Molecular modelling design, synthesis and cytotoxic evaluation of certain substituted 2-(3,4,5-triacetoxybenzoylamino)benzo[d]thiazole and 2-(galloylamino)benzo[d]thiazole derivatives having potential topoisomerase-I inhibitory activity

Figures & data

Figure 1.  Lead compounds of topoisomerase I inhibitors.

Table 1.  Simulation fitting scores of the designed triacetyl (4a-h and 4a-f) and the free hydroxyl derivatives (6a-h and 7a-f) with the generated ideal hypothesis of topoisomerase I inhibitors in comparison to the leads compounds; I-XII.

Triacetyl galloyl derivs.	Compare/fit values/3	No. of conform	Free hydroxyl derivs.	Compare/fit values/3	No. of conform
I lead	2.30	12
III lead	2.46	3
V lead	2.28	1
VII lead	2.27	2
IX Lead	2.90	9
XI Lead	2.30	12
4a	2.69	77	6a	0.67	5
4b	2.67	66	6b	0.67	3
4c	2.74	43	6c	0.68	9
4d	2.56	64	6d	0.75	10
4e	2.74	17	6e	910.	8
4f	2.73	61	6f	0.74	8
4g	2.68	74	6g	0.74	10
4h	2.79	90	6h	0.94	6
5a	2.57	44	7a	0.67	5
5b	2.65	48	7b	0.68	9
5c	2.65	75	7c	0.73	13
5d	2.71	18	7d	0.73	3
5e	2.69	68	7e	0.74	12
5f	2.78	41	7f	0.73	11

Table 2.  Docking energy and binding pattern of the docked triacetyl (4a-h and 5a-f) and the free hydroxyl derivatives (6a-h and 7a-f) with topo-I enzyme in comparison to the lead XI: (numbers of HB, numbers of Wan Der Wall attractions (pi-pi and sigma-pi) interactions and [pi-(+) interaction distance with Arg364 at the binding sites).

Comp. no.	No. of HB	No./kind of Van der Wall	Distances(Å) of pi-(+) interactions distances with Arg364	Docking energy (−)	Comp. no.	No. of HB	No./kind of Van der Walls	Distances(Å) pi-(+) interactions distances with Arg364	Docking energy (−)
XI	1 HB	8 pi-pi	6.95	44.41
4a	4 HB	6 pi-pi	4.41	58.89	6a	2 HB	5 pi-pi	5.70	42.46
4b	3HB	7 pi-pi	4.56	63.79	6b	3HB	6 pi-pi	5.69	45.10
4c	1 HB	7 pi-pi	4.42	64.65	6c	3 HB	5 pi-pi	5.11	42.06
4d	6 HB	7 pi-pi	4.38	66.42	6d	3 HB	5 pi-pi	5.76	42.42
4e	5 HB	7 pi-pi	4.46	64.58	6e	2 HB	5 pi-pi	5.67	42.23
4f	2 HB	9 pi-pi	4.88	63.15	6f	3 HB	6 pi-pi	5.91	43.57
4g	3 HB	11 pi-pi	4.49	63.58	6g	2 HB	5 pi-pi	5.65	43.25
4h	3 HB	6 pi-pi	4.71	66.05	6h	3 HB	6 pi-pi	5.81	39.31
5a	3 HB	7 pi-pi	4.71	62.42	7a	3 HB	5 pi-pi and 1 sigma-pi	5.67	44.14
5b	3 HB	6 pi-pi	4.52	66.05	7b	1 HB	5 pi-pi	5.98	40.54
5c	3 HB	7 pi-pi	4.52	67.14	7c	3 HB	4 pi-pi and 1 sigma-pi	5.69	43.29
5d	3 HB	10 pi-pi	4.09	62.34	7d	2 HB	5 pi-pi	5.48	42.42
5e	1 HB	9 pi-pi	4.48	62.00	7e	2 HB	6 pi-pi	5.80	43.68
5f	5 HB	7 pi-pi	4.49	67.55	7f	2 HB	6 pi-pi	5.67	42.18

Scheme 1.  Synthesis of the designed compounds (4a~7h). 

Figure 2.  Constraint distances in the ideal Hypothesis of Topoisomerase-I inhibitors. (HBA = Hydrogen bond acceptor feature, AR =Ring Aromatic vector feature).

Figure 3.  Constraint angles in the ideal hypothesis of topoisomerase-I inhibitors.

Figure 4.  Hypothesis no. 7 and the top fitted compound no. 5f (Fit value = 2.78/3).

Figure 5.  Hypothesis no. 7 and the top fitted compound no. 4h (Fit value = 2.79/3).

Figure 6.  Publication quality 3D diagram of the X-ray crystal structure of lead (XI)complexed with topoisomerase-I enzyme (redocked with RMSD = 0.0023) and Docking value = −44.41. The binding pattern showed: [1HB with Arg364 (as reported²⁷ and 8 lipophilic pi-pi interactions with the surrounded amino acids and DNA nucleotides, and a [ pi-(+)] interaction between it and Arg364 by distance = 6.95 Å.

Figure 7.  Publication quality of the top docked compound 5f with topoisomerase-I enzyme with Docking value = −67.55. The binding pattern showed: [5 HB with the surrounded amino acids and DNA nucleotides including Arg364 (as crucial SAR), 7 lipophilic pi-pi interactions with the surrounded amino acids and DNA nucleotides, and a [pi-(+)] interaction between it and Arg364 by distance =4.49 Å].

Figure 8.  Publication quality of the lowest docked compound 6b with topoisomerase-I enzyme with Docking value = −45.10. The binding pattern showed: [3HB with the surrounded amino acids and DNA nucleotides including Arg364 (as a crucial SAR), 6 lipophilic pi-pi interactions with the surrounded amino acids and DNA nucleotides, and a [ pi-(+)] interaction between it and Arg364 by distance =5.69 Å].

Table 3.  Effects of test set compounds (4a~7f) and the reference drugs (doxorubicin and camptothecin) toward the growth of human cervix carcinoma (Hela) and human breast carcinoma (MCF7) cell lines expressed in IC50 values, % Relative IC50 and numbers of folds of more activity than the given reference drugs.

Tested compds	IC50 (µM)		Cytotoxic activity evaluations towards Hela and MCF7 cell cultures in comparison to the reference drugs; doxorubicin^a and camptothecin^b
	Hela	MCF7	Hela	MCF7	Hela	MCF7
			% Relative IC50 to doxorubicin^a	% Relative IC50 to doxorubicin^a	% Relative IC50 to camptothecin^b	% Relative IC50 to camptothecin^b
Doxorubicin	0.016	0.017	100	100	–	–
Camptothecin	0.019	0.020	–	–	100	100
4a	0.078	0.065	20	26	24	31
4b	0.067	0.081	33	21	28	25
4c	0.072	0.030	22	56	26	67
4d	0.021	0.012	76	142 (=~1.4 folds)	90	167 (=~1.7 folds)
4e	0.051	0.018	31	94	37	111 (=~1.1 folds)
4f	0.057	0.045	28	38	33	44
4g	0.047	0.074	34	23	40	27
4h	0.025	0.015	64	113 (=~1.1 folds)	76	133 (=~1.3 folds)
5a	0.058	0.066	27	25	32	30
5b	0.015	0.016	106 (=~1.1 folds)	106 (=~1.1 folds)	126 (=~1.2 folds)	125 (=~1.2 folds)
5c	0.012	0.012	133 (=~1.3 folds)	141 (=~1.4 folds)	158 (=~1.6 folds)	167 (=~1.7 folds)
5d	0.020	0.022	80	77	95	90
5e	0.011	0.019	146 (=~1.5 folds)	89	172 (=~1.7 folds)	105 (=~1.1 folds)
5f	0.012	0.009	153 (=~1.5 folds)	189 (=1.9 folds)	158 (=~1.6 folds)	222 (=~2.2 folds)
6a	0.132	0.146	12	11	14	14
6b	0.122	0.097	13	17	15	20
6c	0.122	0.105	13	16	18	19
6d	0.063	0.185	25	9	30	10
6e	0.063	0.194	25	8	30	10
6f	0.041	0.115	39	14	46	17
6g	0.165	0.102	10	16	12	20
6h	0.184	0.157	8	10	10	13
7a	0.215	0.195	7	8	8	10
7b	0.168	0.185	10	9	11	11
7c	0.215	0.177	7	10	8	11
7d	0.150	0.119	11	14	12	17
7e	0.150	0.108	11	15	12	19
7f	0.180	0.130	9	13	14	15

^aA Break-Through comparative IC₅₀ values of test compounds with the selective topoisomerase-II inhibitor reference; doxorubicin.

^bA Me-Too comparative IC₅₀ values of test compounds with the selective topoisomerase-I inhibitor reference; camptothecin.

Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M. Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis. J Med Chem 2005;48:4803–4814.

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