Synthesis and evaluation of anticancer activity of new 9-acridinyl amino acid derivatives

RSC Med Chem. 2020 Feb 14;11(3):378-386. doi: 10.1039/c9md00597h.

Jelena Rupar ¹ ², Vladimir Dobričić ¹, Jelena Grahovac ³, Siniša Radulović ³, Žiga Skok ⁴, Janez Ilaš ⁴, Mara Aleksić ², Jasmina Brborić ¹, Olivera Čudina ¹

Affiliations

1 Department of Pharmaceutical Chemistry , University of Belgrade - Faculty of Pharmacy , Vojvode Stepe 450 , 11000 Belgrade , Serbia . Email: vladimir@pharmacy.bg.ac.rs.
2 Department of Physical Chemistry and Instrumental Methods , University of Belgrade - Faculty of Pharmacy , Vojvode Stepe 450 , 11000 Belgrade , Serbia.
3 Department of Experimental Oncology , Institute for Oncology and Radiology of Serbia , Pasterova 14 , Belgrade , Serbia.
4 Chair of Pharmaceutical Chemistry , University of Ljubljana, Faculty of Pharmacy , Aškerčeva 7 , SI-1000 Ljubljana , Slovenia.

PMID: 33479643 DOI: 10.1039/c9md00597h

Abstract

A series of eleven 9-acridinyl Amino Acid Derivatives were synthesized using a two-step procedure. Cytotoxicity was tested on the K562 and A549 Cancer cell lines and normal diploid cell line MRC5 using the MTT assay. Compounds 6, 7, 8 and 9 were the most active, with IC₅₀ values comparable to or lower than that of chemotherapeutic agent amsacrine. 8 and 9 were especially effective in the A549 cell line (IC₅₀ ≈ 6 μM), which is of special interest since amsacrine is not sufficiently active in lung Cancer patients. Cell cycle analysis revealed that 7 and 9 caused G2/M block, amsacrine caused arrest in the S phase, while 6 and 8 induced apoptotic cell death independently of the cell cycle regulation. In comparison to amsacrine, 6, 7, 8, and 9 showed similar inhibitory potential towards Topoisomerase II, whereas only 7 showed DNA intercalation properties. In contrast to amsacrine, 6, 7, 8 and 9 showed a lack of toxicity towards unstimulated normal human leucocytes.

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