Structural modification of ellipticine derivatives with alkyl groups of varying length is influential on their effects on human DNA topoisomerase II: a combined experimental and computational study

Abstract

The compounds reducing tumor cell viability and disrupting DNA topoisomerase reactions have been widely used in anticancer drug development. Ellipticine (5,carbazole) is a potent intercalating agent that interferes with nucleic acid processing through interaction with DNA topoisomerase II. Although ellipticine is a wellcharacterized compound, it is not a widely-accepted drug due to the adverse effects detected upon administration. We have previously reported two novel ellipticine derivatives, N-methyl-5-demethyl ellipticine (ET-1) and 2-methyl-N-methyl-5demethyl ellipticinium iodide (ET-2) as potent compounds targeting DNA topoisomerase II. This study covers an extended synthesis, characterization, and activity data for five new salts of N-methyl 5-demetyl ellipticine (Z-1, Z-2, Z-4, Z-5 and Z-6) having several organic halides and their effects on human topoisomerase II enzymes. Moreover, combined in silico studies were conducted for better understanding of modes of action of studied molecules at the binding pocket of target. Our results showed that three of the derivatives (Z-1, Z-2, and Z-6) have considerable effect on the catalytic activity of human topoisomerase II implying the influence of alkyl groups added to the parental structure of ellipticine.

Bioactivities and Action Mechanisms of Ellipticine Derivatives Reported Prior to 2023

“…Compounds 3, 5, 7, 19, 31, 35 and 37 all inhibited human topoisomerase II activity. [36,53,70,74,76] The elipticine derivative 38, a Topo II-targeting compound, induces the formation of DNA breaks and the suppression of ALTassociated phenotypes in telomerase-negative cells. [77] The mechanism of Topo II inhibition is shown in Figure 5.…”

“…described the synthesis, characterization, and activity of five new salts of N‐methyl 5‐demethyl ellipticine with several organic halides and their effects on human topoisomerase II enzymes and reported that lead compound 37 exhibited potent antitumor activity against HeLa, SiHa, MCF‐7 and MDA‐MB‐231 cell lines, with IC 50 values of 0.09, 0.46, 0.42 and 0.34 μM, respectively. Their mechanistic investigation revealed that compound 37 had a considerable inhibitory effect on the catalytic activity of human topoisomerase II [76] …”

“…The occurrence of topoisomerase‐mediated DNA cleavage appears to be responsible for the observed antitumor activity. Compounds 3 , 5 , 7 , 19 , 31 , 35 and 37 all inhibited human topoisomerase II activity [36,53,70,74,76] . The elipticine derivative 38 , a Topo II‐targeting compound, induces the formation of DNA breaks and the suppression of ALT‐associated phenotypes in telomerase‐negative cells [77] .…”

“…Their mechanistic investigation revealed that compound 37 had a considerable inhibitory effect on the catalytic activity of human topoisomerase II. [76] In 2020, Zencir et al selected two ellipticine derivatives to assess their effects on the reaction of DNA breaks and suppression of the alternative lengthening of telomere (ALT) pathway. The authors demonstrated that the ellipticine derivative 38 was a topoisomerase II-based cytotoxic agent, especially against ALT cancer cells.…”

Anticancer and Immunomodulatory Activities of a Novel Water-Soluble Derivative of Ellipticine

“…Ellipticine derivatives such as 9-hydroxy-2-methylellipticinium acetate (NHME) had been introduced into the market, but were later withdrawn. [6] The search for other ellipticine derivatives is under way [10][11][12][13][14][15][16]. However, low water solubility of ellipticine derivatives is a crucial obstacle for the wide practical application in cancer therapies.…”