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Synthesis of Pregnane–Cholesterol and Cholesterol–Cholesterol Prodrugs via Ring A–Ring A Connection. Potential Cytotoxic Activity against Cervical Cancer Cell Line HeLa

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Abstract

Two novel pregnane–cholesterol and cholesterol–cholesterol prodrugs have been synthesized. The synthetic route involved preparation of 2-(cholest-5-en-3-yloxycarbonyl)benzoic acid (2) by the esterification of cholesterol (1) with phthalic anhydride. The pregnane–cholesterol prodrug (4) was synthesized by treating 2-(cholest-5-en-3-yloxycarbonyl)benzoic acid (2) with 3β-hydroxypregna-5,16-dien-20-one (3), and cholesterol–cholesterol prodrug (5) was synthesized by treating acid 2 with cholesterol. The synthesized compounds have been characterized with the help of spectroscopic techniques like 1H and 13C NMR, FT-IR, UV-visible spectroscopy, and mass spectrometry. The prodrugs have shown potential cytotoxic effect in cervical cancer cell line HeLa. Compounds 2 and 4 were found to be effective prodrugs, the latter being the most effective. It showed less than 10% cell viability at 1 µM concentration, which signifies that these prodrugs may help to reduce cancer burden in human populations. Quantum chemical calculations of compounds 2–5 were performed in the ground state using the DFT of B3LYP level with 6-31G(d,p) basis set. The electronic properties such as HOMO and LUMO energies were determined by the time-dependent DFT approach. Intramolecular interactions have been identified by the AIM (Atoms in Molecules) approach. The reactivity and reactive sites within the synthesized prodrugs were examined with reactivity descriptors (global and local). The calculated dipole moments, polarizabilities, and first static hyperpolarizabilities indicated that the synthesized compounds might behave as good nonlinear optical materials. The probable reaction paths of prodrugs were calculated with molecular electrostatic potential (MEP) surface analysis.

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Funding

This work was supported by UGC Postdoc Fellowship for women 2015-16 [F.15-1/2015-17/PDFWN-2015-17-UTT-36157(SA-II)].

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Authors and Affiliations

  1. Department of Chemistry, University of Lucknow, 226007, Lucknow, India

    P. Yadav, A. Sethi & J. Sarkar

  2. Uttar Pradesh Jal Nigam Rural, Rana Pratap Marg, 226001, Lucknow, India

    P. Yadav

  3. College of Pharmacy, Gachon University, Yeonsu-gu, 21936, Incheon, Korea

    N. Yadav

  4. Department of Applied Science & Humanities, Faculty of Engineering & Technology, University of Lucknow, 226031, Lucknow, India

    R. P. Singh

  5. Department of Applied Science & Humanities, Institute of Engineering & Technology, 226021, Lucknow, India

    S. Srivastava

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  1. P. Yadav
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Yadav, P., Yadav, N., Sethi, A. et al. Synthesis of Pregnane–Cholesterol and Cholesterol–Cholesterol Prodrugs via Ring A–Ring A Connection. Potential Cytotoxic Activity against Cervical Cancer Cell Line HeLa. Russ J Org Chem 59, 1797–1806 (2023). https://doi.org/10.1134/S1070428023100159

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