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3 results on '"LAPC-4"'

1. Synthesis and Biological Evaluation of New Isoxazolyl Steroids as Anti-Prostate Cancer Agents.

Author

Rudovich, Anton S., Peřina, Miroslav, Krech, Anastasiya V., Novozhilova, Maria Y., Tumilovich, Anastasia M., Shkel, Tatyana V., Grabovec, Irina P., Kvasnica, Miroslav, Mada, Lukáš, Zavialova, Maria G., Mekhtiev, Arif R., Jorda, Radek, Zhabinskii, Vladimir N., and Khripach, Vladimir A.

Subjects
*ANDROGENS, *BIOSYNTHESIS, *ANDROGEN receptors, *MOLECULAR docking, *STEROIDS, *PROSTATE cancer, *CELL lines
Abstract

Steroids with a nitrogen-containing heterocycle in the side chain are known as effective inhibitors of androgen signaling and/or testosterone biosynthesis, thus showing beneficial effects for the treatment of prostate cancer. In this work, a series of 3β-hydroxy-5-ene steroids, containing an isoxazole fragment in their side chain, was synthesized. The key steps included the preparation of Weinreb amide, its conversion to acetylenic ketones, and the 1,2- or 1,4-addition of hydroxylamine, depending on the solvent used. The biological activity of the obtained compounds was studied in a number of tests, including their effects on 17α-hydroxylase and 17,20-lyase activity of human CYP17A1 and the ability of selected compounds to affect the downstream androgen receptor signaling. Three derivatives diminished the transcriptional activity of androgen receptor and displayed reasonable antiproliferative activity. The candidate compound, 24j (17R)-17-((3-(2-hydroxypropan-2-yl)isoxazol-5-yl)methyl)-androst-5-en-3β-ol, suppressed the androgen receptor signaling and decreased its protein level in two prostate cancer cell lines, LNCaP and LAPC-4. Interaction of compounds with CYP17A1 and the androgen receptor was confirmed and described by molecular docking. [ABSTRACT FROM AUTHOR]

Published
2022
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2. Synthesis and Biological Evaluation of New Isoxazolyl Steroids as Anti-Prostate Cancer Agents

Author

Anton S. Rudovich, Miroslav Peřina, Anastasiya V. Krech, Maria Y. Novozhilova, Anastasia M. Tumilovich, Tatyana V. Shkel, Irina P. Grabovec, Miroslav Kvasnica, Lukáš Mada, Maria G. Zavialova, Arif R. Mekhtiev, Radek Jorda, Vladimir N. Zhabinskii, and Vladimir A. Khripach

Subjects
Male, Organic Chemistry, Steroid 17-alpha-Hydroxylase, Prostatic Neoplasms, Antineoplastic Agents, General Medicine, Catalysis, Computer Science Applications, Inorganic Chemistry, Molecular Docking Simulation, Receptors, Androgen, Cell Line, Tumor, Humans, Steroids, Physical and Theoretical Chemistry, Molecular Biology, prostate cancer, androgen signaling, androgen receptor, CYP17A1, isoxazoles, Weinreb amide, LNCaP, LAPC-4, molecular docking, Spectroscopy
Abstract

Steroids with a nitrogen-containing heterocycle in the side chain are known as effective inhibitors of androgen signaling and/or testosterone biosynthesis, thus showing beneficial effects for the treatment of prostate cancer. In this work, a series of 3β-hydroxy-5-ene steroids containing an isoxazole fragment in the side chain was synthesized. The key steps included the preparation of Weinreb amide, its conversion to acetylenic ketones, and the 1,2- or 1,4-addition of hydroxylamine, depending on the solvent used. The biological activity of the obtained compounds was studied in a number of tests, including their effects on 17α-hydroxylase and 17,20-lyase activity of human CYP17A1 and the ability of selected compounds to affect the downstream androgen receptor signaling. Three derivatives diminished the transcriptional activity of androgen receptor and displayed reasonable antiproliferative activity. The candidate compound24j, (17R)-17-((3-(2-hydroxy-propan-2-yl)isoxazol-5-yl)methyl)-androst-5-en-3β-ol, suppressed the androgen receptor signaling and decreased its protein level in two prostate cancer cell lines, LNCaP and LAPC-4. Interaction of compounds with CYP17A1 and androgen receptor was confirmed and described by molecular docking.

Published
2022
Full Text
View/download PDF

3. Identification of Prostate Cancer Metastasis-Suppressor Genes Using Genomic shRNA Libraries

Author

ROSWELL PARK CANCER INST BUFFALO NY, Gelman, Irwin H., ROSWELL PARK CANCER INST BUFFALO NY, and Gelman, Irwin H.

Abstract

The so-called "lethal phenotype" in prostate cancer (CaP) involves the recurrence of metastatic disease after androgen-ablation therapy. However, little is known regarding the genetics that control disease recurrence. Our proposed research was to screen for metastasis- inducing genes in LNCaP and LAPC-4 CaP cells using libraries expressing RNAi covering the entire human genome. We have infected the CaP cell lines with two librades a retrovirus library encoding validated shRNAs for 983 "cancer genes" and a lentivirus genomic shRNA library (GIPZ). We have identified cells with significantly increased capabilities for Matrigel invasion over spontaneous rates and we are now identifying and validating individual genes whose knockdown contributes to the increased invasive potential of CaP cells. In addition to potentially serving as clinically predictive biomarkers these genes will be useful in understanding the molecular events required for metastatic progression in CaP., The original document contains color images.

Published
2008

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