Table 1 Synthetic derivatives acting against different breast cancer cell lines

Synthetic azidothymidine (AZT) derivatives containing tellurium (Te)

MDA-MB-231

7 m: 24.95 ± 6.05 µM (24 h), 11.76 ± 2.97 µM (48 h)

7r: 21.61 ± 2.44 µM (24 h), 9.62 ± 1.35 µM (48 h)

Decreased cell proliferation rate, and promotion of cell cycle arrest in the S phase

[59]

Synthetic

α-Methylene-δ-Lactones

Hormone-independent MDA-MB-231, hormone-dependent MCF-7

DL-1: 11.4 ± 2.10 µM (MDA-MB-231), 8.17 ± 0.58 µM (MCF-7)

DL-2: 15.1 ± 1.82 µM (MDA-MB-231), 12.67 ± 0.29 µM (MCF-7)

DL-3: 5.3 ± 0.69 µM (MDA-MB-231), 3.54 ± 0.76 µM (MCF-7)

DL-4: 7.9 ± 0.99 µM (MDA-MB-231), 4.75 ± 1.09 µM (MCF-7)

The activated intrinsic pathway of apoptosis by loss of mitochondrial membrane potential, and change in Bax/Bcl-2 ratio, the inhibited movement of both types of cancer cells, suppressed cell migration and invasion due to decreased secretion of enzymes that cause degradation of cellular matrix, MMP-9, and uPA

[37]

Piperidinyl-diethylstilbestrol, Pyrrolidinyl-diethylstilbestrol

MCF-7

Piperidinyl diethylstilbestrol: 19.7 ± 0.95 μg/mL (LC50, in vitro), 7.9 ± 0.38 μg/mL (ED50, in vivo)

Pyrrolidinyl diethylstilbestrol: 17.6 ± 0.4 μg/mL (LC50, in vitro), 15.6 ± 1.3 μg/mL (ED50, in vivo)

Exhibited toxicity and cytotoxicity of synthetic compounds on shrimp larvae, and cell culture, inhibited G0/G1-phase of the MCF-7 cell cycle

[36]

A synthetic curcuminoid, (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (DK1)

MCF-7 and compared with MDA-MB-231 and MCF-10

24 h: 96.83 ± 4.87 µM (MCF-7), 104.17 ± 5.23 µM (MDA-MB-231), > 208 µM (MCF-10)

48 h: 33.33 ± 3.50 µM for MCF-7, 45.83 ± 4.66 µM (MDA-MB-231), 125.38 ± 3.67 µM (MCF-10)

72 h: 25 ± 3.71 µM (MCF-7), 37.50 ± 4.82 µM (MDA-MB-231), 104.17 ± 5.21 µM (MCF-10)

Induced cytotoxicity against MCF-7 breast cancer cells, induced p53 mediated apoptosis through ROS induction, and inhibition of GSH, induced G2/M cell cycle arrest through up-regulating p21, and down-regulating PLK-1

[38]

Synthetic antiestrogen 4-hydroxytamoxifen (OH-Tam), antiprogestin 17β-hydroxy-11β-(4-methylaminophenyl)-17-(1-propynyl)estra-4,9-dien-3-one-6–7 (RU486)

MCF-7, MDA-MB-231, BT20

A triggered third type of receptor-mediated cytotoxicity by antiestrogens. Similar activity was seen for antiprogestin indicating anti-hormone, and antiproliferative effect

[67]

Synthetic Vit-E supplement, dl-α-tocopherol

MDA-MB-231

Not mentioned

Reduced lipid peroxidation results in suppressed tumor growth. Stabilized membrane fatty acids in the acyl chain show antitumor activity

[40]

Synthetic isoflavones (1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

Hormone-independent MDA-MB-231, hormone-dependent MCF-7

1: 11.1 ± 5.0 µM

2: 8.2 ± 2.0 µM

5: 0.04 ± 0.01 µM

6: 6.3 ± 1.0 µM

7: 2.1 ± 0.4 µM

9: 1.8 ± 0.6 µM

10: 2.9 ± 0.2 µM

Activated mechanism of celldeath and affected breast cancer cell survival by acting on multiple signaling pathways

[41]

Synthetic caffeic acid phenethyl ester (CAPE) isolated from propolis

MCF-7

Incorporation of [3H] thymidine into the DNA of human breast carcinoma MCF-7 is 50% inhibited at 5 μg/mL CAPE

Inhibited incorporation of [3H] thymidine into carcinoma cell results in cytotoxic activity

[66]

Synthetic derivatives of benzochromene, 4a, 4b, 4c, 4d, 4e

MCF-7, MDA-MB-231, T-47D

4a: 9.9 ± 0.57 μM (MCF-7), 11.7 ± 1.8 μM (MDA-MB-231), 6.9 ± 0.65 μM (T-47D)

4b: 10.3 ± 0.58 μM (MCF-7), 6.1 ± 2.3 μM (MDA-MB-231), 5.3 ± 0.66 μM (T-47D)

4c: 9.3 ± 0.61 μM (MCF-7), 6 ± 0.7 μM (MDA-MB-231), 8.7 ± 0.55 μM (T-47D)

4d: 11.07 ± 0.87 μM (MCF-7), 18.1 ± 1.8 μM (MDA-MB-231), 6.9 ± 0.67 μM (T-47D)

4e: 11.6 ± 0.44 μM (MCF-7), 21.5 ± 1.8 μM (MDA-MB-231), 4.6 ± 0.068 μM (T-47D)

Increased ROS and NO production through direct modification of proteins, lipids, and DNA that induces apoptosis in cancer cell lines

[39]

Synthetic oleanolic acid derivative, Methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate (HIMOXOL)

MDA-MB-231

24 h: 21.08 ± 0.24 μM

72 h: 7.33 ± 0.79 μM

Increased apoptotic pathway via activation of caspase-8, caspase-3, and PARP-1 protein, increased ratio of Bax/Bcl-2 protein level, triggered microtubule-associated protein LC3-II expression, and upregulated bectin 1

[62]

Four groups of synthetic derivatives of isoliquiritigenin analogues including, hydroxy-substituted chalcones (2a-2f), chalcones substituted with methoxy group (3a-3 l), flavanones (4a-4b), dihydro-chalcones (5a-5c)

MCF-7, MDA-MB-231

IC50 < 10 μM are shown

3c: 1.5 ± 0.18 μM (MCF-7), 7.9 ± 1.0 μM (MDA-MB-231)

3d: 3.1 ± 0.65 μM (MCF-7), > 10 μM (MDA-MB-231)

3f: > 10 μM (MCF-7), 6.6 ± 0.75 μM (MDA-MB-231)

3 g: > 10 μM (MCF-7), 7.4 ± 1.16 μM (MDA-MB-231)

3 h: 0.71 ± 0.17 μM (MCF-7), 6.5 ± 0.83 μM (MDA-MB-231)

3 l: 7.0 ± 1.54 μM (MCF-7), > 10 μM (MDA-MB-231)

The second group showed antitumor activity. Methylated hydroxyl groups in chalcones escalated the cytotoxic activity

[68]

Synthetic genistein glycosides, G15, G16, G17, G21, G23, G24, G26, G30, G31

MCF-7

LC50 values:

G15: 34 μM

G21: 45 μM

G23: 32 μM

G24: 43 μM

G26: 63 μM

G30: 51 μM

G31: 67 μM

Increased lipophilicity, acetylated sugar hydroxyls, directedly bound double CC bond in sugar to aglycone, α configured genistein-sugar glycoside bond, localized sugar substituent at the 7-OH position in genistein molecule contributes to the cytostatic/ cytotoxic activity

[69]

Synthetic conjugates of genistein, Ram-3 (8b)

MCF-7, SKBR-3

Ram-3: 8.88 ± 0.75 μM (MCF-7)

28.02 ± 6.89 μM (SKBR-3)

Inhibited cellcycle, interaction with mitotic spindles, and apoptotic cell death leads to cancer cell anti-proliferative activity

[70]

Synthetic flavagline, 3 (FL3)

MCF-7

FL3: 1 μM

Induced cancer cell death via activation of the apoptosis-inducing factor and caspase-12 pathway

[71]

Synthetic peptides derived from Bovine lactoferricin sequences, LfcinB (20–25): 20RRWQWR25, LfcinB (20–30): 20RRWQWRMKKLG30, and [Ala19]-LfcinB (17–31): 17FKARRWQWRMKKLGA31 containing (i) a linear; (ii) a dimeric; (iii) a cyclic; (iv) a tetrameric peptide

MDA-MB-468, MDA-Mb-231

Only tetrameric and dimeric peptides showed cytotoxicity against both cancer cells

LfcinB (20–25)4: 6 μM (MDA-MB-468), 15 μM (MDA-Mb-231)

LfcinB (20–30)2: 5 μM (MDA-MB-468), 14 μM (MDA-Mb-231)

LfcinB (20–30)4: 2 μM (MDA-MB-468), 6 μM (MDA-Mb-231)

[Ala19]-LfcinB (17–31)2: 11 μM (MDA-MB-468), 31 μM (MDA-Mb-231)

[Ala19]-LfcinB (17–31)4: 5 μM (MDA-MB-468), 9 μM (MDA-Mb-231)

Not mentioned

[72]

Synthetic 3-isopropyl-2-methyl-4-methyleneisoxazolidin-5-one (MZ-6)

MCF-7, MDA-MB-231

MZ-6: 7.25 μM (MCF-7)

6.5 μM (MDA-MB-231)

Inhibited incorporation of [3H]thymidine dose-dependently, up-regulated Bax, and down-regulated Bcl-2 mRNA, elevated end products of lipid peroxidation, malondialdehyde results in apoptosis and cell-cycle arrest in G0/G1 phase

[65]

Synthetic diterpene 1, 2

MCF-7, NCI/ADR/RES, MDA-MB-231, HS 578 T, MDA-MB-435, BT-549, T-47D

1: > 100 μMC50 for all cell-lines

2: 26.6 μM (MCF-7)

28.3 μM (NCI/ADR/RES)

34.6 μM (MDA-MB-231)

 > 50.0 μM (HS 578 T)

37.7 μM (MDA-MB-435)

 > 50.0 μM (BT-549)

39.7 μM (T-47D)

Inhibited cancer cell proliferation results in cytostatic activity

[73]

Synthetic derivatives of novel N-substituted bis-benzimidazole, 9a, 9b, 9c, 9d, 9e, 9f, 9 g, 9 h, 9i

MCF-7, MDA-MB-453

9c: 52.09 µg/mL(MCF-7), 55.89 µg/mL (MDA-MB-453)

9 g: > 100 µg/mL (MCF-7), > 100 µg/mL (MDA-MB-453)

9i: > 100 µg/mL (MCF-7), > 100 µg/mL (MDA-MB-453)

Well-documented apoptosis or programmed cell death is the key mechanism to exert cytotoxicity

[74]

Synthetic ( ±)-kusunokinin and its derivative ( ±)-bursehernin

MCF-7, MDA-MB-468, MDA-MB-231

( ±)-kusunokinin: 4.30 ± 0.65 μM (MCF-7), 5.90 ± 0.44 μM (MDA-MB-468), 7.57 ± 0.92 μM (MDA-MB-231)

( ±)-bursehernin: 11.96 ± 0.62 μM (MCF-7), 8.24 ± 0.08 μM (MDA-MB-468), 14.26 ± 0.61 μM (MDA-MB-231)

Suppressed STAT3 and topoisomerase II including cell-cycle arrest and apoptosis through multi-caspase activity including caspase-1, -3, -4, -5, -6, -7, -8, and -9

[75]

Synthetic ginsenoside-M1 (5) and synthetic three novel mono-esters ginsenoside-DM1 (6), PM1 (7), and SM1 (8)

MCF-7

M1 (5): 8.48 μg/mL

DM1 (6): 0.50 μg/mL

PM1 (7): 2.31 μg/mL

SM1 (8): 1.65 μg/mL

Inhibited cell proliferation and induced apoptosis lead to cytotoxic activity

[76]

A synthetic derivative of ursolic acid, FZU3010

SUM149PT, HCC1937

4–6 μM

Induced cell-cycle arrest at S and G0/G1 phase show apoptotic activity

[77]

Synthetic derivatives of novel ursolic acid containing an acyl piperazine moiety, 4b, 4c, 4d, and 4 k

Bcap-37

4b: 9.24 ± 0.53 μM

4c: 4.32 ± 0.42 μM

4d: 7.26 ± 0.46 μM

4 k: 5.34 ± 0.41 μM

Incorporated acyl piperazine moiety at C-28 while maintaining the polar group at C-3 effectively improves the antitumor activity of the compounds

[78]

Synthetic derivatives of hexahydrobenzo [g]chromen-4-one, (7a-7 k)

MCF-7, MDA-MB-231, T-47D

Lowest values for each cell-line are shown below:

(MCF-7):

7e: 3.1 ± 0.8 μg/mL

7 g: 3.3 ± 0.1 μg/mL

(MDA-MB-231):

7 h: 2.4 ± 0.6 μg/mL

7e: 2.5 ± 0.8 μg/mL

(T-47D):

7 h: 1.8 ± 0.6 μg/mL

7 g: 2.9 ± 0.9 μg/mL

Induced apoptosis, increased ROS, and NO production

[42]

Synthetic derivatives of 2-aryl-3-nitro-2H-chromene, (4a-4u)

MCF-7, T-47D, MDA-MB-231

MCF-7:

4 l: 0.2 ± 0 μM

4 h: 1.6 ± 0.2 μM

T-47D:

4c: 2.1 ± 0.9 μM

MDA-MB-231:

4b: 0.4 ± 0.2 μM

4 m: 0.5 ± 0.2 μM

Induced apoptosis by the unsubstituted and 8-methoxylated chromene series

[43]

Synthetic derivatives of boldine, (2–4)

MCF-7, MDA-MB-231

2: > 100 μM for both cell-lines

3: 96.4 ± 14.2 μM

(MCF-7), 100.2 ± 9.5 μM (MDA-MB-231)

4: 64.8 ± 4.2 μM

(MCF-7), 70.2 ± 5.7 μM (MDA-MB-231)

Inhibited cancer cell growth

[79]

Synthetic gallic acid-based indole derivatives, (2a, 3a, 3b, 3c, 3d, 3e, 3f, 7a)

MCF-7

3e: 19.2 ± 1.1 μM

3f: 13.3 ± 0.9 μM

Observed a limited degree of agreement between cytotoxic and antioxidant activity. Position of imine link and different substituents on indole moiety contributes to the cell cytotoxicity

[80]

Synthetic steroid derivatives, (8, 12, 17, 20, 22c, 24c, 30a, and 30b)

MCF-7

8: 7.5 μM

17: 2.5 μM

20: 4.7 μM

22c: 7.3 μM

Result for 48 h incubation

Decreased breast cancer-related geneexpression (VEGF, CYP19, and hAP-2γ)

[81]

Synthetic β-nitrostyrene derivative, CYT-Rx20

MCF-7, MDA-MB-231, ZR75-1

CYt-Rx20: 0.81 ± 0.04 μg/mL (MCF-7)

1.82 ± 0.05 μg/mL (MDA-MB-231)

1.12 ± 0.06 μg/mL (ZR75-1)

Arrested cancer cells at the G2/M phase, decreased cell viability by activating caspase cascade, increased PARP cleavage, and γ-H2AX expression, induced autophagy by upregulation of Bectin-1, ATG5, LC-3, and formation of ROS results in cell death

[63]

Synthetic derivatives of thiazolidin-based resveratrol, (3–14)

MCF-7, SKBR-3

9: 2.58 μM (MCF-7)

10: 5 μM (MCF-7)

12: 0.81 μM (SKBR-3)

13: 0.25 μM (SKBR-3)

14: 0.23 μM (SKBR-3)

Interfered ERα -dependent pathway of ER-positive MCF-7 cells by 9–10 compounds and antagonized GPER-dependent pathway of ER-negative and GPER positive SKBR-3 cells by 12–14 compounds (under investigation)

[82]

Synthetic derivatives of (1,3)dioxolo[4,5-g]chromen-8-one, (4a–4e)

MCF-7, T-47D, MDA-MB-231

4a: 6.2 ± 0.1 μg/mL (MCF-7)

4.6 ± 0.1 μg/mL (T-47D)

9.3 ± 2.1 μg/mL (MDA-MB-231)

4b: 5.7 ± 0.007 μg/mL (T-47D)

Induced apoptosis in the cancer cell lines

[44]