@conference{
author = "Dobričić, Vladimir and Oluić, Jelena and Nikolić, Katarina and Vučićević, Jelica and Gagić, Žarko and Filipić, Slavica and Agbaba, Danica and Čudina, Olivera",
year = "2019",
abstract = "Multi-target compounds are designed to act on at least two targets in synergistic way, in order to produce stronger biological effect. The link
between cancer and inflammation has been intensively studied in last years and inhibition of both COX-2 and 5-LOX enzymes may be an
effective therapeutic approach for colon cancer treatment [1]. Acridines are known as DNA-topoisomerase II inhibitors. These compounds
intercalate into the DNA and inhibit topoisomerase II by their side chain. Recent studies showed additional activities of acridine derivatives,
depending on the side chain structure, such as inhibition of Src, MEK and VEGFR2 kinases [2,3]. Altered activity of PI3K/mTOR signaling pathway
is one of the most common aberrations found in various forms of neoplastic lesions. Dual inhibition of PI3K and mTOR represents a reasonably
attractive concept in potential cancer treatment [4]. In this paper, design of three groups of multi-target compounds with potential anticancer
activity is presented. Designed compounds are potential inhibitors of COX-2 and 5-LOX, DNA-topoisomerase II complex and kinases (Src, MEK
and VEGFR2), as well as dual inhibitors of mTOR and PI3K. A set of 27 compounds with published inhibitory activity on COX-2 and 5-LOX was
formed and two QSAR models, for both activities, were created in Pentacle program. On the basis of models’ interpretation, nine new
compounds were designed and activity on both targets predicted by developed models. Twenty-three acridine derivatives were designed and
their interactions with DNA-topoisomerase II complex, Src, MEK and VEGFR2 were tested using AutoDock Vina program. Nineteen designed
compounds bind to DNA similarly to inhibitor amsacrine and among them, ten derivatives show key binding interactions with tested kinases and
therefore possess potential to inhibit them. A dataset of eighty-five compounds with dual PI3K/mTOR inhibitory activities was formed,
divided into two groups based on their structural analogy and 3D-QSAR analysis of each group was performed in Pentacle program,
9
resulting in four QSAR models. On the basis of these results, new compounds were designed and further evaluated by use of molecular
docking, virtual screening and ADMET predictions. Finally, seven compounds were chosen as the most promising new dual mTOR/PI3K inhibitors.",
publisher = "COST Action 17104 (STRATAGEM)",
journal = "STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug-Resistant Tumors, first Working-Group Meeting, WG1 - WG4, 30 - 31. January 2019, Turin, Italy",
title = "Rational design of multi-target compounds with potential anticancer activity",
pages = "8-9",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5473"
}
