Synthesis, structural studies, and cytotoxic evaluation of novel ursolic acid hybrids with capabilities to arrest breast cancer cells in mitosis

Abstract

Some novel chemically modified frameworks of ursolic acid have been designed and synthesized. The key step was the cycloaddition of azidopropyl-3β-hydroxy-urs-12-en-28-oate with the appropriate C28 propargyl esters of ursolic, corosolic, asiatic, oleanolic, and betulinic acid under Click reaction conditions, and the products were obtained in 74-84% yields. In view of their intriguing structural diversity, they have been subjected to detailed 1D and 2D NMR studies and their structures are thoroughly assigned. The synthesized compounds were screened for their anticancer potential against two human breast cancer cell lines (MCF-7 & MDA-MB-231) using sulforhodamine B cell proliferation assay. The GI data revealed that the synthesized compounds exhibit highly potent activities against the two tested cell lines. Interestingly, the synthesized compounds showed selectivity and higher activity against MDA-MB-231 cell line than MCF-7. Among the tested compounds, compound 17 is the most potent one with GI value of 1.4 ± 0.1 μM and showed 2.9 times more activity than the standard doxorubicin against MDA-MB-231. In addition, 17 arrests cells in mitotic phase of cell cycle, resulting in a change in cell phenotype. In view of the selective and highly promising activity against breast cancer cell lines, these compounds can serve as promising leads for further development.

In Vitro Cytotoxicity of Oleanolic/Ursolic Acids-Loaded in PLGA Nanoparticles in Different Cell Lines

“…Due to their similar chemical structure, the biological activity and therapeutic interest of OA and UA are rather similar, which is highly related to their dose-dependent cytotoxicity profile [6]. Previous studies have shown that these triterpenes exhibited cytotoxicity in several types of cancer cell lines [6,7,8]. Besides targeting tumor cells by induction of apoptosis, oleanolic and ursolic acids also modulate the tumor environment exhibiting antiangiogenic and anti-inflammatory activities, together with antioxidant effects and cell differentiation (e.g., [3]).…”

Pentacyclic Triterpenoids with Nitrogen-Containing Heterocyclic Moiety, Privileged Hybrids in Anticancer Drug Discovery

“…High cytotoxicity was observed for ursolic acid derivative, 32 ( Figure 3 , Table 1 ) modified at position C-28. This compound GI 50 values was 1.4 µM against the human breast tumor cell lines (MDA-MB-231) [ 73 , 74 ]. Ursolic acid derivatives ( 33 ) ( Figure 3 , Table 1 ) containing heterocyclic fragments such as 1,2,3-triazole and 3-(methyl)-4-methyl-1,2,5-oxadiazole-2-oxide linked at position C-28 displayed the best cytotoxic activity against MCF-7 cells with IC 50 value of 1.55 ± 0.08 µM comparable to doxorubicin.…”

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

“…This cycloaddition reaction gives 1,2,3-triazoles and has been widely used to synthesize 1,2,3-triazole-linked BA derivatives [14] (Scheme 18). This methodology allowed the functionalization of BA at positions 2 [55,59], 3 [54,60,61,62], 28 [20,26,63,64,65,66,67,68,69,70], and 30 [71,72,73], with different substrates, including peptides, approved drugs as AZT, β-cyclodextrins, sugars, and other triterpenes, as shown in the following examples.…”

“…Another interesting example of the use of click chemistry to functionalize BA was reported by Pattnaik et al [65]. The authors synthesized several triterpenoid dimers linked through a 1,2,3-triazole moiety (Scheme 23).…”