Newer human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents

Figures & data

Figure 1. Currently used IMPDH inhibitor drugs.

Figure 2. Recently reported MPA analogues.

Scheme 1. General scheme for synthesis of mycophenolic acid amides (14–28): Reagents and conditions: Method A: DMAP, EDCI.HCl, DMF, 0 °C 6 h, RT, 48–72 h; Method B: DIPEA, HATU, DMF, 0 °C 6 h, RT, 48–72 h.

Figure 3. hIMPDH2 % inhibition of compounds 14–28.

Table 1. hIMPDH2 enzyme inhibition of MPA amides (14–28 at 10 µM).

Compound	R	hIMPDH2 enzyme
		% Inhibition^a	IC50 (µM) ± SD^b
1	Mycophenolic acid	99.90 ± 1.20	0.25 ± 0.03
14	(S)-(−)-α-Methylbenzyl	59.15 ± 1.91	n.d.^c
15	(R)-(+)-α-Methylbenzyl	73.94 ± 2.84	0.82 ± 0.32
16	2-Chlorobenzyl	72.04 ± 1.11	0.73 ± 0.06
17	2-Furfuryl	67.18 ± 4.16	n.d.^c
18	4-Methoxybenzyl	96.13 ± 2.51	0.33 ± 0.11
19	4-Methylbenzyl	73.42 ± 3.62	0.60 ± 0.13
20	4-Chlorobenzyl	81.36 ± 1.95	0.57 ± 0.11
21	4-Pyridylmethyl	57.38 ± 1.02	n.d.^c
22	2-Pyridylmethyl	59.38 ± 1.81	n.d.^c
23	2-Methylbenzyl	84.00 ± 2.13	0.50 ± 0.18
24	4-Phenylbutyl	93.62 ± 3.17	0.48 ± 0.02
25	3,4-(Methylenedioxy)benzyl	87.09 ± 4.54	0.51 ± 0.08
26	2-Morpholinoethyl	36.05 ± 3.86	n.d.^c
27	3-Methoxyphenyl	30.82 ± 2.82	n.d.^c
28	4-Methoxyphenyl	54.84 ± 1.15	n.d.^c

^aAll the data are expressed as ± SD (results are average of duplicate analysis).

^bAll the data are expressed as ± SD (results are average of triplicate analysis). IC₅₀ value was determined when the inhibitory rate of compound is higher than 70% at the concentration of 10 µM.

^cn.d.: not determined.

Figure 4. Cytotoxicity of MPA amide derivatives.

Table 2. Cytotoxicity of MPA amide derivatives

S. No.	Compound	Cell lines [IC50 (μM) ± SD^a]
		MDA-MB-231^b	DU145^c	U87 MG^d
1	Cisplatin	50.40 ± 1.1	34.47 ± 0.78	21.32 ± 0.39
2	Doxorubicin HCl	0.54 ± 0.08	0.21 ± 0.06	0.11 ± 0.02
3	MPA (1)	4.38 ± 0.06	2.94 ± 0.09	10.69 ± 0.21
4	18	2.42 ± 0.11	1.8 ± 0.07	5.26 ± 0.18
5	20	4.10 ± 0.23	2.69 ± 0.11	7.31 ± 0.17
6	23	0.77 ± 0.04	1.28 ± 0.04	4.66 ± 0.07
7	24	1.46 ± 0.07	1.09 ± 0.02	3.35 ± 0.09
8	25	1.86 ± 0.16	2.53 ± 0.15	8.16 ± 0.27

^aAll the data are expressed as ± SD (results are average of triplicate analysis).

^bMDA-MB-231 (breast adenocarcinoma).

^cDU145 (prostate carcinoma).

^dU87 MG (glioblastoma astrocytoma).

Bold values indicate the most potent molecule in each cell line.