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

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Published: Sep 22, 2022
DOI: https://doi.org/10.18097/BMCRM00167
Keywords:
steroid conjugates; chemical synthesis; tetrapyrrolic macrocycles; molecular models; prostate carcinoma cells; phospholipid micelles

Main Article Content

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

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.

Article Details

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
Vol. 5 No. 3 (2022)
Section
EXPERIMENTAL RESEARCH

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