The Anti-Breast Cancer Activity of Dihydroartemisinin-5-methylisatin Hybrids Tethered via Different Carbon Spacers

Abstract

Sixteen dihydroartemisinin-5-methylisatin hybrids 6a–c and 7a–m tethered via different carbon spacers were assessed for their antiproliferative activity against MCF-7, MDA-MB-231, MCF-7/ADR and MDA-MB-231/ADR breast cancer cell lines as well as cytotoxicity towards MCF-10A cells to investigate the influence of the length of carbon spacers on the activity. The preliminary results illustrated that the length of the carbon spacer was the main parameter which affected the activity, and hybrids tethered via the two-carbon linker showed the highest activity. Amongst the synthesized hybrids, the representative hybrid 7a (IC50: 15.3–20.1 µM) not only demonstrated profound activity against both drug-sensitive and drug-resistant breast cancer cell lines, but also possessed excellent safety and selectivity profile. Collectivity, hybrid 7a was a promising candidate for the treatment of both drug-sensitive and drug-resistant breast cancers and worthy of further preclinical evaluations.

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

“…Cao et al reported [ 86 , 87 ] a series of dihydroartemisinin–isatin hybrids conjugated through a nucleophilic substitution by reacting a series of tosylate derivatives of dihydroartemisinin ( 2 ) with isatin derivatives substituted at C-3 with different groups such as methoxy, fluorine and methyl. The synthesis of the most potent hybrids of the series is reported in Scheme 27 .…”

“…The synthesis of the most potent hybrids of the series is reported in Scheme 27 . The new hybrids 149a [ 86 ] and 149b [ 87 ] presented alkyl chains of different lengths and different substituents at the C-5 position of the isatin moiety. Hybrids 149a and 149b were in turn modified at the C-3 position of the isatin moiety with, among others, hydroxime and thiosemicarbazide moieties, leading to hybrids 150a and 150b , respectively.…”

“…Lung, breast [85][86][87] Cytotoxic activity + Safety profile Ester Breast [88,89] Cytotoxic activity Artemisininsulfasalazine Ester Glioma [90] Apoptotic cell death Migration inhibition…”

The anti‐breast cancer potential of indole/isatin hybrids

“…A significant part of alkyl tethered isatin-dihydroartemisinin hybrids 6 (Figure 3; IC 50 : 18.9-88.3 µM) were active against MDA-MB-231, MCF-7, and their multidrug-resistant counterparts MCF-7/ ADR as well as MDA-MB-231/ADR BC cell lines, and the activity was better compared with that of artemisinin (IC 50 : 72.4->100 µM) and dihydroartemisinin (IC 50 : 69.6-82.8 µM). [29,30] The SARs illustrated that (1) the activity was increased by extending the carbon spacer between the isatin and dihydroartemisinin motifs; (2) the activity benefited from the presence of hydrogen bond donors like thiosemicarbazide and oxime at the C-3 position and fluorine at the C-5 position of the isatin skeleton. In particular, hybrids 6a-c (IC 50 :…”

“…A significant part of alkyl tethered isatin‐dihydroartemisinin hybrids 6 (Figure 3; IC 50 : 18.9–88.3 µM) were active against MDA‐MB‐231, MCF‐7, and their multidrug‐resistant counterparts MCF‐7/ADR as well as MDA‐MB‐231/ADR BC cell lines, and the activity was better compared with that of artemisinin (IC 50 : 72.4–>100 µM) and dihydroartemisinin (IC 50 : 69.6–82.8 µM). [ 29,30 ] The SARs illustrated that (1) the activity was increased by extending the carbon spacer between the isatin and dihydroartemisinin motifs; (2) the activity benefited from the presence of hydrogen bond donors like thiosemicarbazide and oxime at the C‐3 position and fluorine at the C‐5 position of the isatin skeleton. In particular, hybrids 6a–c (IC 50 : 15.1–18.3, 15.3–20.1, and 18.9–26.6 µM, respectively) were comparable to doxorubicin (IC 50 : 18.9 µM) against MCF‐7 cancer cells and >3.7 times more potent than doxorubicin (IC 50 : >100 µM) against multidrug‐resistant MCF‐7/ADR and MDA‐MB‐231/ADR BC cell lines, highlighting their ability to overcome drug resistance.…”