Aminoguanidine Hydrazone Derivatives: The Antioxidant, Antineoplastic Profile, and Interaction with ctDNA Studies

Guimarães, Ari S.; Oliveira, Woodland S.; Araújo, Aline R. S.; Foglio, Mary Ann; Aquino, Pedro G. V.; Araújo-Júnior, João X. de; Schmitt, Martine; Ruiz, Ana Lúcia T. G.; Figueiredo, Isis M.; Santos, Josué C. C.

doi:10.21577/0103-5053.20230177

Ari S. Guimarães

conceptualization

investigation

methodology

writing original draft

Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, 57072-970 Maceió-AL, Brazil

Woodland S. Oliveira

investigation

methodology

writing original draft

Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, 57072-970 Maceió-AL, Brazil

Aline R. S. Araújo

investigation

methodology

Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas, 13083-970 Campinas-SP, Brazil

Mary Ann Foglio

investigation

methodology

writing review

editing

Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas, 13083-970 Campinas-SP, Brazil

https://orcid.org/0000-0001-7715-4452

Pedro G. V. Aquino

formal analysis

investigation

methodology

validation

writing-original draft

review

editing

Universidade Federal do Agreste de Pernambuco, 55292-278 Garanhuns-PE, Brazil

João X. de Araújo-Júnior ^**e-mail: josue@iqb.ufal.brjoao.araujo@icf.ufal.br

formal analysis

funding acquisition

investigation

methodology

project administration

validation

writing-original draft

review

editing

Instituto de Ciências Farmacêuticas, Universidade Federal de Alagoas, 57072-900 Maceió-AL, Brazil

https://orcid.org/0000-0003-3187-183X

Martine Schmitt

formal analysis

investigation

methodology

project administration

supervision

writing-original draft

review

editing

Laboratoire d’Innovation Thérapeutique, UMR 7200, Université de Strasbourg, 60024-67401, Illkirch, France

Ana Lúcia T. G. Ruiz

investigation

methodology

writing original draft

Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), Universidade Estadual de Campinas, 13148-218 Paulínia-SP, Brazil

Isis M. Figueiredo

investigation

methodology

project administration

visualization

writing original draft

Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, 57072-970 Maceió-AL, Brazil

Josué C. C. Santos ^**e-mail: josue@iqb.ufal.brjoao.araujo@icf.ufal.br

conceptualization

formal analysis

project administration

supervision

visualization

writing-original draft

review

editing.

Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, 57072-970 Maceió-AL, Brazil

https://orcid.org/0000-0002-9525-5123

*e-mail: josue@iqb.ufal.br joao.araujo@icf.ufal.br

Editor handled this article: Hector Henrique F. Koolen (Associate)

Compound	Antioxidant capacity
	IC₅₀ / μM		FRAP (A₇₀₀, 10 mg mL^-1)	FRAP^a a Normalized absorbance (A700 per concentration in µM). Values are presented as mean ± standard deviation (n = 3). Values followed by different superscript letters (a-f) in the same column correspond to significant differences by Tukey’s test (p < 0.05). IC50: concentration required to reduce 50% of the radical species; FRAP: FeIII reduction assay; DPPH•: 2,2-diphenyl-2-picrylhydrazyl radical; ABTS•+: 2,2-azinobis(3-ethylbenzothiazoline-6‑sulfonic acid. (normalized)
	DPPH^·	ABTS^·+	FRAP (A₇₀₀, 10 mg mL^-1)
AGH-1	1160 ± 37^a a Normalized absorbance (A700 per concentration in µM). Values are presented as mean ± standard deviation (n = 3). Values followed by different superscript letters (a-f) in the same column correspond to significant differences by Tukey’s test (p < 0.05). IC50: concentration required to reduce 50% of the radical species; FRAP: FeIII reduction assay; DPPH•: 2,2-diphenyl-2-picrylhydrazyl radical; ABTS•+: 2,2-azinobis(3-ethylbenzothiazoline-6‑sulfonic acid.	33.4 ± 11.9^a,b	0.375 ± 0.050^a a Normalized absorbance (A700 per concentration in µM). Values are presented as mean ± standard deviation (n = 3). Values followed by different superscript letters (a-f) in the same column correspond to significant differences by Tukey’s test (p < 0.05). IC50: concentration required to reduce 50% of the radical species; FRAP: FeIII reduction assay; DPPH•: 2,2-diphenyl-2-picrylhydrazyl radical; ABTS•+: 2,2-azinobis(3-ethylbenzothiazoline-6‑sulfonic acid.	2.02 ± 0.27^a a Normalized absorbance (A700 per concentration in µM). Values are presented as mean ± standard deviation (n = 3). Values followed by different superscript letters (a-f) in the same column correspond to significant differences by Tukey’s test (p < 0.05). IC50: concentration required to reduce 50% of the radical species; FRAP: FeIII reduction assay; DPPH•: 2,2-diphenyl-2-picrylhydrazyl radical; ABTS•+: 2,2-azinobis(3-ethylbenzothiazoline-6‑sulfonic acid.
AGH-2	273 ± 3^b	47.3 ± 4.⁴c	0.367 ± 0.010^a a Normalized absorbance (A700 per concentration in µM). Values are presented as mean ± standard deviation (n = 3). Values followed by different superscript letters (a-f) in the same column correspond to significant differences by Tukey’s test (p < 0.05). IC50: concentration required to reduce 50% of the radical species; FRAP: FeIII reduction assay; DPPH•: 2,2-diphenyl-2-picrylhydrazyl radical; ABTS•+: 2,2-azinobis(3-ethylbenzothiazoline-6‑sulfonic acid.	1.83 ± 0.05^a a Normalized absorbance (A700 per concentration in µM). Values are presented as mean ± standard deviation (n = 3). Values followed by different superscript letters (a-f) in the same column correspond to significant differences by Tukey’s test (p < 0.05). IC50: concentration required to reduce 50% of the radical species; FRAP: FeIII reduction assay; DPPH•: 2,2-diphenyl-2-picrylhydrazyl radical; ABTS•+: 2,2-azinobis(3-ethylbenzothiazoline-6‑sulfonic acid.
AGH-3	48.9 ± 1.5^c	32.3 ± 3.⁴b	0.496 ± 0.010^b	2.62 ± 0.05^b
AGH-4	181.4 ± 0.4^d	124 ± 1^d	0.351 ± 0.030^a a Normalized absorbance (A700 per concentration in µM). Values are presented as mean ± standard deviation (n = 3). Values followed by different superscript letters (a-f) in the same column correspond to significant differences by Tukey’s test (p < 0.05). IC50: concentration required to reduce 50% of the radical species; FRAP: FeIII reduction assay; DPPH•: 2,2-diphenyl-2-picrylhydrazyl radical; ABTS•+: 2,2-azinobis(3-ethylbenzothiazoline-6‑sulfonic acid.	1.94 ± 0.05^a a Normalized absorbance (A700 per concentration in µM). Values are presented as mean ± standard deviation (n = 3). Values followed by different superscript letters (a-f) in the same column correspond to significant differences by Tukey’s test (p < 0.05). IC50: concentration required to reduce 50% of the radical species; FRAP: FeIII reduction assay; DPPH•: 2,2-diphenyl-2-picrylhydrazyl radical; ABTS•+: 2,2-azinobis(3-ethylbenzothiazoline-6‑sulfonic acid.
Gallic acid	15.3 ± 7.8^e	9.90 ± 5.82^a a Normalized absorbance (A700 per concentration in µM). Values are presented as mean ± standard deviation (n = 3). Values followed by different superscript letters (a-f) in the same column correspond to significant differences by Tukey’s test (p < 0.05). IC50: concentration required to reduce 50% of the radical species; FRAP: FeIII reduction assay; DPPH•: 2,2-diphenyl-2-picrylhydrazyl radical; ABTS•+: 2,2-azinobis(3-ethylbenzothiazoline-6‑sulfonic acid.	0.854 ± 0.020^c	2.91 ± 0.07^b,c
Trolox	66.3 ± 4.8^f	41.9 ± 2.0^b	0.515 ± 0.030^b	2.58 ± 0.02^b
Quercetin	19.2 ± 7.4^e	4.63 ± 3.28^a a Normalized absorbance (A700 per concentration in µM). Values are presented as mean ± standard deviation (n = 3). Values followed by different superscript letters (a-f) in the same column correspond to significant differences by Tukey’s test (p < 0.05). IC50: concentration required to reduce 50% of the radical species; FRAP: FeIII reduction assay; DPPH•: 2,2-diphenyl-2-picrylhydrazyl radical; ABTS•+: 2,2-azinobis(3-ethylbenzothiazoline-6‑sulfonic acid.	0.496 ± 0.030^b	2.99 ± 0.18^c
Caffeic acid	26.6 ± 4.2^e	21.1 ± 6.4^a,c	0.768 ± 0.010^d	2.77 ± 0.04^b,c

Parameter	AGH-1		AGH-2		AGH-3		AGH-4		Doxorubicin
Parameter	GI₅₀ / µM	SI	GI₅₀ / µM	SI	GI₅₀ / µM	SI	GI₅₀ / µM	SI	GI₅₀ / µM	SI
U251	> 900	n.c.	164.0	1.5	20.4	0.6	96.3	0.9	0.48	1.0
MCF-7	> 900	n.c.	239.0	1.0	30.7	0.4	99.8	0.9	0.31	1.5
NCI-ADR/RES	> 900	n.c.	90.9	2.8	85.3	0.1	94.3	1.0	0.57	0.8
786-0	> 900	n.c.	28.0	8.9	6.3	2.0	91.2	1.0	0.09	5.3
NCI-H460	> 900	n.c.	289.0	0.9	15.1	0.8	99.0	0.9	0.18	2.7
PC-3	> 900	n.c.	314.0	0.8	28.1	0.5	98.4	0.9	1.43	0.3
OVCAR-03	> 900	n.c.	59.8	4.2	11.0	1.2	92.0	1.0	1.99	0.2
HT-29	> 900	n.c.	273.0	0.9	13.5	0.9	96.2	0.9	2.21	0.2
K562	> 900	n.c.	191.0	1.3	16.0	0.8	113.0	0.8	0.69	0.7
Mean log(GI₅₀)	n.c.	n.c.	2.2	-	1.3	-	2.0	-	-0.2	-
HaCaT	> 900	-	250	-	12.7	-	90.1	-	0.48	-

[1] *e-mail: josue@iqb.ufal.br joao.araujo@icf.ufal.br

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Aminoguanidine Hydrazone Derivatives: The Antioxidant, Antineoplastic Profile, and Interaction with ctDNA Studies