Abstract
The combination of an androstane-3,17-diol nucleus and a 2β-N-alkylamidopiperazino sidechain is important for the anticancer activity of a new family of steroid derivatives. As the structure-activity relationship studies have so far been limited to the beta orientation of the substituent at position 2 of the steroid nucleus, a series of analogs (compounds 1–4) were synthesized to investigate the impact on biological activity of A-ring substitution. Nuclear magnetic resonance (NMR) analysis, especially using a series of 2D experiments, such as correlation spectroscopy (COSY), homonuclear Overhauser effect spectroscopy (NOESY), heteronuclear single-quantum correlation (HSQC), and heteronuclear multiple-bond correlation (HMBC) provided crucial information that was found essential in confirming the sidechain position and orientation of compounds 1–4. Assessment of their antiproliferative activity on leukemia HL-60 cells confirmed the best efficiency of the 2β-sidechain/3α-OH orientation (compound 1) compared to the other configurations tested (compounds 2–4).
Highlights
Steroid derivatives with a N-substituted piperazino sidechain at position C2β of 5αandrostane-3α,17β-diol showed antiproliferative activity on different cancer cell lines [1,2,3,4,5,6]and promising results were obtained with two representative candidates tested in mouse xenograft tumor models [6,7,8]
Structure-activity relationship (SAR) studies have made it possible to optimize the composition of the sidechain added at position 2β of the 5α-androstane-3α, 17β-diol steroid nucleus [2,3,4], but the impact on the biological activity of the sidechain and hydroxyl group positioning on A-ring has never been studied
Since the therapeutic target was not known for these aminosteroids, which precluded the use of molecular modeling, it was crucial to extend the SAR
Summary
Steroid derivatives with a N-substituted piperazino sidechain at position C2β of 5αandrostane-3α,17β-diol showed antiproliferative activity on different cancer cell lines [1,2,3,4,5,6]. Promising results were obtained with two representative candidates tested in mouse xenograft tumor models [6,7,8] They were designed by combining two crucial elements: A steroid core and a lateral piperazino sidechain in A-ring (Figure 1A). It was necessary to obtain other derivatives with the same sidechain (N-nonanoylpiperazinyl), albeit in another orientation or position In addition to their chemical synthesis and biological evaluation, our challenge was to fully characterize the four steroid derivatives 1–4 by 1D and 2D nuclear magnetic resonance (NMR) experiments and to confirm both sidechain and OH orientations in A-ring. Representation ainhibit new cancer family ofcell anticancer agents showing theirsteroid crucial structural elements. Both sidechain and steroid core areneeded neededtoof toinhibit cancercell proliferation.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
