4.7 Article

Design, synthesis, and antitumor activity evaluation of steroidal oximes

期刊

BIOORGANIC & MEDICINAL CHEMISTRY
卷 46, 期 -, 页码 -

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2021.116360

关键词

Steroids; Olefins; Epoxides; Oximes; Synthesis; Antitumour activity

资金

  1. Foundation for Science and Technology (FCT), Portugal [UIDB/00102/2020, UIDB/04539/2020, UIDP/04539/2020]
  2. FEDER-European Regional Development Fund through COMPETE Programme (Operational Programme for Competitiveness)
  3. FCT [REEQ/481/QUI/2006, RECI/QEQ-QFI/0168/2012, CENTRO-07-CT62-FEDER-002012]
  4. FCT through Rede Nacional de Ressonancia Magnetica Nuclear (RNRMN)

向作者/读者索取更多资源

Steroidal oxime compounds were synthesized and evaluated for their cytotoxicity in multiple cancer cell lines, with (17E)-5 alpha-androst-3-en-17-one oxime (3,4 - OLOX) showing the most promising results in decreasing tumor cell proliferation. These compounds may serve as a starting point for the discovery of new steroidal oximes for anticancer treatment.
Steroidal compounds were proven to be efficient drugs against several types of cancer. Oximes are also chemical structures frequently associated with anticancer activity. The main goal of this work was to combine the two referred structures by synthesizing steroidal oximes and evaluating them in several cancer cell lines. Compounds (17E)-5 alpha-androst-3-en-17-one oxime (3,4 - OLOX), (17E)-3 alpha,4 alpha-epoxy-5 alpha-androstan-17-one oxime (3,4 - EPOX), (17E)-androst-4-en-17-one oxime (4,5 - OLOX) and (17E)-4 alpha,5 alpha-epoxyandrostan-17-one oxime (4,5 - EPOX) were synthesized and their cytotoxicity evaluated in four human cancer cell lines, namely colorectal adenocarcinoma (WiDr), non-small cell lung cancer (H1299), prostate cancer (PC3) and hepatocellular carcinoma (HepG2). A human non-tumour cell line, CCD841 CoN (normal colon cell line) was also used. MTT assay, flow cytometry, fluorescence and hemocompatibility techniques were performed to further analyse the cytotoxicity of the compounds. 3,4 - OLOX was the most effective compound in decreasing tumour cell proliferation in all cell lines, especially in WiDr (IC50 = 9.1 mu M) and PC3 (IC50 = 13.8 mu M). 4,5 - OLOX also showed promising results in the same cell lines (IC50 = 16.1 mu M in WiDr and IC50 = 14.5 mu M in PC3). Further studies also revealed that 3,4 - OLOX and 4,5 - OLOX induced a decrease in cell viability accompanied by an increase in cell death, mainly by apoptosis/necroptosis for 3,4 - OLOX in both cell lines and for 4,5 - OLOX in WiDr cells, and by necrosis for 4,5 - OLOX in PC3 cells. These compounds might also exert their cytotoxicity by ROS production and are not toxic for non-tumour CCD841 CoN cells. Additionally, both compounds did not induce haemoglobin release, proving to be safe for intravenous administration. 3,4 - OLOX and 4,5 - OLOX might be the starting point for an optimization program towards the discover of new steroidal oximes for anticancer treatment.

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