Synthesis and Cytotoxicity of Novel 10-Substituted Dihydroartemisinin Derivatives Containing N-Arylphenyl-ethenesulfonamide Groups

Abstract

Abstract:The manuscript describes the synthesis of 10-substituted dihydroartemisinin derivatives containing N-aryl phenylethenesulfonamide groups and their in vitro anti-tumor activities against the HT-29, MDA-MB-231, U87MG, H460, A549 and HL-60 cancer cell lines and the normal WI-38 cell line. Most tested compounds showed enhanced cytotoxic activities and good selectivity toward the MDA-MB-231, HT-29 and HL-60 cell lines, with IC 50 values in the single-digit μM range as compared with dihydroartemisinin (DHA), and all of them displayed less toxicity towards WI-38 cells. Among them, compounds 3c and 6c with trifluoromethoxy groups on the N-phenyl ring were found to be most active compounds against the six tested cancer cell lines.

A simplified and scalable synthesis of artesunate

“…After destroying the excess of NaBH 4 with acetic or hydrochloric acid, DHA is usually precipitated by the addition of water. Through this procedure, DHA could be obtained in satisfactory yields (79–89%) as published previously [16, 19, 21]. In an alternative strategy, the yield of DHA could be further enhanced by neutralization with 30% acetic acid/MeOH at 0–5 °C, concentration, and multiple extraction of the white residue using Et-OAc.…”

“…The transformation of artemisinin into artesunate was commonly realized by a two-step process involving the reduction with NaBH 4 [15–19], KBH 4 [20, 21] or diisobutylaluminium hydride (DIBAL) [22, 23], followed by esterification using succinic anhydride [24, 25]. However, these syntheses described in the scientific literature are not suitable for an industrial large-scale process because they require very low temperature, highly expensive or toxic reagents and solvents or provide only moderate yields.…”

Dihydroartemisinin–Bile Acid Hybridization as an Effective Approach to Enhance Dihydroartemisinin Anticancer Activity

“…In recent years, many C10‐derivatized DHA hybrids have been reported in the literature. For example, DHA conjugated with naturally occurring active molecules such as coumarin, cinnamic acid, chalcones, N ‐aryl phenylethenesulfonamides, thymoquinone and estradiol, all with anticancer activity themselves, have been tested against a variety of cancer cell lines. Our research has been mainly focused on the study of biologically active hybrids based on bile acids (BAs); therefore, we considered BAs as suitable partners for the preparation of novel DHA hybrids.…”

“…properties can improve the cytotoxicity and cytoselectivity toward target cancerc ells or other properties, such as bioavailability.T his latter approachm ight represent an interesting strategyf or the development of new anticancer drugs. In recent years, many C10-derivatized DHA hybridsh ave been reported in the literature.F or example, DHA conjugated with naturallyo ccurring active molecules such as coumarin, [10] cinnamic acid, [11] chalcones, [12] N-aryl phenylethenesulfonamides, [13] thymoquinone [14] and estradiol, [15] all with anticancer activity themselves, have been tested against av arietyo f cancer cell lines. Our research has been mainly focusedo nt he study of biologically active hybrids based on bile acids (BAs); [16] therefore, we considered BAs as suitable partners for the preparation of novel DHA hybrids.…”

Synthesis and anti-glioblastoma effects of artemisinin-isothiocyanate derivatives

“…The DHA derivatives 4a-c were synthesized according to the literature. 28,29 The reaction of DHA with the corresponding bromo-substituted alkanol in CH 2 Cl 2 by using boron triuoride ethyl ether (BF 3 $Et 2 O) as a catalyst afforded substituted ART enantiomers. 1a-c were obtained by silica gel column chromatography elution with petroleum ether/ethyl acetate (97 : 3) as the b conguration (indicated the coupling constants between 9-H and 10-H in 1 H NMR, J 9,10 ¼ 3-4 Hz).…”