Estrogen alpha receptor antagonists for the treatment of breast cancer: a review

Abstract

Background: Cancer is at present one of the leading causes of death in the world. It accounts for 13% of deaths occurred worldwide and is continuously rising, with an estimated million of deaths up to 2030. Due to poor availability of prevention, diagnosis and treatment of breast cancer, the rate of mortality is at alarming level globally. In women, hormone-dependent estrogen receptor positive (ER+) breast cancer making up approximately 75% of all breast cancers. Hence, it has drawn the extensive attention of researchers towards the development of effective drugs for the treatment of hormone-dependent breast cancer. Estrogen, a female sex hormone has a vital role in the initiation and progression of breast malignancy. Therefore, estrogen receptor is the central target for the treatment of breast cancer.

Conclusion: In this review, we have studied various classes of antiestrogens that have been designed and synthesized with selective binding for estrogen alpha receptor (ER). Since estrogen receptor α is mainly responsible for the breast cancer initiation and progression, therefore there is need of promising strategies for the design and synthesis of new therapeutic ligands which selectively bind to estrogen alpha receptor and inhibit estrogen dependent proliferative activity.

Keywords: Antiestrogens; Breast cancer; Estrogen receptor alpha; Molecular docking; Relative binding affinity.

Fig. 1

Role of estrogen alpha receptor and estrogen alpha receptor antagonists (tamoxifen, fulvestant, letrozole and anastrozole) in breast cancer

Fig. 2

Marketed drugs for breast cancer

Fig. 3

Molecular structures of compounds (1–10)

Fig. 4

Pictorial presentation of interaction of compound 1 and tamoxifen with ER alpha

Fig. 5

Structure activity relationship study of compound 2

Fig. 6

Pictorial presentation of best conformation of compounds 3–5

Fig. 7

Docking model of compound 8

Fig. 8

Pictorial presentation of compound 10

Fig. 9

Molecular structures of compounds (11–19)

Fig. 10

Structure activity relationship study of compound 12

Fig. 11

Pictorial presemtation of compound 12

Fig. 12

Pictoial presentation of compound 13 and 14

Fig. 13

Structure activity relationship study of compound 13 and 14

Fig. 14

Superimposition of docking model of compound 2PJL ligand (cyan) and compound 15 (reddish brown) was docked into ERRα crystal structure. Dotted yellow lines shows hydrogen binding interactions

Fig. 15

Visual presentation of compound 16 and 17 with receptor ER α. Dotted red lines show the hydrogen bond formation

Fig. 16

Pictorial presentation of compounds 18 (a, b) and reservatol

Fig. 17

Pictorial pesentation of compound 19

Fig. 18

Molecular structures of compounds (20–25)

Fig. 19

Pictorial presentation of compound 23 and 24

Fig. 20

Molecular structures of compounds (26–37)

Fig. 21

Pictorial presentation of compound 26

Fig. 22

Pictorial presentation f compound 27 (a, b)

Fig. 23

Pictorial presentation of compound 28 in ER alpha (a) and tamoxifen in ER alpha (b)

Fig. 24

Pictorial presentation of docked compound 31

Fig. 25

Structure activity relationship of compound 32

Fig. 26

Pictorial presentation of compounds 33–35

Fig. 27

Pictorial presentation of compound 36 and 37

Fig. 28

Molecular structures of compounds (38–46)

Fig. 29

Pictorial presentation of compound 38 and 39

Fig. 30

Pictorial presentation of compound 41

Fig. 31

Structure activity relationship study of compound 42

Fig. 32

Structure activity relationship study of compound 46

Fig. 33

Molecular structures of compounds (47–50)

Fig. 34

Pictorial presentation and surface view of compound 47

Fig. 35

Top scoring binding pose of the most active substituted THIQ analogs at the active site of ERα-4-OHT complex (3ERT)

Fig. 36

Strcuture activity relationship study of compound 36

Fig. 37

Molecular structures of compounds (51–55)

Fig. 38

Molecular structures of compounds (56–57)

Fig. 39

Molecular structure of compound (58)

Fig. 40

Structure activity relationship study of organometallic compound 58