Abstract
A series of artemisinin-indoloquinoline hybrids were designed and synthesized in an attempt to develop potent and selective anti-tumor agents. Compounds 7a–7f, 8 and 9 were prepared and characterized. Their antiproliferative activities against MV4-11, HCT-116, A549, and BALB/3T3 cell lines in vitro were tested. Nearly all of the tested compounds (7–9, except for compounds 7d and 7e against HCT-116) showed an increased antitumor activity against HCT-116 and A549 cell lines when compared to the dihydroartemisinin control. Especially for the artemisinin-indoloquinoline hybrid 8, with an 11-aminopropylamino-10H-indolo[3,2-b]quinoline substituent, the antiproliferative activity against the A549 cell line had improved more than ten times. The IC50 value of hybrid 8 against A549 cell lines was decreased to 1.328 ± 0.586 μM, while dihydroartemisin showed IC50 value of >20 µM in the same cell line. Thus, these results have proven that the strategy of introducing a planar basic fused aromatic moiety, such as the indoloquinoline skeleton, could improve the antiproliferative activity and selectivity towards cancer cell lines.
Highlights
Artemisinin (1), a sesquiterpene lactone from Artemisia annua, was isolated as a result of an extensive survey for antimalarial agents in Chinese traditional herb medicines by Chinese scientists since the early 1970s [1]
The artesunate-indoloquinoline hybrids 7, 8 and 9 were obtained using the synthetic process shown in Scheme 1
6-(ω-aminoalkylamino)-11H-indolo[3,2-c]quinolines 6 were carried out according to the method that we previously described in the literature [50,51,52]
Summary
Artemisinin (1), a sesquiterpene lactone from Artemisia annua, was isolated as a result of an extensive survey for antimalarial agents in Chinese traditional herb medicines by Chinese scientists since the early 1970s [1]. 1,2,4-trioxane moiety, which can react with an iron complex to produce cytotoxic free radicals and selectively induces apoptosis in many high free iron level cell lines, such as cancer cells [13]. This biological sequence makes artemisinin and its analogs potent anticancer lead compounds. Compared with many traditional cancer chemotherapeutic medicines of natural origin, such as camptothecin [14], doxorubicin [15], etc., simple artemisinin analogs are still less potent [4,16]. High dosage and frequent administration would be required in order to achieve the same effectiveness in the anticancer treatment due to their short half-lives
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