Isoflavone Derivatives as Potential Anticancer Agents: Synthesis and Bioactivity Studies

Abstract

Isoflavones are phenolic natural compounds with a C₆C₃C₆ framework. They possess a plethora of biological activities that are associated with putative benefits to human health. In particular, the cancer chemopreventive and chemotherapeutic potential of isoflavones has attracted the interest of researchers. Several isoflavone derivatives have been synthesised and probed for their anticancer activities. The isoflavone analogues are mainly synthesised by molecular hybridisation and other strategies that enable diversification through early or late-stage functionalisation of A-, B- and C-rings of the isoflavones. This has resulted in the discovery of isoflavone analogues with improved antiproliferative activities against several cancer cells and different mechanisms of action. In this review, the synthesis of isoflavone derivatives and their anticancer activity studies are discussed.

Keywords: Anticancer; Derivatives; Isoflavones; Natural compounds.

Figure 1

Isoflavone core structure and isoflavone analogues with potential anticancer activity.

Scheme 1

Synthesis of 5‐Fluorouracil‐genistein analogues. Reagents and conditions: a) DIPEA, DMF, 61–71 %; b) NaN₃, DMF, 40 °C, US, 78–89 %; c) DIPEA, KI, DMF, US, 40 %; d) Ascorbic acid, Cu(OAc)₂, DMF‐H₂O, 40 °C, US, 43–93 %.

Scheme 2

Synthesis of 1,3,5‐triazine analogues of genistein. Reagents and conditions: a) Secondary amine, Acetone, K₂CO₃, −20 °C; b) Acetone, K₂CO₃, rt, 69–81 %.

Scheme 3

Synthesis of formononetin nitrogen mustard derivatives. Reagents and conditions: a) concentrated HNO₃, concentrated H₂SO₄, AcOH, 50 °C, 12 h, 75 %; b) Method A: K₂CO₃, R−Br, acetone, reflux, 3–8 h, 79–87 % (for 12 a‐l); Method B: DIAD, PPh₃, THF, R‐OH, 0 °C to rt, overnight, 65–77 % (for 12 m‐o); c) Zn, EtOH, HOAc, reflux, 1–2 h, 78–85 %, d) ethylene oxide, HOAc, rt, overnight, 70–82 %; e) SOCl₂, DCM, reflux, 1.5 h, 66–75 %.

Scheme 4

Synthesis of formononetin nitrogen mustard derivative 17. Reagents and conditions: a) H₂, 10 % Pd/C, MeOH, rt, 1 h, 90 %; b) SOCl₂, DCM, reflux, 1.5 h, 70 %.

Scheme 5

Synthesis of formononetin‐dithiocarbamate conjugate 19. Reagents and conditions: a) 1,3‐dibromopropane, K₂CO₃, THF, reflux, 70–83 % yield; (b) CS₂, tert‐butyl piperazine‐1‐carboxylate, Na₃PO₄⋅12H₂O, acetone, rt, 78–85 % yield.

Scheme 6

Synthesis of formononetin hydrazide derivative 22. Reagents and conditions: a) ethyl bromoacetate, acetone, K₂CO₃, reflux, 10 h, 95 %; b) hydrazine hydrate, ethanol, reflux, 10 h, 87 %; c) 4‐benzyloxybenzaldehyde, glacial acetic acid, ethanol, reflux, 6 h, 69 %.

Scheme 7

Synthesis of podophyllotoxin‐formononetin hybrid. Reagents and conditions: a) Et₃N, DCM; b) 10, K₂CO₃, KI, DMF, 64–85 % over two steps.

Scheme 8

Synthesis of the formononetin‐coumarin hybrid 29. Reagents and conditions: a) propargyl bromide, NaOH, acetone, reflux; b) 1,3‐dibromopropane, K₂CO₃, DCM, reflux, 50.7 %; c) NaN₃, CH₃CN, reflux, 41.3 %; d) intermediate 25, CuSO₄.5H₂O, sodium ascorbate, DMSO:H₂O (1 : 1), rt, 32.9 %.

Figure 2

Glaziovianin A and derivatives.

Scheme 9

Synthesis of 6‐O‐benzylglaziovianin A (31). Reagents and conditions: a) DMF‐DMA, 95 °C; b) I₂, py, CHCl₃, rt, 86 % in two steps; c) 38, PdCl₂(dppf).DCM, 1 M Na₂CO₃ aq, 1,4‐dioxane, rt, 76 %.

Scheme 10

Synthesis of gatastatin analogues. Reagents and conditions: a) 38, PdCl₂(dppf)⋅DCM, 1 M Na₂CO₃ aq, 1,4‐dioxane, rt, 61 % for 32 and 97 % for 42; b) p‐TSOH⋅H₂O, CHCl₃, MeOH, rt, 75 % c) propargyl bromide, K₂CO₃, acetone, reflux, 97 %.

Scheme 11

Synthesis of B‐ring modified barbigerone analogues. Reagents and conditions: a) 1,1‐diethoxy‐3‐methyl‐2‐butene, 3‐picoline, xylene, reflux, 24 h (48.4 %); b) ArB(OH)₂, 10 % Pd/C, Na₂CO₃, H₂O, DME, 45 °C, 1 h (49.6–89.7 %).

Scheme 12

Synthesis of A‐ring modified barbigerone analogues. Reagents and conditions: a) Br₂, CH₂Cl₂, 0 °C (92.3 %); b) n‐BuLi, trimethyl borate, THF, −78 °C (37.7 %); c) 10 % Pd/C, Na₂CO₃, H₂O, DME, 45 °C, 1 h (61.4 %); d) p‐TsOH, CH₃OH, THF, 60 °C, 1 h (87.1 %); e) RX, K₂CO₃, acetone, rt, overnight, or RCOOH, DCC, DMAP, DCM, rt, overnight (18.7–99.4 %).

Scheme 13

Synthesis of barbigerone analogue 59. Reagents and Conditions: a) 51, 10 % Pd/C, Na₂CO₃, H₂O, DME, 45 °C, 65.8 %; b) 1‐bromo‐2‐(bromomethyl)benzene, K₂CO₃, MeCN, reflux, 92.2 %.

Figure 3

Natural diprenylated isoflavones with preferential cytotoxic activity against pancreatic cancer cell line.

Scheme 14

Synthesis of prenylated isoflavone derivatives 69 a‐b. Reagents and Conditions: a) MeSO₃H, 60 °C, 31 % for 65 a and 65 b; b) MsCl, BF₃⋅OEt₂, DMF, 80 °C, 77 % for 66 a and 69 % for 66 b; c) i: MOMCl, NaH, THF; ii) AllylBr, NaH, THF, reflux, 88 % for 67 a and 51 % for 67 b; d) Eu(fod)₃, ClCH₂Cl, 100 °C, sealed tube, 90 % for 68 a and 83 % for 68 b; e) i: isobutene, G2, benzene, 100 °C, sealed tube; ii: conc. HCl, MeOH, 64 % for 69 a and 51 % for 69 b.

Scheme 15

Synthesis of prenylated isoflavone derivatives 74 a‐h. Reagents and Conditions: a) (PhCN)₂PdCl₂, dppb, Na₂CO₃, toluene/EtOH/H₂O, 70 °C, 35–98 %; b) I₂, MeOH, 72–95 %.

Scheme 16

Synthesis of 8‐prenylated isoflavone derivative 77. Reagents and Conditions: a) (PhCN)₂PdCl₂, dppb, Na₂CO₃, toluene/EtOH/H₂O, 70 °C, 57 %; b) 10 % HCl, MeOH, 40 °C, 40 %.

Figure 4

Glabrescione B (79) and derivatives.

Scheme 17

Synthesis of glabrescione B derivatives. Reagents and Conditions: a) BF₃⋅OEt₂, 90 °C, 90 min 50–60 %; b) BF₃⋅OEt₂, (chloromethylene)dimethyliminium chloride, DMF, rt, 2 h, 28–32 %; c) alkyl‐ or benzylbromide, K₂CO₃, acetone, 45 °C, 17 h, 88–95 %.

Scheme 18

Synthesis of cytisine and piperazine isoflavone analogues. Reagents and Conditions: a) K₂CO₃, BrCH₂CH₂Br (62–88 %); b) piperazine, NaI, K₂CO₃, DMF (79 % for 91c); or N‐(2‐hydroxyethyl)piperazine, NaI, K₂CO₃, DMF (60–74 %); c) cytisine, NaI, iPr₂NH, DMF (62–76 %).

Scheme 19

Synthesis of isoflavone linked pyrazolo[3,4‐d]pyrimidine derivatives. Reagents and Conditions: a) K₂CO₃, DMF, rt, 83 %; b) Pd(PPh₃)₄, Na₂CO₃, DMF, 45.3 % for 1 and 86.9 % for 2.

Scheme 20

Synthesis of isoflavone linked purinone derivative 99. Reagents and Conditions: a) 100, K₂CO₃, DMF, 47.7 %.

Scheme 21

Synthesis of 3‐phenylquinazolinone linked pyrazolo[3,4‐d]pyrimidine derivative 110. Reagents and Conditions: a) K₂CO₃, DMF, rt, 72.6 %; b) Pd(PPh₃)₄, Na₂CO₃, DMF, 49.7 %.

Scheme 22

Synthesis of genistein‐curcumin inspired hybrids. Reagents and Conditions: a) Toluene, 70 °C, 5 h, 75–99 %; b) Toluene, PTSA, 100 °C, overnight, 11–58 %.

Scheme 23

Synthesis of the most active BT‐isoflavone analogues. Reagents and conditions: a) i: DMF−DMA, xylene, 150 °C, 99, 87, 87 % for anaminone a, b and c, respectively; ii) I₂, CHCl₃, rt, 75, 78, 91 % for 117 a, b and c, respectively; (b) Pd(PPh₃)₄, 2 M Na₂CO₃(aq), PhH, reflux, 67, 82, and 88 % for 119 a, b and c, respectively.

Scheme 24

Synthesis of isoflavonequinone SIRT1 inhibitors. Reagents and conditions: (a) i. DMF−DMA, ii. 2,5‐dimethylbenzoquinone or 3,5‐dimethylbenzoquinone, HOAc; (b) BBr₃ (3 equiv. per methoxy), CH₂Cl₂, 0−rt, 66, 42, 11 % for 120 a‐c, respectively.

Scheme 25

Regioselective modification of 7‐hydroxyisoflavones 126 and 7‐hydroxy‐8‐methylisoflavones 128. Reagents and conditions: a) CH₂(NMe)₂, ⁱ PrOH, 80 °C, 2–4 h, 68–91 %; b) CH₂(NMe)₂, dioxane, 100 °C, 16 h, 72–99 %.

Scheme 26

Diels–Alder reaction of N,N‐dimethylaminoisoflavones 127 and 129 with dienophiles. Reagents and conditions: a) 2,3‐dihydrofuran, DMF, reflux, 24–40 h, 27–75 %; b) 3,4‐dihydro‐2H‐pyran, DMF, reflux, 36–40 h, 15–55 %; c) 3‐(dimethylamino)‐5,5‐dimethylcyclohex‐2‐en‐1‐one, DMF, reflux; 4 h, 68–92 %; d) 4‐cyclopent‐1‐en‐1‐yl morpholine, DMF, reflux, 4 h, 53–58 %; e) 4‐cyclohex‐1‐en‐1‐yl morpholine, DMF, reflux, 4 h, 51–91 %.

Figure 5

Second and third generation super‐benzopyran analogues.

Scheme 27

Synthesis of third generation super‐benzopyrans. Reagents and conditions: a) ZnCl₂, POCl₃, 70 °C, 2 h, 87 % (145 a) and 41 %(145 b); b) DiPEA, Ac₂O, 135 °C, 18 h, 76 % (147 a) and 68 % (147 b); c) THF, BH₃⋅Me₂S in THF, 35 °C, 18 h, 53 % from 147 a and 53 % from 147 b; d) H₂, Pd/C, EtOH, 3 bar, 40 °C, 18 h, 88 % (141) and 60 % (142).