Novel ester tethered dihydroartemisinin‐3‐(oxime/thiosemicarbazide)isatin hybrids as potential anti‐breast cancer agents: Synthesis, in vitro cytotoxicity and structure–activity relationship

Abstract

A series of ester tethered dihydroartemisinin‐3‐(oxime/thiosemicarbazide)isatin hybrids 7a–p were designed, synthesized, and assessed for their antiproliferative activity against MCF‐7, MDA‐MB‐231, MCF‐7/ADR, and MDA‐MB‐231/ADR breast cancer cell lines. Among them, hybrids 7a,f (IC50: 1.33–3.84 µM) showed potent activity against triple‐negative (MDA‐MB‐231 and MDA‐MB‐231/ADR) breast cancer cell lines, and hybrid 7f (IC50: 3.90 and 10.18 µM) also demonstrated promising activity against estrogen receptor‐positive breast cancer cells (MCF‐7 and MCF‐7/ADR), and the activity was superior to these of artemisinin, dihydroartemisinin, and ADR, revealing their potential to fight against both drug‐sensitive and drug‐resistant breast cancers. The enriched structure–activity relationships may facilitate further design of more active candidates.

Molecular Hybridization as a Strategy for Developing Artemisinin-Derived Anticancer Candidates

“…Xu et al reported [ 88 , 89 ] a series of dihydroartemisinin–isatin hybrids conjugated through ester linkers of different lengths. In particular, dihydroartemisinin ( 2 ) was reacted with isatin carboxylic acid homologue derivatives 151a – d ( Scheme 28 ) and their C-5 derivatives substituted with fluorine, methyl and methoxy moieties.…”

“…The synthesis of the most potent hybrids of the series 153a – c is reported in Scheme 28 . Hybrid 153a [ 89 ], presenting the shortest linker (two-carbon alkyl chain) and the thiosemicarbazide moiety at the C-3 position of isatin, showed high activity and cytoselectivity, being 53- and 46-fold more potent than parent dihydroartemisinin ( 2 ) towards triple-negative MDA-MB-231 and MDA-MB-231/ADR breast cell lines and 75- and 55-fold more potent than in MCF-7 and MCF-7/ADR cell lines, respectively ( Scheme 28 ). Analogously, hybrid 153b (R = OBn) [ 88 ], with a three-carbon alkyl chain and the benzoxime moiety at the C-3 skeleton of isatin, showed a similar activity profile to that of hybrid 153a ( Scheme 28 ).…”

“…On the contrary, hybrid 153b (R = OEt) [ 88 ], with a three-carbon alkyl chain and the ethoxime moiety at the C-3 position of isatin, was found to be cytoselective towards MCF-7 cells with IC 50 = 1.27 μM (MDA-MB-231/MCF-7 = 11.8) ( Scheme 28 ). Hybrid 153c [ 89 ], with a four-carbon alkyl chain and the oxime moiety at the C-3 position of isatin, showed interesting activity in all breast cancer cell lines tested (IC 50 = 2.85–10.18 μM). In particular, hybrid 153c was found to be 29-fold more active than dihydroartemisinin ( 2 ) in multidrug-resistant triple-negative MDA-MB-231/ADR ( Scheme 28 ).…”

The anti‐breast cancer potential of indole/isatin hybrids

“…Additional research revealed that the linker between the isatin and dihydroartemisinin moieties was essential for the activity, and the incorporation of 1,2,3-triazole between the two pharmacophores reduced the activity based on the fact that hybrids 7 (IC 50 : 59.8->100 µM) exhibited marginal efficacy against MCF-7/ADR, MDA-MB-231, and MCF-7 BC cell lines, [31] whereas replacement of the ether linker by ester linker was permitted. [32][33][34][35] For the estertethered isatin-dihydroartemisinin hybrids 8, the SARs revealed that (1) the activity was remarkably impacted by the carbon spacer between the isatin and dihydroartemisinin moieties, and a shorter linker was usually more favorable than the longer ones; (2) the activity was boosted up by benzoxime at position C-3 of isatin motif; and (3) electron-donating group at C-5 position of isatin skeleton attenuated the activity. [32][33][34][35] Among them, hybrids 8a,b (IC 50 : 3.85-9.36 and 3.21-9.53 µM, respectively) were approximately ≥8.4 times more potent than dihydroartemisinin (IC 50 : 79.10 and 82.78 µM), artemisinin (IC 50 : >100 µM), and doxorubicin (IC 50 : >100 µM) against multidrugresistant MDA-MB-231/ADR and MCF-7/ADR cell lines.…”

“…[32][33][34][35] For the estertethered isatin-dihydroartemisinin hybrids 8, the SARs revealed that (1) the activity was remarkably impacted by the carbon spacer between the isatin and dihydroartemisinin moieties, and a shorter linker was usually more favorable than the longer ones; (2) the activity was boosted up by benzoxime at position C-3 of isatin motif; and (3) electron-donating group at C-5 position of isatin skeleton attenuated the activity. [32][33][34][35] Among them, hybrids 8a,b (IC 50 : 3.85-9.36 and 3.21-9.53 µM, respectively) were approximately ≥8.4 times more potent than dihydroartemisinin (IC 50 : 79.10 and 82.78 µM), artemisinin (IC 50 : >100 µM), and doxorubicin (IC 50 : >100 µM) against multidrugresistant MDA-MB-231/ADR and MCF-7/ADR cell lines. [32] In addition, hybrids 8a,b (IC 50 : >100 µM) were found to have no toxicity against healthy MCF-10A breast cells.…”