A review of coumarin derivatives in pharmacotherapy of breast cancer

Abstract

The coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in natural products (such as the anticoagulant warfarin) that display interesting pharmacological properties, has intrigued chemists and medicinal chemists for decades to explore the natural coumarins or synthetic analogs for their applicability as drugs. Many molecules based on the coumarin ring system have been synthesized utilizing innovative synthetic techniques. The diversity oriented synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins, and coumarin sulfamates (COUMATES), which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, and as stimulants for central nervous system, antibacterials, anti-inflammatory, anti-coagulants, and dyes. Of particular interest in breast cancer chemotherapy, some coumarins and their active metabolite 7-hydroxycoumarin analogs have shown sulfatase and aromatase inhibitory activities. Coumarin based selective estrogen receptor modulators (SERMs) and coumarin-estrogen conjugates have also been described as potential antibreast cancer agents. Since breast cancer is the second leading cause of death in American women behind lung cancer, there is a strong impetus to identify potential new drug treatments for breast cancer. Therefore, the objective of this review is to focus on important coumarin analogs with antibreast cancer activities, highlight their mechanisms of action and structure-activity relationships on selected receptors in breast tissues, and the different methods that have been applied in the construction of these pharmacologically important coumarin analogs.

Fig. (1)

Structures of some naturally occurring coumarins.

Fig. (2)

Estrogenic steroid origins showing the sites of action of coumarins AR, aromatase; ST, sulfotransferase; STS, sulfatase; 17(β-HSD, 17β-hydroxysteroid dehydrogenase; ER, estrogen receptor) [43].

Fig. (3)

Structures of coumarin sulfamates and tricyclic coumarin sulfamates.

Fig. (4)

The proposed mechanism of STS inhibition by (30) involving Fgly in the enzyme active site [63].

Fig. (5)

Proposed mechanism of STS inhibition by (30) involving the aldehyde hydrate in the enzyme active site [63].

Fig. (6)

The proposed random specific or non-specific sulfamoylation by (30). Path A: a direct nucleophilic attack by the amino acid residue at the sulfur atom. Path B: elimination of sulfamic acid by an E1cB mechanism [63].

Fig. (7)

Molecular modelling of 667 COUMATE (top) and EMATE (bottom) (adapted from [63] with permission).

Fig. (8)

Proposed pharmacophores of AR inhibiting coumarins [54].

Fig. (9)

Structures of coumarin-based SERMs.

Fig. (10)

SARs of the benzopyranone series (43) incorporating the critical hinge feature 130].

Fig. (11)

Structures of coumarin-estradiol conjugates.

Scheme 1

Pechmann reaction.

Scheme 2

Reagents and conditions: (i) resorcinol (58), CF₃COOH/conc. H₂SO₄ (1:1), 0°C; (ii) NaH/DMF, H₂NSO₂C1; (iii) K₂CO₃/(Bu)₄N⁺Cl-.xH₂0/H₂0/CHC1₃, r.t.

Scheme 3

Perkin reaction.

Scheme 4

Reagents and conditions: (i) Et₃N, Ac₂O/reflux; ii) pyridine, HC1/200°C; iii) Ac₂O/pyridine; iv) NBS /benzoyl peroxide, CCl₄/hv; v) K₂CO₃/MeOH/acetone; vi) LiHMDS/THF/−32°C, then NBS/THF/78°C; vii) BBr₃/ DCM, then NaOH/H⁺.

Scheme 5

Knoevenagel reaction.

Scheme 6

Reagents and conditions: i) Et₃N, CH₂C1₂, 0°C to rt; ii) 10% NaOH, HC1; iii) PhCH₂NH₂, HOAc, reflux, iv) piperidine, ethanol, reflux 1 h. b. Reagents and conditions: (i) C1SO₂CH₂COOCH₃, triethylamine/ THF, N2, rt, 3 h; (ii) 10% NaOH in H₂O; (iii) CH₃COOH, C₆H₅CH₂NH₂; (iv) piperidine, ethanol, reflux, 5 min.

Scheme 7

Reagents and conditions: i) BF3 diethyletherate (Fries reaction); ii) CDI, K₂CO₃, DMAP, 10–90%; iii) K₂CO₃, l-(2-chloroethyl)pyrrolidine, 30–75%; iv) 30–50% HBr, AcOH.

Scheme 8

Reagents: i) Acryloychloride, NaH, reflux; ii) DABCO, CH₂C12, rt, iii) K₂CO₃, CH₃CN, reflux, overnight, iv) NH₂OH, THF, reflux.