. 2020 Oct 5;12(10):2863. doi: 10.3390/cancers12102863

Table 1.

Copper complexes inhibitors of topoisomerases: targeted top isoforms, cancer cell lines responses, and molecular mechanisms are summarized. * Tests were realized in vitro with human Top1 or Top2α/β unless specified. IC50: half-maximal inhibitory concentration. EC50: half-maximal effective concentration. GI50: half-average of growth inhibition.

Ligand Class of Cu-C	Compound Number	Targeted Top(s)	Inhibition of DNA Relaxation Total (µM) (minimal (µM))	Inhibition Mecanism	Cancer Cell Lines	IC50 (µM)	Cell Cycle Arrest	Cell Death Type	Other Specificity	Reference Number
Oxindolimine	1	Top1	50 (25)	Fixation in the DNA Top1 binding site	Neuroblastoma SH-SY5Y Promonocytic U937		G2/M arrest	Apoptosis	ROS induction	[70,71,72,73]
Oxindolimine	1	Top1	50 (25)	Fixation in the DNA Top1 binding site	Neuroblastoma SH-SY5Y Promonocytic U937
Hydrazone with triphenylphosphonium	2	Top1	40	DNA Binding	Lung A549	4.2 ± 0.8				[74]
Hydrazone with triphenylphosphonium	2	Top1	40	Enzyme complex formation	Prostatic PC-3	3.2 ± 0.2
Plumbagin	3	Top1	1.56	DNA intercalation	Breast MCF-7	3.2 ± 1.1				[75]
					Colon HCT116	5.9 ± 1.4
					Hepatoma BEL7404	12.9 ± 3.6
					Hepatoma HepG2	9.0 ± 0.7
					Kidney 786-O	2.5 ± 0.9
					Lung NCI-H460	2.0 ± 1.2
					Nasopharyngeal cancer CNE2	11.8 ± 5.9
Phenanthroline with amino acids	4	Top1	50	DNA intercalation	Nasopharyngeal cancer HK1	2.2–5.2		Apoptosis		[76]
Phenanthroline with amino acids	4		(10)
Pyrophosphate	5	Top1	500	DNA interaction	Ovarian A2780/AD	0.64 ± 0.12				[77]
Heterobimetallic Cu(II)-Sn2(IV) phenanthroline	6	Top1	20	DNA intercalation	Breast Zr-75–1					[78]
				cleavage	Cervix SiHa
					Colon HCT15, SW620	<10 (GI50)
					Kidney 786-O, A498
					Lung Hop-62, A569
					Pancreatic MIA PaCa-2
					Neuroblastoma SH-SY5Y	2–8		Apoptosis		[79]
Analogs										[80]
Tridentate chiral Schiff base	7, 8	Top1	25	DNA binding	Hepatoma HuH7	25			ROS	[81,82]
			(15)	major groove	Hepatoma HepG2	6.2 ± 10			Cytokine TGFb
									mRNA upregulation
Salicylidene	9	Top1	(E. coli) *	DNA binding	Prostatic PC-3	7.3 ± 0.2			antimetastasis	[83]
				DNA cleavage	Breast MCF7	51.1 ± 1.6				[84]
					Colon HT29	16.6 ± 0.6
					Hepatoma HepG2	2.3 ± 0.1
					Lung A549	16.8 ± 1.0
					Ovary A2780	14.6 ± 0.2
					Prostatic LNCaP	25.4 ± 0.8
Chalcone-derived Thiosemicarbazone	10	Top1	3	DNA binding	Breast MCF-7	0.16 ± 0.06				[85]
			(0.75)	DNA cleavage	Leukemia THP-1	0.20 ± 0.06
				Religation inhibition
Pyridyl-substituted tetrazolopyrimidie	11	Top1	(Molecular docking) *	DNA binding	Cervix HeLa	0.565 ± 0.01		Apoptosis	CDK receptor	[86]
			(Molecular docking) *	groove mode	Colon HCT-15	0.358			binding
					Lung A549	0.733
Tetrazolopyrimidine Diimine		Top1	102 ± 1.1	DNA binding	Cervical HeLa	0.620 ± 0.0013		Apoptosis	vEGF receptor	[87]
				groove mode	Colon HCT-15	0.540 ± 0.00015			binding
					Lung A549	0.120 ± 0.002
Piperazine	12	Top1	12.5	DNA binding					SOD mimic	[88]
Piperazine	12		(5)	minor groove
Elesclomol	13	Top1	50	Poison	Erythroleukemic K562	0.0075		Apoptosis	Copper chelator	[89]
								Necrosis	Not a substrat for
								Oxidative stress	ABC transporters
Cu(SBCM)2	14	Top1	* (Molecular	DNA intercalation	Breast MCF7	27	G2/M arrest	Apoptosis	p53 increase	[90]
Cu(SBCM)2	14		docking)	DNA binding	Breast MDA-MB-231	18.7 ± 3.1			No ROS	[91]
TSC and TSC CuC										[92,93,94,95,96,97]
Pyridine-TSC	15	Top2a	50		Breast MDA-MB-231	1.01				[98]
			(10)		Breast MCF7	0.0558
			50	ATP hydrolysis inhibition						[99]
		Top2β	(5)	ATP hydrolysis inhibition						[100]
Piperazine-TSC	16	Top2a	0.9 ± 0.7	Potentially catalytic	Breast MCF7	4.7 ± 0.3				[101,102]
Piperazine-TSC	16				Breast SK-BR-3	1.3 ± 0.3				[99]
Thiazole-TSC	17	Top2a	4		Breast MDA-MB-231	1.41 (EC50)				[103]
	17		(2)		Breast MCF7	0.13 (EC50)
	17–18	Top2a	25	ATP hydrolysis inhibition	Breast					[104,105]
			(10)	+ Poison	HCC 70, HCC 1395,	1 to 20
					HCC 1500, and HCC 1806
					Colon	0.83 to 41.2
					Caco-2, HCT-116 and HT-29
L- and D-Proline-TSC	19	Top2a	300		Ovarian carcinoma CH1	113 ± 16				[106]
Quinoline-TSC	20	Top2a	0.48	Potentially catalytic	Lymphoma U937	0.48-16.2				[107]
Naphthoquinone-TSC	21	Top2α	1 mM		Breast MCF7	3.98 ± 1.01		No apoptosis		[108]
Bis-TSC	22	Top2a	100	Poison	Breast MDA-MB-231	1.45 ± 0.07	G2/M arrest	Apoptosis	DNA synthesis	[109]
			(5)		Colon HCT116	1.23 ± 0.27			inhibition
					Keratinocyte HaCaT	0.65 ± 0.07			No ROS
					Colon HCT116	Delayed mice xenograft
Carbohydrazone	23	Top2α	250	DNA binding	Breast MCF7	9.916		Apoptosis		[110]
			(25)	major groove	Breast MDA-MB-231	7.557
					Breast HCC 1937	3.278
					Breast MX1	4.534
					Breast MDA-MB-436	5.249
					Breast MX-1	Reducted mice xenograft (83%)
Chromone	24	Top2a	25	DNA binding	Breast MCF7	18.6 (GI 50)				[111]
			(15)	major groove	Breast Zr-75-1	25.2 (GI 50)
					Colon HT29	>80 (GI 50)
					Cervix SiHa	34.6 (GI 50)
					Kidney A498	73.3 (GI 50)
					Lung A549	31.7 (GI 50)
					Ovary A2780	17.4 (GI 50)
Quinolinone Shiff Base	25	Top2α	9	No intercalation	Hepatic HepG2	17.9 ± 3.8			DNA synthesis	[112]
									inhibition
									Slight substrate
									for ABC transporter
Bis-pyrazolyl Carboxylate	26	Dual Top1/Top2	(Molecular docking) *	ATP entry (potentially)	Hepatic HepG2	3.3 ± 0.02		Apoptosis	DNA replication	[113]
Bis-pyrazolyl Carboxylate	26	Dual Top1/Top2	(Molecular docking) *	DNA religation inhibition (potentially)					ROS