β-Lactam type molecular scaffolds for antiproliferative activity: Synthesis and cytotoxic effects in breast cancer cells

Figures & data

Figure 1 Structure of tamoxifen, raloxifene and related SERMs.

Scheme 1 Synthesis of β-lactams 12a–u. Scheme Reagents: (a) CH₃CH₂OCOCH₂Br, Zn, TMCS, Benzene, reflux, 6h. (b) aldehyde/ketone, LDA, THF, 78°C, 30min. (c) R₃R₄N-CH₂CH₂Cl, Acetone, reflux, 2 h.

Scheme 2 Synthesis of β-lactams 13a–e. Scheme Reagents: (a) pyridinium chlorochromate, CH₂Cl₂, 25°C

Table I.  Antiproliferative and cytotoxic effects of compounds 12a–l in MCF-7 cells..

Compound	R1	R2, R3	Activity MCF-7 cells IC50 (μM)^*	Cytotoxicity (% death) 10 μM
12a	H	R2 = R3 = CH3	>100 μM	0
12b	OCH3	R2 = R3 = CH3	25.20 ± 16.90	10
12c	H	R2, R3 = –CH2CH2CH2CH2–	15.40 ± 0.04	4
12d	OCH3	R2, R3 = –CH2CH2CH2CH2–	4.63 ± 1.24	14.8
12e	H	R2 = R3 = CH2CH3	15.9 ± 0.59	0
12f	OCH3	R2 = R3 = CH2CH3	23.9 ± 17.7	11.5
12g	H	R2, R3 = –CH2CH2CH2CH2CH2–	18.8 ± 12.9	6.9
12h	OCH3	R2, R3 = –CH2CH2CH2CH2CH2–	21.20 ± 9.41	5.6
12i	H	R2, R3 = –CH2CH2OCH2CH2–	14.40 ± 0.88	0
12j	OCH3	R2, R3 = –CH2CH2OCH2CH2–	34.10 ± 5.57	2.9
12k	H	–	13.46 ± 3.01	2
12l	OCH3	–	21.8 ± 12.3	7

^* IC₅₀ values are half maximal inhibitory concentrations required to block the growth stimulation of MCF-7 cells. Values represent the mean ± SEM (error values × 10^{− 6}) for three experiments performed in triplicate. The IC₅₀ value obtained for Tamoxifen is 2.48 ± 2.83 μM, with cytotoxiciy value 13.4% (10 μM) is in good agreement with the reported IC₅₀ value for tamoxifen using the MTT assay on human MCF-7 cells.

Table II.  Antiproliferative and cytotoxic effects of compounds 13a–e containing carbonyl at C-5 in MCF-7 cells.

Compound	Antiproliferative activity, MCF-7 cells, IC50 (μM)^*	Cytotoxicity % death, 10 μM
13a	20.50 ± 2.94	0
13b	3.95 ± 2.19	2
13c	37.25^†	0
13d	19.30 ± 6.75	14.7

^* IC₅₀ values are half maximal inhibitory concentrations required to block the growth stimulation of MCF-7 cells. Values represent the mean ± SEM (error values × 10^{− 6}) for three experiments performed in triplicate^† Results of single experiment performed in triplicate.

Table III.  Antiproliferative and cytotoxic effects of compounds 12m–u with modifications at the C-5 position in MCF-7 cells.

Compound	Position of substitution	R1	R2	Antiproliferative activity, MCF-7 cells, IC50 value (μM)^*	Cytotoxicity % death, 10 μM
12m	C-2	OCH3	H	10.70 ± 1.22	1
12n	C-3	OCH3	H	5.74 ± 3.80	1.2
12o	C-3	OCH3	CH3	7.91 ± 1.76	0
12p	C-4	OCH3	CH3	14.52 ± 1.24	5
12q	C-3	OCH3	C6H5	4.20 ± 4.33	7.5
12r	C-4	OCH3	C6H5	0.13 ± 0.07	3
12s	C-4	OCH3	CH3	5.25 ± 6.27	2
12t	C-2	OCH3	H	3.21 ± 2.42	7.5
12u	C-4	OCH3	H	5.51 ± 0.02	18

^* IC₅₀ values are half maximal inhibitory concentrations required to block the growth stimulation of MCF-7 cells. Values represent the mean ± SEM (error values × 10^{− 6}) for three experiments performed in triplicate.

Figure 2 Compound 12u inhibited proliferation and induced cytotoxicity of MCF-7 cells. Antiproliferative and cytotoxic activity of compounds 12u on oestrogen sensitive MCF-7 breast cancer cells, IC₅₀ = 5.51 μM. The optical density values are given as a ratio of the treated cells and control cells × 100% and are means of at least 9 replicates. The absence of error bars indicates that the error was smaller than the size of the symbol.

Figure 3 Docked structure for compound 12d in (a) ERα superposed with 4-hydroxytamoxifen (green) and (b) ERβ superposed with raloxifene (yellow).