Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: synthesis, biological evaluation, and molecular docking study

Figures & data

Figure 1. TP and 2dR1P roles in tumour development.

Figure 2. Schematic representation of the pyridimidinedione binding site of hTP and chemical structures of 7-DX and TPI.

Figure 3. General structures of the designed derivatives in series A–D.

Table 1. Synthesis of the pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones 2.

Compound	R^5	R^6	R^7	R^8	R^9	Method	Reaction time (h)	Yield (%)
2a^a	H	H	CH3	H	H	D	72	45^b
2b^a	H	H	H	CH3	H	C	2	56^b
2c^a	H	H	H	H	CH3	A	1^e	25^d
2d^a	H	H	H	OCH3	H	C	2	70^b
2e	H	H	H	OPh	H	C	6	57^d
2f^a	H	H	H	OCH2Ph	H	C	8	66^b
2g^a	H	H	O–CH2–O		H	A	19	75^b
2h^a	H	OCH3	OCH3	OCH3	H	A	2	73^b
2i	H	H	H	CH2Ph	H	C	3	41^d
2j^a	H	H	H	Cl	H	A	100	50^b
2k^a	H	H	H	CF3	H	A	1^e	51^b
2l	H	H	Cl	Cl	H	A	5	17^b
2m^a	H			H	H	A	48	65^b
2n	H	H	H			A	20	32^b
2o	H	H	H			B	3	67^d
2p^a	CH3	H	H	OCH3	H	A	24	77^b
2q^a	CH3	H	O-CH2-O		H	A	4.5	44^b
2r^a	Ar^c	H	O-CH2-O		H	A	67	88^b

^aPreviously described compound²⁷. ^bYield of pure crude product. ^cAr = 3,4,5-trimethoxyphenyl. ^dYield of purified product. ^eIncomplete reaction.

Scheme 1. Synthesis of compound 2s.

Scheme 2. Synthesis of compound 10.

Scheme 3. Synthesis of compounds 13a, 13b, 16a, 16b, and 17.

Scheme 4. Synthesis of compounds 22 and 23a–c.

Scheme 5. Synthesis of compounds 28a–h and 30.

Table 2. Escherichia coli TP inhibition of series A derivatives.

Compound	Structure	TP inhibition (%) at 50 µM or at maximum solubility^a IC50 (µM)
2a		0% at 50 µM
2b		0% at 50 µM
2c		14% at 50 µM
2d		89% at 50 µM IC50 = 28 ± 1 µM
2e		30% at 50 µM^a
2f		0% at 50 µM^a
2g		0% at 15 µM^a
2h		0% at 15 µM^a
2i		30% at 50 µM^a
2j		0% at 50 µM^a
2k		0% at 50 µM
2l		71% at 50 µM IC50 = 42 ± 7 µM
2m		29% at 50 µM
2n		0% at 15 µM^a
2o		0% at 25 µM^a
2p		67% at 50 µM IC50 = 26 ± 3 µM
2q		0% at 50 µM
2r		0% at 25 µM^a
2s		0% at 15 µM^a
	7-DX	60% at 50 µM IC50 = 28 ± 6 µM

^aMaximum solubility.

Table 3. Escherichia coli TP inhibition of series B and C derivatives.

Compound	Structure	TP inhibition (%) at 50 µM or maximum solubility^a
13a		25% at 50 µM
13b		0% at 50 µM
16a		30% at 25 µM^a
16b		30% at 12.5 µM^a
22		25% at 15 µM^a
23a		0% at 50 µM
23b		30% at 50 µM^a
23c		0% at 50 µM
24		20% at 50 µM
	7-DX	60% at 50 µM IC50 = 28 ± 6 µM

^aMaximum solubility.

Table 4. Escherichia coli TP inhibition of series D derivatives.

Compound	Structure	TP inhibition (%) at 50 µM or maximum solubility^a
28a		44% at 50 µM IC50 = 62 ± 7 µM
28b		0% at 50 µM
28c		0% at 50 µM
28d		0% at 30µM^a
28e		0% at 50 µM
28f		0% at 50 µM
28g		0% at 30 µM^a
28h		0% at 50 µM
27		0% at 50 µM
30		31% at 50 µM IC50 = 87 ± 4 µM
	7-DX	60% at 50 µM IC50 = 28 ± 6 µM

^aMaximum solubility.

Figure 4. Docking superposition in the hTP active site of compounds 2d (in blue), 2e (in pink), 2i (in orange), and TPI (in green).

Figure 5. Docking superposition in the hTP active site of TPI (in green), compounds 16b (dark green cloud), and 23b (white cloud).

Figure 6. Docking superposition in the hTP active site of compounds 2i (in orange), 28a (in purple), and 30 (in blue).

Figure 7. Lineweaver–Burk plots of E. coli TP inhibition by 2d and 2p, in the presence of variable concentrations of thymidine demonstrating competitive-type enzyme inhibition. Results are presented as means ± SD; SD denoted by error bars (experiments carried out in triplicate).

Aknin K, Desbène-Finck S, Helissey P, Giorgi-Renault S. A new synthetic approach to functionalize pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones via a three-component one-pot reaction. Mol Divers 2010;14:123–30.

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