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

Abstract

Artemisinin is a natural compound extracted from Artemisia species belonging to the Asteraceae family. Currently, artemisinin and its derivatives are considered among the most significant small-molecule antimalarial drugs. Artemisinin and its derivatives have also been shown to possess selective anticancer properties, however, there are several limitations and gaps in knowledge that retard their repurposing as effective anticancer agents. Hybridization resulting from a covalent combination of artemisinin with one or more active pharmacophores has emerged as a promising approach to overcome several issues. The variety of hybridization partners allows improvement in artemisinin activity by tuning the ability of conjugated artemisinin to interact with various molecule targets involved in multiple biological pathways. This review highlights the current scenario of artemisinin-derived hybrids with potential anticancer activity. The synthetic approaches to achieve the corresponding hybrids and the structure-activity relationships are discussed to facilitate further rational design of more effective candidates.

Keywords: anticancer activity; artemisinin; artesunate; click chemistry; dihydroartemisinin; hybrids; molecular hybridization.

Figure 1

Strategies for the combination of pharmacophores. (A): combination therapy; (B–E): molecular hybridization approaches.

Figure 2

Picture of Artemisia annua and molecular structures of artemisinin (1), dihydroartemisinin (2) and artesunate (3).

Scheme 1

(A) Synthesis of dihydroartemisinin–bile acid hybrids 12–19 via condensation reaction: (i) EDC, DMAP, DMF, 25 °C, 18 h, 25–60% yield; (B) synthesis of dihydroartemisinin–bile acid hybrid 22 via click reaction: (ii) CuI 0.1 eq, r.t., 18 h, 28% yield; (C) selected biological data.

Scheme 2

Structures of dihydroartemisinin–bile acid hybrids 23a,b–25 and selected biological data.

Scheme 3

Synthesis of hybrid 28 and selected biological data. Reaction conditions: (i) EDC, DMAP, DCM, 24 h, 86% yield.

Scheme 4

Synthesis of artesunate–quinoline hybrids and selected biological data. Reaction conditions: (i) EDC, DMAP, DCM, 0 °C to r.t., overnight, 33–69% yield.

Scheme 5

Synthesis of artemisinin–quinoline hybrids 43 and selected biological data. Reaction conditions: (i) MeOH, r.t., 7 h.

Scheme 6

Synthesis of quinoline hybrid 46 and selected biological data. Reaction conditions: (i) EDC, DMAP, DMF, r.t., 3 h, 89% yield.

Scheme 7

Synthesis of dihydroartemisinin–quinoline hybrids 49 and 50 and selected biological data. Reaction conditions (i): DMF, 90–110 °C, 6–8 h.

Scheme 8

Synthesis of artesunate–indoloquinoline hybrids 52a,b and 54 and selected biological data. Reaction conditions: (i) DCM, EDC, OHBt, r.t., 6 h, 40–50% yield.

Scheme 9

Synthesis of artemisinin–quinazoline hybrids 56 and 57 and selected biological data. Reaction conditions: (i) DMF, EDC, DIPEA, OHBt, r.t., 1–3 days, 68–64% yield.

Scheme 10

(A–C): synthesis of artemisinin–quinazoline hybrids; (D) selected biological data. Reaction conditions: (i) BF₃^.Et₂O, DCM, EDC, r.t., overnight, 19–33% yield; (ii) Et₃N, DCM, EDC, r.t., 63–77% yield; (iii) EDC, DMAP, DPEA, DCM, 40 °C, overnight, 42% yield.

Scheme 11

Synthesis of artemisinin–nitrogen mustard hybrids and selected biological data. Reaction conditions: (i) DMAP, EDC, DCM, r.t., overnight, 30–60% yield.

Scheme 12

Synthesis of artesunate hybrid 75 and selected biological data. Reaction conditions: (i) DMAP, EDC, DCM, r.t., overnight, 88% yield.

Scheme 13

Synthesis of artemisinin–tyrosol hybrids and selected biological data. Reaction conditions: (i) K₂CO₃, DMF, 90 °C, overnight, 50% yield; (ii) DMAP, DCC, DCM, r.t., overnight, 53% yield; (iii) Et₂O, BF₃^.Et₂O, 0 °C, overnight, 48%; (iv) PPh₃, DIAD, DMF, r.t., overnight, 60% yield.

Scheme 14

Synthesis of artesunate–camptothecin hybrids and selected biological data. Reaction conditions: (i) EDC, DMAP, DMF, 40–64% yield.

Scheme 15

(A–C): synthesis of artemisinin–thymoquinone hybrids. (D): selected biological data. Reaction conditions: (i) DDC, DMAP, DCM, r.t., overnight, 80–86% yield; (ii) TMSOTf, CHCl₃, 0 °C, 1 h, 32–39% yield; (iii) DCM, DMAP, r.t., overnight, 26% yield.

Scheme 16

Synthesis of dihydroartemisinin–chalcone hybrids and selected biological data. Reaction conditions: (i) K₂CO₃, DMF, DCM, 60 °C, 30 min, 55% yield.

Scheme 17

Synthesis of dihydroartemisinin–chalcone hybrids and selected biological data. Reaction conditions: (i) DCI, DCM, r.t., 24 h, 32–61% yield.

Scheme 18

Synthesis of dihydroartemisinin–chalcone hybrids and selected biological data. Reaction conditions: (i) K₂CO₃, DMF, NaI, 60 °C, 5 h, 70–90% yield.

Scheme 19

(A,B) Synthesis of dihydroartemisinin–coumarin hybrids; (C) selected biological data. Reaction conditions: (i) CuSO₄, DMF, sodium ascorbate, r.t., 8–10 h, 20–40% yield; (ii) (CF₃CO₂)₂, Et₃N, DCM, 0–5 °C, 18 h, 12–17% yield; (iii) K₂CO₂, DMF, 60 °C, 5 h, 38–60% yield.

Scheme 20

Synthesis of artemisinin–tamoxifen hybrids and selected biological data. Reaction conditions: (i) DMAP, THF, DCC, r.t., 80% yield; (ii) DMAP, THF, EDC, TEA, r.t., 68–75% yield.

Scheme 21

(A–C): synthesis of artemisinin–estrogen hybrids; (D) selected biological data. Reaction conditions: (i) EDC, DCM, ACN, r.t., overnight, 45–80% yield; (ii) DCC, DMAP, DCM, r.t., overnight 55–95% yield; (iii) CuSO₄, DCM/H₂O, sodium ascorbate, r.t., overnight, 42% yield.

Scheme 22

Synthesis of artemisinin–estrogen hybrids and selected biological data. Reaction conditions: (i) EDC, DMAP, THF, r.t.; (ii) TBAF, THF, r.t., 2 h; (iii) NH₂SO₂Cl, DMA, r.t., overnight.

Scheme 23

Synthesis of artemisinin–cinnamic acid hybrids and selected biological data. Reaction conditions: (i) EDC, DMAP, DCM, r.t., 12 h, ca. 50% yield.

Scheme 24

Synthesis of artemisinin–acridine hybrids and selected biological data. Reaction conditions: (i) (COCl)₂, DCM, r.t., 1.30 h, then NEt₃, DCM, r.t., 16 h, 55–74% yield.

Scheme 25

Synthesis of artemisinin–acridine hybrids and selected biological data. Reaction conditions: (i) K₂CO₃, KI, ACN, microwave, 10 min, 45 °C, 64–71% yield.

Scheme 26

(A) Synthesis of dihydroartemisinin–isatin hybrids; (B) selected biological data; (C) pharmacokinetic data: maximum plasma concentration (C_max), area under curve (AUC), half-life (t_1/2), peak time (t_max), clearance rate (Cl), bioavailability (F). Reaction conditions: (i) CuSO₄, DMF, 60 °C, 8 h, 28–37% yield; (ii) BF₃^.Et₂O, DCM, 0 °C, overnight, 39–61% yield; (iii) NaHCO₃, THF, 60 °C, 12 h, 87 and 26% yield.

Scheme 27

Synthesis of dihydroartemisinin–isatin hybrids and selected biological data. Reaction conditions: (i) K₂CO₃, DMF, r.t., overnight; (ii) AcONa, THF/H₂O, 60 °C, 12 h.

Scheme 28

Synthesis of dihydroartemisinin-isatin hybrids and selected biological data. Reaction conditions: (i) HATU, DIEA, DMF, r.t., overnight; (ii) AcONa, THF/H₂O, 60 °C, 12 h.

Scheme 29

Synthesis of dihydroartemisinin–sulfasalazine hybrid. Reaction conditions: (i) DCC, DMAP, ACN, 40 °C, 8 h 21% yield.