Binding of G-quadruplex DNA and serum albumins by synthetic non-proteinogenic amino acids: Implications for c-Myc-related anticancer activity and drug delivery (15 views) (PDF public 11 views)
Molecular Therapeutics Nucleic Acids, 2025 Apr 2025; 36: 102478-102478.
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Paper type: Research Journal Article
Impact factor: 6.5, 5-year impact factor: 0
Url: https://www.sciencedirect.com/science/article/pii/S2162253125000320
Keywords: oligonucleotides: Therapies And Applications Non-Natural Amino Acids Asymmetric Synthesis Heterocyclic Compounds C-Myc G-Quadruplex Oncogene Molecular Docking Spectroscopy Fluorescence Scanning Electron Microscopy
Affiliations:
*** IBB - CNR ***
References:
1. Blaskovich, M.A.T. (2016). Unusual Amino Acids in Medicinal Chemistry. J. Med.
Chem. 59, 10807–10836. https://doi.org/10.1021/acs.jmedchem.6b00319.
2. Roviello, G.N. (2018). Novel insights into nucleoamino acids: biomolecular recognition and aggregation studies of a thymine-conjugated l-phenyl alanine. Amino Acids
50, 933–941. https://doi.org/10.1007/s00726-018-2562-2.
3. Qvit, N., Rubin, S.J.S., Urban, T.J., Mochly-Rosen, D., and Gross, E.R. (2017).
Peptidomimetic therapeutics: scientific approaches and opportunities. Drug
Discov. Today 22, 454–462. https://doi.org/10.1016/j.drudis.2016.11.003.
4. Condon, S.M., Mitsuuchi, Y., Deng, Y., LaPorte, M.G., Rippin, S.R., Haimowitz, T.,
Alexander, M.D., Kumar, P.T., Hendi, M.S., Lee, Y.-H., et al. (2014). Birinapant, a
Smac-Mimetic with Improved Tolerability for the Treatment of Solid Tumors and
Hematological Malignancies. J. Med. Chem. 57, 3666–3677. https://doi.org/10.
5. Kabir, E., and Uzzaman, M. (2022). A review on biological and medicinal impact of
heterocyclic compounds. Results in Chemistry 4, 100606–100616. https://doi.org/10.
1016/j.rechem.2022.100606.
6. Abdelli, A., Azzouni, S., Plais, R., Gaucher, A., Efrit, M.L., and Prim, D. (2021). Recent
advances in the chemistry of 1,2,4-triazoles: Synthesis, reactivity and biological activities. Tetrahedron Lett. 86, 153518–153532. https://doi.org/10.1016/j.tetlet.2021.
7. Khushbu, K., Kaushik, N., Lata, N., and Jain, S.C. (2014). Design and synthesis of
novel 2H-chromen-2-one derivatives bearing 1,2,3-triazole moiety as lead antimicrobials. Bioorg. Med. Chem. Lett 24, 1795–1801. https://doi.org/10.1016/j.bmcl.2014.
8. Shivarama Holla, B., Veerendra, B., Shivananda, M.K., and Poojary, B. (2003).
Synthesis characterization and anticancer activity studies on some Mannich bases
derived from 1,2,4-triazoles. Eur. J. Med. Chem. 38, 759–767. https://doi.org/10.
1016/s0223-5234(03)00128-4.
9. Liu, J., Liu, Q., Yang, X., Xu, S., Zhang, H., Bai, R., Yao, H., Jiang, J., Shen, M., Wu, X.,
and Xu, J. (2013). Design, synthesis, and biological evaluation of 1,2,4-triazole bearing
5-substituted biphenyl-2-sulfonamide derivatives as potential antihypertensive candidates. Bioorg. Med. Chem. 21, 7742–7751. https://doi.org/10.1016/j.bmc.2013.
10. Jubie, S., Ramesh, P.N., Dhanabal, P., Kalirajan, R., Muruganantham, N., and Antony,
A.S. (2012). Synthesis, antidepressant and antimicrobial activities of some novel stearic acid analogues. Eur. J. Med. Chem. 54, 931–935. https://doi.org/10.1016/j.ejmech.
11. Lin, G.Q., You, Q.D., and Cheng, J.F. (2011). Chiral Drugs: Chemistry and Biological
Action (John Wiley & Sons), p. 472. ISBN: 978-0-470-58720-1.
12. Andrushko, V., and Andrushko, N. (2013). Stereoselective Synthesis of Drugs and
Natural Products (John Wiley & Sons), p. 1836. ISBN: 978-1-118-03217-6.
13. Saghyan, A.S., and Langer, P. (2016). Asymmetric Synthesis of Optically Pure
Non-proteinogenic Amino Acids, 1st edition (Wiley-VCH), p. 358. ISBN-10:
14. Chaudhuri, R., Bhattacharya, S., Dash, J., and Bhattacharya, S. (2021). Recent Update
on Targeting c-MYC G-Quadruplexes by Small Molecules for Anticancer
Therapeutics. J. Med. Chem. 64, 42–70. https://doi.org/10.1021/acs.jmedchem.
15. Deiana, M., Chand, K., Jamroskovic, J., Das, R.N., Obi, I., Chorell, E., and Sabouri, N.
(2020). A site-specific self-assembled light-up rotor probe for selective recognition
and stabilization of c-MYC G-quadruplex DNA. Nanoscale 12, 12950–12957.
https://doi.org/10.1039/d0nr03404e.
16. Giunta, D., Roviello, G.N., and Solinas, M. (2024). Design and synthesis of new benzoxazole derivatives and study of their interactions with a G4 model by UV spectroscopy and in silico methods. J. Mol. Liq. 410, 125491. https://doi.org/10.1016/j.molliq.
17. Belokon’, Y.N., Sagyan, A.S., Djamgaryan, S.M., Bakhmutov, V.I., and Belikov, V.M.
(1988). Asymmetric synthesis of b-substituted a-amino acids via a chiral Ni(II) complex of dehydroalanine. Tetrahedron 44, 5507–5514. https://doi.org/10.1016/s0040-
18. Belokon, Y.N., Sagyan, A.S., Djamgaryan, S.A., Bakhmutov, V.I., Vitt, S.V., Batsanov,
A.S., Struchkov, Y.T., and Belikov, V.M. (1990). General method for the asymmetric
synthesis of anti-diastereoisomers of b-substituted L-2-aminobutanoic acids via chiral nickel(II) Schiff’s base complexes of dehydroaminobutanoic acid. X-Ray crystal
and molecular structure of the nickel(II) complex of the Schiff’s base from [(benzylprolyl)amino]benzophenone and dehydroaminobutanoic acid. J. Chem. Soc., Perkin
Trans. 1 I, 2301–2310. https://doi.org/10.1039/p19900002301.
19. Deka, S.R., Yadav, S., Kumar, D., Garg, S., Mahato, M., and Sharma, A.K. (2017). Selfassembled dehydropeptide nano carriers for delivery of ornidazole and curcumin.
Colloids Surf. B Biointerfaces 155, 332–340. https://doi.org/10.1016/j.colsurfb.2017.
20. Solanki, R., Rostamabadi, H., Patel, S., and Jafari, S.M. (2021). Anticancer nano-delivery systems based on bovine serum albumin nanoparticles; a critical review. Int. J.
Biol. Macromol. 193, 528–540. https://doi.org/10.1016/j.ijbiomac.2021.10.040.
21. Yan, Y., Zhang, D., Zhou, P., Li, B., and Huang, S.-Y. (2017). HDOCK: a web server
for protein–protein and protein–DNA/RNA docking based on a hybrid strategy.
Nucleic Acids Res. 45, W365–W373. https://doi.org/10.1093/nar/gkx407.
22. Yan, Y., Tao, H., He, J., and Huang, S.-Y. (2020). The HDOCK server for integrated
protein–protein docking. Nat. Protoc. 15, 1829–1852. https://doi.org/10.1038/
23. Scognamiglio, P.L., Riccardi, C., Palumbo, R., Gale, T.F., Musumeci, D., and Roviello,
G.N. (2024). Self-assembly of thyminyl l-tryptophanamide (TrpT) building blocks for
the potential development of drug delivery nanosystems. J Nanostruct Chem 14,
335–353. https://doi.org/10.1007/s40097-023-00523-7.
Molecular Therapy: Nucleic Acids
12 Molecular Therapy: Nucleic Acids Vol. 36 June 2025
24. Haridas, V. (2021). Tailoring of peptide vesicles: a bottom-up chemical approach.
Acc. Chem. Res. 54, 1934–1949. https://doi.org/10.1021/acs.accounts.0c00690.
25. Sargsyan, T., Stepanyan, L., Panosyan, H., Hakobyan, H., Israyelyan, M., Tsaturyan,
A., Hovhannisyan, N., Vicidomini, C., Mkrtchyan, A., Saghyan, A., and Roviello, G.N.
(2025). Synthesis and antifungal activity of Fmoc-protected 1, 2, 4-triazolyl-a-amino
acids and their dipeptides against Aspergillus species. Biomolecules 15, 61. https://
doi.org/10.3390/biom15010061.
26. Jack Li, J., and Johnson, D.S. (2016). Innovative Drug Synthesis (John Wiley & Sons),
p. 360. ISBN: 978-1-118-82005-6.
27. Zou, Y., Han, J., Saghyan, A.S., Mkrtchyan, A.F., Konno, H., Moriwaki, H., Izawa, K.,
and Soloshonok, V.A. (2020). Asymmetric Synthesis of Tailor-Made Amino Acids
Using Chiral Ni(II) Complexes of Schiff Bases. An Update of the Recent Literature.
Molecules 25, 2739. https://doi.org/10.3390/molecules2512273
Molecular Therapeutics Nucleic Acids, 2025 Apr 2025; 36: 102478-102478.
Export to BibTeX Export to EndNote
Paper type: Research Journal Article
Impact factor: 6.5, 5-year impact factor: 0
Url: https://www.sciencedirect.com/science/article/pii/S2162253125000320
Keywords: oligonucleotides: Therapies And Applications Non-Natural Amino Acids Asymmetric Synthesis Heterocyclic Compounds C-Myc G-Quadruplex Oncogene Molecular Docking Spectroscopy Fluorescence Scanning Electron Microscopy
Affiliations:
*** IBB - CNR ***
References:
1. Blaskovich, M.A.T. (2016). Unusual Amino Acids in Medicinal Chemistry. J. Med.
Chem. 59, 10807–10836. https://doi.org/10.1021/acs.jmedchem.6b00319.
2. Roviello, G.N. (2018). Novel insights into nucleoamino acids: biomolecular recognition and aggregation studies of a thymine-conjugated l-phenyl alanine. Amino Acids
50, 933–941. https://doi.org/10.1007/s00726-018-2562-2.
3. Qvit, N., Rubin, S.J.S., Urban, T.J., Mochly-Rosen, D., and Gross, E.R. (2017).
Peptidomimetic therapeutics: scientific approaches and opportunities. Drug
Discov. Today 22, 454–462. https://doi.org/10.1016/j.drudis.2016.11.003.
4. Condon, S.M., Mitsuuchi, Y., Deng, Y., LaPorte, M.G., Rippin, S.R., Haimowitz, T.,
Alexander, M.D., Kumar, P.T., Hendi, M.S., Lee, Y.-H., et al. (2014). Birinapant, a
Smac-Mimetic with Improved Tolerability for the Treatment of Solid Tumors and
Hematological Malignancies. J. Med. Chem. 57, 3666–3677. https://doi.org/10.
5. Kabir, E., and Uzzaman, M. (2022). A review on biological and medicinal impact of
heterocyclic compounds. Results in Chemistry 4, 100606–100616. https://doi.org/10.
1016/j.rechem.2022.100606.
6. Abdelli, A., Azzouni, S., Plais, R., Gaucher, A., Efrit, M.L., and Prim, D. (2021). Recent
advances in the chemistry of 1,2,4-triazoles: Synthesis, reactivity and biological activities. Tetrahedron Lett. 86, 153518–153532. https://doi.org/10.1016/j.tetlet.2021.
7. Khushbu, K., Kaushik, N., Lata, N., and Jain, S.C. (2014). Design and synthesis of
novel 2H-chromen-2-one derivatives bearing 1,2,3-triazole moiety as lead antimicrobials. Bioorg. Med. Chem. Lett 24, 1795–1801. https://doi.org/10.1016/j.bmcl.2014.
8. Shivarama Holla, B., Veerendra, B., Shivananda, M.K., and Poojary, B. (2003).
Synthesis characterization and anticancer activity studies on some Mannich bases
derived from 1,2,4-triazoles. Eur. J. Med. Chem. 38, 759–767. https://doi.org/10.
1016/s0223-5234(03)00128-4.
9. Liu, J., Liu, Q., Yang, X., Xu, S., Zhang, H., Bai, R., Yao, H., Jiang, J., Shen, M., Wu, X.,
and Xu, J. (2013). Design, synthesis, and biological evaluation of 1,2,4-triazole bearing
5-substituted biphenyl-2-sulfonamide derivatives as potential antihypertensive candidates. Bioorg. Med. Chem. 21, 7742–7751. https://doi.org/10.1016/j.bmc.2013.
10. Jubie, S., Ramesh, P.N., Dhanabal, P., Kalirajan, R., Muruganantham, N., and Antony,
A.S. (2012). Synthesis, antidepressant and antimicrobial activities of some novel stearic acid analogues. Eur. J. Med. Chem. 54, 931–935. https://doi.org/10.1016/j.ejmech.
11. Lin, G.Q., You, Q.D., and Cheng, J.F. (2011). Chiral Drugs: Chemistry and Biological
Action (John Wiley & Sons), p. 472. ISBN: 978-0-470-58720-1.
12. Andrushko, V., and Andrushko, N. (2013). Stereoselective Synthesis of Drugs and
Natural Products (John Wiley & Sons), p. 1836. ISBN: 978-1-118-03217-6.
13. Saghyan, A.S., and Langer, P. (2016). Asymmetric Synthesis of Optically Pure
Non-proteinogenic Amino Acids, 1st edition (Wiley-VCH), p. 358. ISBN-10:
14. Chaudhuri, R., Bhattacharya, S., Dash, J., and Bhattacharya, S. (2021). Recent Update
on Targeting c-MYC G-Quadruplexes by Small Molecules for Anticancer
Therapeutics. J. Med. Chem. 64, 42–70. https://doi.org/10.1021/acs.jmedchem.
15. Deiana, M., Chand, K., Jamroskovic, J., Das, R.N., Obi, I., Chorell, E., and Sabouri, N.
(2020). A site-specific self-assembled light-up rotor probe for selective recognition
and stabilization of c-MYC G-quadruplex DNA. Nanoscale 12, 12950–12957.
https://doi.org/10.1039/d0nr03404e.
16. Giunta, D., Roviello, G.N., and Solinas, M. (2024). Design and synthesis of new benzoxazole derivatives and study of their interactions with a G4 model by UV spectroscopy and in silico methods. J. Mol. Liq. 410, 125491. https://doi.org/10.1016/j.molliq.
17. Belokon’, Y.N., Sagyan, A.S., Djamgaryan, S.M., Bakhmutov, V.I., and Belikov, V.M.
(1988). Asymmetric synthesis of b-substituted a-amino acids via a chiral Ni(II) complex of dehydroalanine. Tetrahedron 44, 5507–5514. https://doi.org/10.1016/s0040-
18. Belokon, Y.N., Sagyan, A.S., Djamgaryan, S.A., Bakhmutov, V.I., Vitt, S.V., Batsanov,
A.S., Struchkov, Y.T., and Belikov, V.M. (1990). General method for the asymmetric
synthesis of anti-diastereoisomers of b-substituted L-2-aminobutanoic acids via chiral nickel(II) Schiff’s base complexes of dehydroaminobutanoic acid. X-Ray crystal
and molecular structure of the nickel(II) complex of the Schiff’s base from [(benzylprolyl)amino]benzophenone and dehydroaminobutanoic acid. J. Chem. Soc., Perkin
Trans. 1 I, 2301–2310. https://doi.org/10.1039/p19900002301.
19. Deka, S.R., Yadav, S., Kumar, D., Garg, S., Mahato, M., and Sharma, A.K. (2017). Selfassembled dehydropeptide nano carriers for delivery of ornidazole and curcumin.
Colloids Surf. B Biointerfaces 155, 332–340. https://doi.org/10.1016/j.colsurfb.2017.
20. Solanki, R., Rostamabadi, H., Patel, S., and Jafari, S.M. (2021). Anticancer nano-delivery systems based on bovine serum albumin nanoparticles; a critical review. Int. J.
Biol. Macromol. 193, 528–540. https://doi.org/10.1016/j.ijbiomac.2021.10.040.
21. Yan, Y., Zhang, D., Zhou, P., Li, B., and Huang, S.-Y. (2017). HDOCK: a web server
for protein–protein and protein–DNA/RNA docking based on a hybrid strategy.
Nucleic Acids Res. 45, W365–W373. https://doi.org/10.1093/nar/gkx407.
22. Yan, Y., Tao, H., He, J., and Huang, S.-Y. (2020). The HDOCK server for integrated
protein–protein docking. Nat. Protoc. 15, 1829–1852. https://doi.org/10.1038/
23. Scognamiglio, P.L., Riccardi, C., Palumbo, R., Gale, T.F., Musumeci, D., and Roviello,
G.N. (2024). Self-assembly of thyminyl l-tryptophanamide (TrpT) building blocks for
the potential development of drug delivery nanosystems. J Nanostruct Chem 14,
335–353. https://doi.org/10.1007/s40097-023-00523-7.
Molecular Therapy: Nucleic Acids
12 Molecular Therapy: Nucleic Acids Vol. 36 June 2025
24. Haridas, V. (2021). Tailoring of peptide vesicles: a bottom-up chemical approach.
Acc. Chem. Res. 54, 1934–1949. https://doi.org/10.1021/acs.accounts.0c00690.
25. Sargsyan, T., Stepanyan, L., Panosyan, H., Hakobyan, H., Israyelyan, M., Tsaturyan,
A., Hovhannisyan, N., Vicidomini, C., Mkrtchyan, A., Saghyan, A., and Roviello, G.N.
(2025). Synthesis and antifungal activity of Fmoc-protected 1, 2, 4-triazolyl-a-amino
acids and their dipeptides against Aspergillus species. Biomolecules 15, 61. https://
doi.org/10.3390/biom15010061.
26. Jack Li, J., and Johnson, D.S. (2016). Innovative Drug Synthesis (John Wiley & Sons),
p. 360. ISBN: 978-1-118-82005-6.
27. Zou, Y., Han, J., Saghyan, A.S., Mkrtchyan, A.F., Konno, H., Moriwaki, H., Izawa, K.,
and Soloshonok, V.A. (2020). Asymmetric Synthesis of Tailor-Made Amino Acids
Using Chiral Ni(II) Complexes of Schiff Bases. An Update of the Recent Literature.
Molecules 25, 2739. https://doi.org/10.3390/molecules2512273
Binding of G-quadruplex DNA and serum albumins by synthetic non-proteinogenic amino acids: Implications for c-Myc-related anticancer activity and drug delivery
This study delves into the impact of two synthetic non-natural amino acids, 7 and 8, on the structural dynamics of serum albumin and their potential significance in anticancer drug delivery systems. Crucially, the dihydrofuran-containing compound 7 has been identified to bind to the G-quadruplex (G4) DNA sequence 22-mer Pu22, a mimic of the proto-oncogene c-Myc, as ascertained by circular dichroism (CD) and UV spectroscopy. Our docking studies suggest that 7 binds to the G4 structure from the side of the G-quartet in a quasi-parallel manner, engaging in ten intermolecular interactions, including hydrogen bonds, π-lone pair and π-alkyl interactions. Notably, one interaction involves the heterocyclic ring of the compound. Compound 7 emerges as a notable structure modulator, showcasing a significant enhancement in protein α helix formation, as observed in a serum albumin binding CD experiment, and the capability to form supramolecular networks, as evidenced by dynamic light scattering (DLS) and Scanning Electron Microscopy (SEM), with the added benefit of encapsulating the natural anticancer drug curcumin within its self-assemblies. Toxicity assessments on human fibroblast cell lines demonstrate that both compounds are non-toxic, highlighting their biocompatibility and potential for safe biomedical applications. Interestingly, the triazole-based compound 8 induces distinctive structural changes in serum albumins, elucidated through CD and UV spectra using bovine serum albumin (BSA) as a model albumin target.
This study delves into the impact of two synthetic non-natural amino acids, 7 and 8, on the structural dynamics of serum albumin and their potential significance in anticancer drug delivery systems. Crucially, the dihydrofuran-containing compound 7 has been identified to bind to the G-quadruplex (G4) DNA sequence 22-mer Pu22, a mimic of the proto-oncogene c-Myc, as ascertained by circular dichroism (CD) and UV spectroscopy. Our docking studies suggest that 7 binds to the G4 structure from the side of the G-quartet in a quasi-parallel manner, engaging in ten intermolecular interactions, including hydrogen bonds, π-lone pair and π-alkyl interactions. Notably, one interaction involves the heterocyclic ring of the compound. Compound 7 emerges as a notable structure modulator, showcasing a significant enhancement in protein α helix formation, as observed in a serum albumin binding CD experiment, and the capability to form supramolecular networks, as evidenced by dynamic light scattering (DLS) and Scanning Electron Microscopy (SEM), with the added benefit of encapsulating the natural anticancer drug curcumin within its self-assemblies. Toxicity assessments on human fibroblast cell lines demonstrate that both compounds are non-toxic, highlighting their biocompatibility and potential for safe biomedical applications. Interestingly, the triazole-based compound 8 induces distinctive structural changes in serum albumins, elucidated through CD and UV spectra using bovine serum albumin (BSA) as a model albumin target.
Binding of G-quadruplex DNA and serum albumins by synthetic non-proteinogenic amino acids: Implications for c-Myc-related anticancer activity and drug delivery
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