Synthesis, Antitumor Activity and Docking of 2,3-(Substituted)-1,4-Naphthoquinone Derivatives Containing Nitrogen, Oxygen and Sulfur

Delarmelina, Maicon; Daltoé, Renata D.; Cerri, Murilo F.; Madeira, Klesia P.; Rangel, Leticia B. A.; Lacerda Júnior, Valdemar; Romão, Wanderson; Taranto, Alex G.; Greco, Sandro J.

doi:10.5935/0103-5053.20150157

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Articles • J. Braz. Chem. Soc. 26 (9) • Sept 2015 • https://doi.org/10.5935/0103-5053.20150157 copy

Synthesis, Antitumor Activity and Docking of 2,3-(Substituted)-1,4-Naphthoquinone Derivatives Containing Nitrogen, Oxygen and Sulfur

Authorship SCIMAGO INSTITUTIONS RANKINGS

Eleven 2,3-(substituted)-1,4-naphthoquinone derivatives were synthesized in yields ranging from 52-89%. These derivatives were evaluated for their cytotoxic effects on human lungs (H460), triple-negative breast (MDA-MB-231) and ovarian (A2780) cancer cell lines. Compounds 5f and 8 showed IC₅₀values of 3.048 × 10^-5 mol L^-1 and 4.24 × 10^-6 mol L^-1 for H460; 5c and 8showed IC₅₀ values of 2.16 × 10^-5 mol L^-1 and 1.60 × 10^-5 mol L^-1 for MDA-MB-231, and 5gand 8 showed IC50 values of 2.68 × 10^-6 mol L^-1 and 3.89 × 10^-6 mol L^-1 for A2780. Additionally, we conducted a docking study with the four most active compounds and the therapeutic targets PI3K and topoisomerase II showing the pharmacophoric conformation of these compounds.

Keywords:
1,4-naphthoquinone; antineoplastic activity; topoisomerase; PI3K; nucleophilic substitution

Entry No.	Solvent	Temperature / oC	time / h	Catalyst
1	CH₃OH	r.t.	1	not used
2	CH₃OH	r.t.	24	AgNO₃
3	CH₃OH	65	24	AgNO₃
4	C₂H₅OH	r.t.	24	AgNO₃
5	C₂H₅OH	78	24	AgNO₃
6	H₂O	r.t.	24	AgNO₃
7	H₂O	50	24	AgNO₃
8	CH₃OH/ H₂O	50	24	AgNO₃
9	C₂H₅OH / H₂O	50	24	AgNO₃
10	H₂O	r.t.	24	AlCl₃
11	H₂O	50	24	AlCl₃
12	(H₃C)₂CO	56	72	AlCl₃
13	H₃CCN	r.t.	24	AlCl₃
14	H₂O	50 oC	24	CeCl₃.7H₂O
15	H₃CCN	r.t.	12	CeCl₃/NaI
16	H₃CCN	82 °C	24	CeC_l3/NaI

Compound	IC₅₀ / mol L^-1
Compound	H460	MDA-MB-231	A2780
Cisplatin	8.586 × 10^-5	−^a a Routinely prescribed as chemotherapy agents;	4.01 × 10^-5
Etoposide	3.441 × 10^-5	−^a a Routinely prescribed as chemotherapy agents;	−^a a Routinely prescribed as chemotherapy agents;
Doxorubicine	−^a a Routinely prescribed as chemotherapy agents;	1.7 × 10^-4	−^a a Routinely prescribed as chemotherapy agents;
Paclitaxel	−^a a Routinely prescribed as chemotherapy agents;	1 × 10^-6	1.36 × 10^-5
5a	1.960 × 10^-4	−^b b no antiproliferative activity.	3.04 × 10^-4
5b	5.008 × 10^-4	8.6 × 10^-4	2.43 × 10^-4
5c	1.293 × 10^-4	2.13 × 10^-5	6.29 × 10^-5
5d	2.292 × 10^-4	6.08 × 10^-5	4.97 × 10^-5
5e	1.861 × 10^-4	1.1 × 10^-3	−^b b no antiproliferative activity.
5f	3.048 × 10^-5	1.3 × 10^-4	3.38 × 10^-5
5g	4.410 × 10^-5	4.28 × 10^-5	2.68 × 10^-6
6a	7.595 × 10^-4	9.4 × 10^-4	2.77 × 10^-5
6b	6.635 × 10^-4	7.8 × 10^-4	1.91 × 10^-5
6c	2.334 × 10^-4	−^b b no antiproliferative activity.	−^b b no antiproliferative activity.
8	4.24 × 10^-6	1.603 × 10^-5	3.89 × 10^-6

Compound	Interaction Energy / (kcal mol^-1)
Compound	PI3Kγ	Topoisomerase II
Wortmannim	−7.7	−
Dexrazone	−	−7.8
Etoposide	−	−8.1
5a	−7.7	−4.0
5b	−6.7	−6.9
5c	−6.5	−7.1
5d	−7.0	−6.6
5e	−7.0	−5.2
5f	−6.5	−4.8
5g	−6.1	−4.8
6a	−7.9	−5.0
6b	−6.8	−7.5
6c	−6.7	−7.8
8	−6.6	−7.2

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