Design, Synthesis, and In Vitro Anticancer Activities of Diethylene Glycol Tethered Isatin‐1,2,3‐triazole‐coumarin Hybrids

Abstract

A series of novel diethylene glycol tethered isatin‐1,2,3‐triazole‐coumarin hybrids 9a–l were designed, synthesized, and evaluated for their in vitro anticancer activities against HepG2 (liver carcinoma), Hela (cervical cancer), A549 (lung adenocarcinoma), DU145 (prostatic cancer), SKOV3 (ovarian carcinoma), MCF‐7 (breast cancer), and drug‐resistant MCF‐7/DOX (doxorubicin‐resistant MCF‐7) human cancer cell lines. The results showed that most of the synthesized hybrids exhibited considerable in vitro activities against the tested seven cancer cell lines, and these hybrids can be acted as starting points for further investigation.

An Overview of Coumarin as a Versatile and Readily Accessible Scaffold with Broad-Ranging Biological Activities

“…Firstly, the scavenging activity of the compounds was evaluated on ABTS (2,2 -azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt), DPPH (2,2-diphenyl-1-picrylhydrazyl) and galvinoxyl radicals as Trolox (a Vitamin E analogue) equivalent antioxidant capability (TEAC). The results showed that, whereas 1 did not exhibit radical scavenging activity, 2 resulted more active than Trolox against the ABTS•+ radical (EC 50 30.83 µM) and 3 displayed better antioxidant activity than Trolox against ABTS•+, DPPH and galvinoxyl radicals (EC 50 values of 39.98, 150.99 and 13.19 µM, respectively). It is likely that such differences in antioxidant activity may rely on the differences in the relative positions of hydroxy groups [31].…”

“…When PC3 and DU145 human PCa cells were treated with different concentrations of both 4-MMPB and 18 for 24, 48 and 72 h, a dose-dependent and time-dependent decrease in the survival of the cells was exhibited. PC3 cells resulted to be more sensitive than DU145 cells to both inhibitors (IC 50 Concerning the mechanism of action, it was found that 5-farnesyloxycoumarin acts as a cytotoxic agent causing chromatin condensation and DNA damage and induces the arrest of the cell cycle in G 0 /G 1 phase. A similar study was carried out on 8-farnesyloxycoumarin (19, Figure 8) by Hosseinymehr and collaborators [46].…”

“…Again, the coumarin derivative showed inhibitory activity on 15-LOX-1 in PC3 and DU145 cell lines, thus inducing apoptosis of the cancer cell, with the same mechanism of compound 18. PC3 cells resulted to be more sensitive to 19 inhibition than DU145 cells; IC 50 Halawa et al synthesized and characterized a new series of 4-arylamino-3-nitrocoumarin analogues from 4-hydroxycoumarin and tested them on the human cervix carcinoma cell line KB-3-1 [47]. These compounds were found to target the DNA-Topo I (human Topoisomerase I) complex, thus blocking cell replication and leading to cell death.…”

“…Ten compounds were tested on HepG2 (liver carcinoma), HeLa (cervical cancer), A549 (lung adenocarcinoma), DU145 (prostatic cancer), SKOV3 (ovarian carcinoma), MCF-7 (breast cancer) and drug-resistant MCF-7/DOX (doxorubicin-resistant MCF-7) As coumarin nucleus can be widely decorated, it can be used in the synthesis of hybrid compounds, targeting different proteins involved not only in tumor growth but also in metastatic and angiogenetic processes. In this context, Diao and collaborators synthesized a series of diethylene glycol tethered isatin-1,2,3-triazole-coumarin derivatives (22a-l, Figure 11) [50]. Several isatin-based or 1,2,3-triazole or coumarin-based compounds (semaxanib, carboxyamidotriazole and STX64) are involved in clinical trials or have already been used the treatment of various cancers (as colon-rectal, prostatic, endometrial and breast cancer) [51,52], whereas isatin-1,2,3-triazole-coumarin derivatives showed activity against different cancer types.…”

“…In addition, 23 inhibited implanted 4T1 breast cancer growth in vivo. The antiproliferative effects of compound 23 on normal cells were investigated by MTT assays comparing it to the STAT3 inhibitor Stattic, which showed growth inhibition activity in both tumor and normal cells, whereas compound 23 exhibited selective inhibitory activity against cancer cells (IC 50 14.62 µM for MCF-10A cells and IC 50 35.60 µM for L02 cells), indicating a higher selectivity than Stattic.…”