Biomedical Chemistry: Research and Methods 2024, 7(3), e00241

New Nitrogen-Containing Androstane Derivatives Suppressing Prostate Carcinoma Cells Proliferation

A.S. Latysheva1*, A.Yu. Misharin1, A.V. Veselovsky1, G.E. Morozevich1, R.A. Novikov2, V.A. Zolottsev1

1Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow, 119121 Russia; *e-mail: aidanlinch@gmail.com
2Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov str., Moscow, 119991 Russia

Keywords: nitrogen-containing steroid derivatives; prostate carcinoma cells; CYP17A1 inhibitors; synthesis of steroid derivatives; antiproliferative activity; molecular docking

DOI:10.18097/BMCRM00241

The whole version of this paper is available in Russian.

Derivatives of 3β-hydroxyandrost-5,16-diene and 3β-hydroxyandrost-5-ene containing 2-oxazoline, 2-benzoxazole, and 2-benzimidazole substituents at C-17 position were synthesized. Docking of the synthesized compounds into the active site of human CYP17A1 predicted their high affinity for the enzyme. Of the 6 new compounds, 5 suppressed the proliferation of prostate carcinoma cells LNCaP and PC-3, and the activity of the oxazoline and benzimidazole derivatives of androsta-5,16-diene significantly exceeded the activity of the known anticancer agents abiraterone and galeterone.
Figure 1. Structures of nitrogen-containing androstane derivatives 1-8.

Figure 2. a – Ph3P, CCl4 / CH3CN, 2°C, 2 h, NH2(CH2)2OH, Et3N / CH3CN, 2°C→20̊С, 2 h; b – K2CO3 / MeOH - H2O, Δ, 40 min; c – Ph3P, CCl4 / CH3CN, Py, 2°C, 2 h, o-NH2(C6H4)OH, Py / CH3CN, +50°C, 3 h; d – (COCl)2 / toluene, 2°C→20°С, 2 h; e – o-NH2(C6H4)NH2, Et3N/ CH2Cl2, 2°C, 2 h; f – Al2O3, MW irradiation.

Figure 3. Docking of test compounds into the active site of CYP17A1. A – abiraterone 1 (cyan, ΔG = -9.3 kcal/mol), galeterone 2 (blue, ΔG = -12.9 kcal/mol); B – oxazolines 3 (blue, ΔG = -9.3 kcal/mol) and 6 (cyan, ΔG = -9.2 kcal/mol); C – benzoxazoles 4 (blue, ΔG = -10.5 kcal/mol) and 7 (cyan, ΔG = -8.2 kcal/mol); D – benzimidazoles 5 (blue, ΔG = -10.7 kcal/mol) and 6 (cyan, ΔG = -8.3 kcal/mol)

FUNDING

The work was performed within the framework of the Program for Basic Research in the Russian Federation for a long-term period (2021-2030) (no. 122030100170-5).

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