Facile Synthesis of a Cholesterol–Doxorubicin Conjugate Using Cholesteryl-4-nitrophenolate as an Activated Ester and Biological Property Analysis
Pedro Freitas, Dina Maciel, Jolanta Jaśkowska, Kamila Zeńczak-Tomera, Yanbiao Zhou, Guoyin Yin, Ruilong Sheng
Organics · pp. 6–6 · Published 9 Feb 2025
10.3390/org6010006Abstract
Developing new biomolecule–drug conjugates as prodrugs is a promising area for natural products and pharmaceutical chemistry. Herein, a cholesterol–doxorubicin (Chol-DOX) conjugate was synthesized using cholesteryl-4-nitrophenolate as a facile, stable, and controllable activated ester. This approach offers an alternative to the conventional HCl-emitting cholesteryl chloroformate method. Semi-empirical theoretical calculations showed that cholesteryl-4-nitrophenolate exhibits moderate reactivity, greater thermodynamic stability, a higher dipole moment, and a lower HOMO-LUMO energy gap compared to cholesteryl chloroformate, suggesting that cholesteryl-4-nitrophenolate could be used as a more controllable acylating agent. The structure of the synthesized Chol-DOX conjugate was characterized using NMR, MS, and FT-IR techniques. Biological properties of the Chol-DOX conjugate were analyzed with a comparison of theoretical and experimental data. This work provides a facile and controllable method to synthesize natural lipid–DOX prodrugs and offers an in-depth data analysis of the related biological properties.
References (23)
- 1 Sritharan, S., and Sivalingam, N. (2021). A comprehensive review on time-tested anticancer drug doxorubicin. Life Sci., 278. [DOI]
- 2 Mignani, 2020, A glance over doxorubicin based-nanotherapeutics: From proof-of-concept studies to solutions in the market [DOI]
- 3 Wang, Z., Luo, T., Cao, A., Sun, J., Jia, L., and Sheng, R. (2018). Morphology-Variable Aggregates Prepared from Cholesterol-Containing Amphiphilic Glycopolymers: Their Protein Recognition/Adsorption and Drug Delivery Applications. Nanomaterials, 8. [DOI]
- 4 Sheng, R., Wang, Z., Luo, T., Cao, A., Sun, J., and Kinsella, J.M. (2018). Skeleton-Controlled pDNA Delivery of Renewable Steroid-Based Cationic Lipids, the Endocytosis Pathway Analysis and Intracellular Localization. Int. J. Mol. Sci., 19. [DOI]
- 5 Sheng, 2014, Cholesterol-based cationic lipids for gene delivery: Contribution of molecular structure factors to physico-chemical and biological properties [DOI]
- 6 Wang, 2021, Natural steroid-based cationic copolymers cholesterol/diosgenin-r-PDMAEMAs and their pDNA nanoplexes: Impact of steroid structures and hydrophobic/hydrophilic ratios on pDNA delivery [DOI]
- 7 Zhu, Z., Zhang, L., Sheng, R., and Chen, J. (2022). Microfluidic-Based Cationic Cholesterol Lipid siRNA Delivery Nanosystem: Highly Efficient In Vitro Gene Silencing and the Intracellular Behavior. Int. J. Mol. Sci., 23. [DOI]
- 8 Wang, 2023, Controlled preparation of cholesterol-bearing polycations with pendent l-lysine for efficient gene delivery [DOI]
- 9 Wang, Z., Guo, X., Hao, L., Zhang, X., Lin, Q., and Sheng, R. (2022). Charge-Convertible and Reduction-Sensitive Cholesterol-Containing Amphiphilic Copolymers for Improved Doxorubicin Delivery. Materials, 15. [DOI]
- 10 Olim, F., Neves, A.R., Vieira, M., Tomás, H., and Sheng, R. (2021). Self-Assembly of Cholesterol-Doxorubicin and TPGS into Prodrug-Based Nanoparticles with Enhanced Cellular Uptake and Lysosome-Dependent Pathway in Breast Cancer Cells. Eur. J. Lipid Sci. Technol., 123. [DOI]
- 11 Polik, W.F., and Schmidt, J.R. (2022). WebMO: Web-based computational chemistry calculations in education and research. WIREs Comput. Mol. Sci., 12. [DOI]
- 12 Amić, A., and Gotal, E. (2021). Selected Thermodynamic Parameters of Antioxidant Activity of Coumarin Based Heterocyclic Compounds. Chem. Proc., 3. [DOI]
- 13 Lu, 2022, A broadly applicable quantitative relative reactivity model for nucleophilic aromatic substitution (SNAr) using simple descriptors [DOI]
- 14 Darvishmanesh, 2011, Physicochemical Characterization of Solute Retention in Solvent Resistant Nanofiltration: The Effect of Solute Size, Polarity, Dipole Moment, and Solubility Parameter [DOI]
- 15 Brahmachari, 2018, Triethylamine—A Versatile Organocatalyst in Organic Transformations: A Decade Update [DOI]
- 16 Cai, 2010, Elucidating Colorization in the Functionalization of Hydroxyl-Containing Polymers Using Unsaturated Anhydrides/Acyl Chlorides in the Presence of Triethylamine [DOI]
- 17 Fu, Z., Zhang, L., Hang, S., Wang, S., Li, N., Sun, X., Wang, Z., Sheng, R., Wang, F., and Wu, W. (2022). Synthesis of Coumarin Derivatives: A New Class of Coumarin-Based G Protein-Coupled Receptor Activators and Inhibitors. Polymers, 14. [DOI]
- 18 Grolier, 1993, Heat capacities and densities of mixtures of very polar substances 2. Mixtures containing N, N-dimethylformamide [DOI]
- 19 Mokbel, 2009, Experimental Vapor Pressures of 2-Phenylethylamine, Benzylamine, Triethylamine, and cis-2,6-Dimethylpiperidine in the Range between 0.2 Pa and 75 kPa [DOI]
- 20 Bakchi, B., Krishna, A.D., Sreecharan, E., Ganesh, V.B.J., Niharika, M., Maharshi, S., Puttagunta, S.B., Sigalapalli, D.K., Bhandare, R.R., and Shaik, A.B. (2022). An overview on applications of SwissADME web tool in the design and development of anticancer, antitubercular and antimicrobial agents: A medicinal chemist’s perspective. J. Mol. Struct., 1259. [DOI]
- 21 Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 7. [DOI]
- 22 Han, 2021, Lipophilic Conjugates of Drugs: A Tool to Improve Drug Pharmacokinetic and Therapeutic Profiles [DOI]
- 23 Lamoureux, 2022, Novel one-pot synthesis of a library of 2-aryloxy-1,4-naphthoquinone derivatives. Determination of antifungal and antibacterial activity [DOI]
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