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Research Article Open access CC BY 4.0

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/org6010006

Abstract

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.

Conjugate Doxorubicin Chemistry Cholesteryl ester Cholesterol Combinatorial chemistry Biochemistry Lipoprotein

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