activity.…”

Asymmetric Synthesis of Saturated and Unsaturated Hydroxy Fatty Acids (HFAs) and Study of Their Antiproliferative Activity

“…At the same time, Calonghi et al synthesized derivatives of 9HSA and studied their antiproliferative activity on HT29 cancer cells [12]. Most recently, Calonghi et al studied the effect of regioisomerism on the antiproliferative activity of HSAs on human cancer cell lines and reported that 5HSA not only presented antiproliferative activity, but also induced changes in cell displacement, directionality and speed [13]. To extend our knowledge on HFA bioactivities and to complete structure-activity relationship studies, we decided to synthesize chiral HPAs and HSAs carrying a hydroxyl group at the 6-, 8-and 11-positions and (R)-and (S)-7-hydroxymargaric acids (7HMAs), as well as unsaturated 7-hydroxyoleic acid and 7-hydroxypalmitoleic acid, which have not previously been prepared and tested.…”