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International Journal of Nanomedicine Volume 14, 2019 - Issue
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Original Research

BCESA: a nano-scaled intercalator capable of targeting tumor tissue and releasing anti-tumoral β-carboline-3-carboxylic acid

Jianhui Wu1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China;2 Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China
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Yue Cui1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China;2 Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China
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Xiaoyi Zhang1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China;2 Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China
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Lin Gui1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China;2 Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China
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Yaonan Wang1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China;2 Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China
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Shiqi Peng1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China;2 Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China
&
Ming Zhao1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China;2 Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing100069, People’s Republic of China;3 Beijing Laboratory of Biomedical Materials and Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing, People’s Republic of ChinaCorrespondence[email protected]
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Pages 3027-3041 | Published online: 30 Apr 2019

Figures & data

Figure 1 Pharmacophore analysis, CDOCKER energy comparison and docking feature resulted in a national design of BCESA.

Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; CEAB, N-(3-Benzyloxycarbonylcarboline-1-yl)ethylalanine benzylesters; CBCES, N-(9-Benzyl-3-carboxyl-β-carboline-1-yl)-ethyl-serine; CBCEA, N-(9-Benzyl-3-carboxyl-β-carboline-1-yl) ethyl-alanine; AWW, Tripeptide sequence AWW benzyl ester; WWS, Tripeptide sequence WWS benzyl ester.

Figure 1 Pharmacophore analysis, CDOCKER energy comparison and docking feature resulted in a national design of BCESA.Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; CEAB, N-(3-Benzyloxycarbonylcarboline-1-yl)ethylalanine benzylesters; CBCES, N-(9-Benzyl-3-carboxyl-β-carboline-1-yl)-ethyl-serine; CBCEA, N-(9-Benzyl-3-carboxyl-β-carboline-1-yl) ethyl-alanine; AWW, Tripeptide sequence AWW benzyl ester; WWS, Tripeptide sequence WWS benzyl ester.

Scheme 1 Synthetic route of BCESA. (i) TFA, 1,1,3,3-tetramethoxypropane, CH2Cl2; (ii) KMnO4, THF; (iii) HCl, HOAc, H2O; (iv) DCC, HOBt, NMM; (v) hydrogen chloride in EtOAc (4 M); (vi) NaBH3CN, MeOH, NaOH.

Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; DCC, dicyclohexylcarbodiimide; HOBt, N-hydroxybenzotriazole; NMM, N-methylmorpholine.

Scheme 1 Synthetic route of BCESA. (i) TFA, 1,1,3,3-tetramethoxypropane, CH2Cl2; (ii) KMnO4, THF; (iii) HCl, HOAc, H2O; (iv) DCC, HOBt, NMM; (v) hydrogen chloride in EtOAc (4 M); (vi) NaBH3CN, MeOH, NaOH.Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; DCC, dicyclohexylcarbodiimide; HOBt, N-hydroxybenzotriazole; NMM, N-methylmorpholine.

Figure 2 FT-MS and NOESY 2D1H NMR spectra of BCESA. (A) FT-MS spectrum of BCESA in ultrapure water (1 nM), the spectrum of the tetramer (2378.00696) is locally amplified and inserted; (B) qCID spectrum of BCESA in ultrapure water (1 nM); (C) NOESY 2D1HNMR spectrum of BCESA, in which an interesting cross-peak is marked with red ring; (D) Energy-minimized conformations of the monomer and the tetramer, in the impeller-like conformation of the tetramer the distance is locally amplified and inserted.

Abbreviation: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl.

Figure 2 FT-MS and NOESY 2D1H NMR spectra of BCESA. (A) FT-MS spectrum of BCESA in ultrapure water (1 nM), the spectrum of the tetramer (2378.00696) is locally amplified and inserted; (B) qCID spectrum of BCESA in ultrapure water (1 nM); (C) NOESY 2D1HNMR spectrum of BCESA, in which an interesting cross-peak is marked with red ring; (D) Energy-minimized conformations of the monomer and the tetramer, in the impeller-like conformation of the tetramer the distance is locally amplified and inserted.Abbreviation: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl.

Figure 3 Faraday-Tyndall effect, zeta potential and nano-size of BCESA in water or PBS. (A) Ultrapure water radiated by 650 nm laser; (B) BCESA dissolved in ultrapure water (pH 6.8, 10 μM) and radiated by 650 nm laser; (C) BCESA dissolved in ultrapure water (pH 6.8, 1 μM) and radiated by 650 nm laser; (D) BCESA dissolved in ultrapure water (pH 6.8, 0.1 μM) and radiated by 650 nm laser; (E) BCESA dissolved in ultrapure water (pH 6.8, 0.01 μM) and radiated by 650 nm laser; (F) BCESA dissolved in PBS (pH 7.4, 10 μM) and radiated by 650 nm laser; (G) BCESA dissolved in PBS (pH 7.4, 1 μM) and radiated by 650 nm laser; (H) BCESA dissolved in PBS (pH 7.4, 0.1 μM) and radiated by 650 nm laser; (I) BCESA dissolved in PBS (pH 7.4, 0.01 μM) and radiated by 650 nm laser; (J) BCESA dissolved in ultrapure water (pH 1.2, 10 μM) and radiated by 650 nm laser; (K) BCESA dissolved in ultrapure water (pH 1.2, 1 μM) and radiated by 650 nm laser; (L) BCESA dissolved in ultrapure water (pH 1.2, 0.1 μM) and radiated by 650 nm laser; (M) BCESA dissolved in ultrapure water (pH 1.2, 0.01 μM) and radiated by 650 nm laser; (N) Nanosize of BCESA in pH7.0 and pH1.2 ultrapure water as well as pH 7.4 PBS (0.01 μM, 0.1 μM and 1 μM) during 7 days; (O) Zeta potential of BCESA in pH6.8 ultrapure water (0.01 μM); (P) Zeta potential of BCESA in pH7.4 PBS (0.01 μM); (Q) Zeta potential of BCESA in pH1.2 ultrapure water (0.01 μM).

Abbreviation: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl.

Figure 3 Faraday-Tyndall effect, zeta potential and nano-size of BCESA in water or PBS. (A) Ultrapure water radiated by 650 nm laser; (B) BCESA dissolved in ultrapure water (pH 6.8, 10 μM) and radiated by 650 nm laser; (C) BCESA dissolved in ultrapure water (pH 6.8, 1 μM) and radiated by 650 nm laser; (D) BCESA dissolved in ultrapure water (pH 6.8, 0.1 μM) and radiated by 650 nm laser; (E) BCESA dissolved in ultrapure water (pH 6.8, 0.01 μM) and radiated by 650 nm laser; (F) BCESA dissolved in PBS (pH 7.4, 10 μM) and radiated by 650 nm laser; (G) BCESA dissolved in PBS (pH 7.4, 1 μM) and radiated by 650 nm laser; (H) BCESA dissolved in PBS (pH 7.4, 0.1 μM) and radiated by 650 nm laser; (I) BCESA dissolved in PBS (pH 7.4, 0.01 μM) and radiated by 650 nm laser; (J) BCESA dissolved in ultrapure water (pH 1.2, 10 μM) and radiated by 650 nm laser; (K) BCESA dissolved in ultrapure water (pH 1.2, 1 μM) and radiated by 650 nm laser; (L) BCESA dissolved in ultrapure water (pH 1.2, 0.1 μM) and radiated by 650 nm laser; (M) BCESA dissolved in ultrapure water (pH 1.2, 0.01 μM) and radiated by 650 nm laser; (N) Nanosize of BCESA in pH7.0 and pH1.2 ultrapure water as well as pH 7.4 PBS (0.01 μM, 0.1 μM and 1 μM) during 7 days; (O) Zeta potential of BCESA in pH6.8 ultrapure water (0.01 μM); (P) Zeta potential of BCESA in pH7.4 PBS (0.01 μM); (Q) Zeta potential of BCESA in pH1.2 ultrapure water (0.01 μM).Abbreviation: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl.

Figure 4 Nano-feature of BCESA in ultrapure water and mouse plasma imaged with TEM, SEM and AFM. (A) Nano-feature of BCESA in ultrapure water (pH 6.8, 0.01 μM) imaged with TEM; (B) Size distribution of the nano-particles of BCESA in ultrapure water (pH 6.8, 0.01 μM) imaged with TEM; (C) Nano-feature of the powders lyophilized from a solution of BCESA in ultrapure water (pH 6.8, 0.01 μM) imaged with SEM; (D) Size distribution of the powders lyophilized from a solution of BCESA in ultrapure water (pH 6.8, 0.01 μM) imaged with SEM; (E) AFM imaged particles of 17.06 nm in height of BCESA in ultrapure water (pH 6.8, 0.01 μM); (F) AFM imaged particles of 53.58 nm in height of BCESA in mouse serum (0.01 μM); (G) AFM image of mouse plasma alone.

Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; TEM, transmission electron microscopy; SEM, scanning electron microscopy; AFM, atomic force microscopy.

Figure 4 Nano-feature of BCESA in ultrapure water and mouse plasma imaged with TEM, SEM and AFM. (A) Nano-feature of BCESA in ultrapure water (pH 6.8, 0.01 μM) imaged with TEM; (B) Size distribution of the nano-particles of BCESA in ultrapure water (pH 6.8, 0.01 μM) imaged with TEM; (C) Nano-feature of the powders lyophilized from a solution of BCESA in ultrapure water (pH 6.8, 0.01 μM) imaged with SEM; (D) Size distribution of the powders lyophilized from a solution of BCESA in ultrapure water (pH 6.8, 0.01 μM) imaged with SEM; (E) AFM imaged particles of 17.06 nm in height of BCESA in ultrapure water (pH 6.8, 0.01 μM); (F) AFM imaged particles of 53.58 nm in height of BCESA in mouse serum (0.01 μM); (G) AFM image of mouse plasma alone.Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; TEM, transmission electron microscopy; SEM, scanning electron microscopy; AFM, atomic force microscopy.

Figure 5 The course of mesoscale simulation to predict the formation and the size of a nanoparticle of BCESA.

Abbreviation: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl.

Figure 5 The course of mesoscale simulation to predict the formation and the size of a nanoparticle of BCESA.Abbreviation: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl.

Figure 6 Intercalation of BCESA towards CT DNA. (A) BCESA changes the UV spectrum of CT DNA; (B) BCESA changes the fluorescence spectrum of CT DNA; (C) BCESA changes the CD spectrum of CT DNA; (D) BCESA changes the viscosity of CT DNA; (E) BCESA changes the Tm of CT DNA.

Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; CT DNA, calf thymus DNA; UV, ultraviolet; CD, circular dichroism.

Figure 6 Intercalation of BCESA towards CT DNA. (A) BCESA changes the UV spectrum of CT DNA; (B) BCESA changes the fluorescence spectrum of CT DNA; (C) BCESA changes the CD spectrum of CT DNA; (D) BCESA changes the viscosity of CT DNA; (E) BCESA changes the Tm of CT DNA.Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; CT DNA, calf thymus DNA; UV, ultraviolet; CD, circular dichroism.

Figure 7 The anti-tumor activities of BCESA. (A) In vitro anti-proliferation activity of BCESA; (B) BCESA dose-dependently slows the tumor growth of S180 mice; n=12.

Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; CMCNa, carboxymethylcellulose sodium; Dox, doxorubicin.

Figure 7 The anti-tumor activities of BCESA. (A) In vitro anti-proliferation activity of BCESA; (B) BCESA dose-dependently slows the tumor growth of S180 mice; n=12.Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; CMCNa, carboxymethylcellulose sodium; Dox, doxorubicin.

Figure 8 Effect of BCESA on the health of S180 mice. (A) Effect of BCESA on body weight of S180 mice; (B) Effect of BCESA on organ index of S180 mice; (C) Effect of BCESA on serum ALT of S180 mice; (D) Effect of BCESA on serum AST of S180 mice; (E) Effect of BCESA on serum Cr of S180 mice; n=12.

Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; CMCNa, carboxymethylcellulose sodium; Dox, doxorubicin.

Figure 8 Effect of BCESA on the health of S180 mice. (A) Effect of BCESA on body weight of S180 mice; (B) Effect of BCESA on organ index of S180 mice; (C) Effect of BCESA on serum ALT of S180 mice; (D) Effect of BCESA on serum AST of S180 mice; (E) Effect of BCESA on serum Cr of S180 mice; n=12.Abbreviations: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl; CMCNa, carboxymethylcellulose sodium; Dox, doxorubicin.

Figure 9 FT-MS(+)-MS spectra of the homogenate extracts of the tumor, the blood and the organs of S180 mice treated with 1.0 μmol/kg/day BCESA for nine consecutive days. (A) FT-MS(+)-MS spectra of the homogenate extract of the blood, in the local amplified inset only an ion peak of BCESA plus H is found at 595.25368; (B) FT-MS (+)-MS spectrum of the homogenate extract of the tumor tissue, in the local amplified insets the ion peaks of BCESA plus H, Ser-Ala plus H, β-carboline-3-carboxylic acid plus H, 1-methyl-β-carboline-3-carboxylic acid plus H, 1-carbonylmethyl-β-carboline-3-carboxylic acid plus H, 1-methyl-β-carboline-3-car- boxylic benzyl ester plus Na, 1-carbonylmethyl-β-carboline-3-carboxylic benzyl ester plus H, N-[(3-carboxyl-β-carboline-1-yl)ethyl]-Ser-Ala plus Na, N-[2-hydroxyl-(3-benzyloxycarbonyl-β-carboline-1-yl)-ethyl]-Ser-Ala-OBzl plus H and N-[(3-benzyloxycarbonyl-β-carboline-1-yl)-ethenyl]-Ser-Ala-OBzl plus Na occur at 595.25283, 177.08574, 213.06634, 227.07921, 255.07739, 339.11039, 345.12512, 437.14378, 611.24340 and 615.22143, respectively; (C-H) FT-MS(+)-MS spectra of the homogenate extracts of the heart, the liver, the spleen, the lung, the kidney and the brain, in which occur no any ion peak related to BCESA.

Abbreviation: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl.

Figure 9 FT-MS(+)-MS spectra of the homogenate extracts of the tumor, the blood and the organs of S180 mice treated with 1.0 μmol/kg/day BCESA for nine consecutive days. (A) FT-MS(+)-MS spectra of the homogenate extract of the blood, in the local amplified inset only an ion peak of BCESA plus H is found at 595.25368; (B) FT-MS (+)-MS spectrum of the homogenate extract of the tumor tissue, in the local amplified insets the ion peaks of BCESA plus H, Ser-Ala plus H, β-carboline-3-carboxylic acid plus H, 1-methyl-β-carboline-3-carboxylic acid plus H, 1-carbonylmethyl-β-carboline-3-carboxylic acid plus H, 1-methyl-β-carboline-3-car- boxylic benzyl ester plus Na, 1-carbonylmethyl-β-carboline-3-carboxylic benzyl ester plus H, N-[(3-carboxyl-β-carboline-1-yl)ethyl]-Ser-Ala plus Na, N-[2-hydroxyl-(3-benzyloxycarbonyl-β-carboline-1-yl)-ethyl]-Ser-Ala-OBzl plus H and N-[(3-benzyloxycarbonyl-β-carboline-1-yl)-ethenyl]-Ser-Ala-OBzl plus Na occur at 595.25283, 177.08574, 213.06634, 227.07921, 255.07739, 339.11039, 345.12512, 437.14378, 611.24340 and 615.22143, respectively; (C-H) FT-MS(+)-MS spectra of the homogenate extracts of the heart, the liver, the spleen, the lung, the kidney and the brain, in which occur no any ion peak related to BCESA.Abbreviation: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl.

Figure 10 FT-MS(+)-MS spectra based degradation course of BCESA in tumor tissue.

Abbreviation: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl.

Figure 10 FT-MS(+)-MS spectra based degradation course of BCESA in tumor tissue.Abbreviation: BCESA, N-[(3-Benzyloxycarbonyl-β-carboline-1-yl)ethyl]-Ser-Ala-OBzl.

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