High antineoplastic activity of new heterocyclic compounds in cancer cells with resistance against classical DNA topoisomerase II‐targeting drugs

Abstract

Twenty previously synthesized fused heterocyclic DNA-topoisomerase II (Topo II)-inhibiting compounds were investigated for their potential efficacy in various human cancer cell lines that were derived from different tumor entities. Moreover, different multidrug-resistant variants of these cancer cell lines with decreased Topo II expression were investigated. In parental, drugsensitive cells merely the compounds BD3 and G35 showed efficacies, in terms of lM, which were similar to that of the classical Topo II inhibitor etoposide. On the other hand, most of the tested heterocyclic compounds were found more effective in drug-resistant cells than in the parental, drug-sensitive ones, and some of the compounds showed high antineoplastic efficacy in several drug-resistant cell models. Compounds BD13, BD14 and BD16 exhibited high antineoplastic activities against the drug-resistant sublines EPG85-257RNOV and EPG85-257RDB derived from gastric carcinoma, EPP85-181RNOV and EPP85-181RDB derived from pancreatic carcinoma, MCF-7/Adr derived from breast cancer, D79/ 86RNOV derived from fibrosarcoma, and MeWoETO1 derived from melanoma. Furthermore, compound D23 was found highly efficient in the multidrug-resistant variants HT-29RNOV and HT-29RDB derived from colon carcinoma, and compound D24 exhibited the highest antineoplastic activity among the tested compounds in the drug-resistant subline MDA-MB-231ROV derived from breast cancer. Key words: benzoxazole; benzimidazole; benzoxazin; DNA topisomerase II inhibitors; multidrug resistance DNA topoisomerases (Topo) 1 are enzymes that isomerise the tertiary structure of DNA without changing its primary structure. The high degree of conservation of these enzymes among prokaryotes and eukaryotes indicates an essential role in cell biology. Because its structure is a double helix, DNA is under tortional stress that results in multiplex twisting of the molecule. To be processed for replication or gene expression, the supercoiled DNA must become accessible to nucleic acids polymerases or components of the transcription machinery. This change requires relaxation and untangling of the intertwined DNA strands, which are the typical tasks of Topo.In humans, 2 classes of Topo are well characterized, type I and type II. Topo type II (Topo II) are useful as drug target, since they have an indispensable function in cell biology and they lack biological redundancy. Inhibitors of these enzymes have become central parts of both primary and adjuvant chemotherapy regimens in neoplastic diseases, and they probably will remain so for the foreseeable future. 2 Two Topo II isoforms, the 170 kDa Topo IIa and the 180 kDa Topo IIb, exist as homodimers and their amino acid sequences show homology at regions believed to be functionally significant (72% identical amino acid residues), 3 suggesting a comparable mode of action. The expression of Topo IIa varies during the cell cycle. It is low in quiescent cells, but maximal in the G 2 -M phase, whereas the expression level of Topo IIb remains constant througho...

Minor structural modifications to alchemix influence mechanism of action and pharmacological activity

“…In contrast to ICT2902 and ICT2903, alchemix and ICT2901 formed stable complexes with DNA (Table 1), however they were shown to be less potent topo IIα inhibitors. The MCF-7/adr cell line has been shown to possess a reduction in topo IIα protein compared to the MCF-7 cell line [26], which support why loss of activity of the two most potent topo IIα inhibitors ICT2902 and ICT2903 is observed.…”

Possible Mechanism of Action of Neurokinin-1 Receptors (NK1R) Antagonists

“…Over the last decade our group have been working on the drug design studies on the new anticancer active compounds by using both computational techniques and experimental work such as synthesis and activity studies [12][13][14][15][16][17][18][19][20]. Some of the benzoxazole and benzamide compounds, which were previously synthesized in our laboratory, showed strong inhibitory activity for human DNA Topoisomerases and Glutathione S-Transferases and also anticancer effects observed on various cell cultures [12][13][14][15][16][17][18][19][20].…”

“…Some of the benzoxazole and benzamide compounds, which were previously synthesized in our laboratory, showed strong inhibitory activity for human DNA Topoisomerases and Glutathione S-Transferases and also anticancer effects observed on various cell cultures [12][13][14][15][16][17][18][19][20]. These findings encouraged us to search for the new anticancer target NK1R by comparing their activities with the well-known NK1R antagonist aprepitant.…”

The dichotomy in the DNA-binding behaviour of ruthenium(II) complexes bearing benzoxazole and benzothiazole groups

“…A range of compounds containing benzoxazole groups have displayed significant biological potency and selectivity against human topoisomerase II, by stabilizing the cleaved DNA strand and preventing recombination [22][23][24]. As such, they are currently being explored as antitumour agents and so their inclusion in a ruthenium(II) polypyridine complex could encourage new and interesting structural selectivity.…”