Conjugates of Pyropheophorbide a with 17-Substituted Steroidal Androgens. Synthesis, Molecular Modeling, Interaction with Some Cancer Cells

Authors

  • V.A. Zolottsev Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russia; RUDN University, 6 Miklukho-Maklaya str., 117198, Moscow, Russia
  • A.M. Korolchuk Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russia; Institute of Fine Chemical Technologies, MIREA – Russian Technological University, 86 Vernadskogo av., Moscow, 119454 Russia
  • A.S. Lukin Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russia; Mendeleev University of Chemical Technology of Russia, 9 Miusskaya sq., Moscow, 125047 Russia
  • G.E. Morozevich Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russia
  • A.R. Mekhtiev Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russia
  • R.A. Novikov Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova str., Moscow, 119991 Russia
  • Y.V. Tkachev Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova str., Moscow, 119991 Russia
  • N.V. Suvorov Institute of Fine Chemical Technologies, MIREA – Russian Technological University, 86 Vernadskogo av., Moscow, 119454 Russia
  • A.Y. Misharin Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russia

DOI:

https://doi.org/10.18097/BMCRM00167

Keywords:

steroid conjugates; chemical synthesis; tetrapyrrolic macrocycles; molecular models; prostate carcinoma cells; phospholipid micelles

Abstract

Five new bifunctional conjugates of pyropheophorbide a with 17-substituted testosterone, dihydrotestosterone and epitestosterone differing in the length of linker (1 – 5) and two new complex conjugates 6 and 7 (containing three functional units: pyropheophorbide a, 17α-substituted testosterone, and lipophylic hexadecyl chain, connected with L-lysine joining block) were synthesized. Mutual influence of steroidal and macrocyclic fragments in conjugates (1 – 7) was established by analysis of 1H NMR spectra and molecular models of conjugates. Studies of interaction of conjugates 1 – 5 with prostate carcinoma cells revealed that their uptake and internalization were dependent on the structure of conjugates, particularly on the stereochemical configuration of 17-hydroxyl group in steroidal moiety, and the length of linker connecting pyropheophorbide a with steroid fragments. Conjugates 1 – 5 significantly decreased the growth and proliferation of LNCaP and PC-3 cells. The highest anti-proliferative activity demonstrated by epitestosterone derivative 3, comprising short linker. Irradiation of labeled cells with light (λ = 660 nm) was significantly increased cytotoxicity. Trifunctional conjugates 6 and 7 easily formed mixed micells with phosphatidyl choline and pluronic F68; these mixed micelles efficiently internalized by human hepatocarcinoma Hep G2 cells. The binding of conjugates 6 and 7 in the form of mixed micelles to Hep G2 cells depended on the conjugate structure, rather than on the method of solubilization.

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Published

2022-09-22

How to Cite

Zolottsev, V., Korolchuk, A., Lukin, A., Morozevich, G., Mekhtiev, A., Novikov, R., Tkachev, Y., Suvorov, N., & Misharin, A. (2022). Conjugates of Pyropheophorbide a with 17-Substituted Steroidal Androgens. Synthesis, Molecular Modeling, Interaction with Some Cancer Cells. Biomedical Chemistry: Research and Methods, 5(3), e00167. https://doi.org/10.18097/BMCRM00167

Issue

Section

EXPERIMENTAL RESEARCH