Structural Optimization of Indole Derivatives Acting at Colchicine Binding Site as Potential Anticancer Agents

Abstract

A new series of indole analogues based on our earlier lead compound, 2-(1H-indol-5-yl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine (42), was prepared as tubulin inhibitors in an effort to find a molecule with improved cytotoxic potency and metabolic stability. A series of indolyl-imidazopyridines (IIP) were synthesized and exhibited potent tubulin polymerization inhibitory activity with potent IC 50 values ranging from 3 to 175 nM against a panel of human melanoma and prostate cancer cell lines. Among these compounds, the 6-indolyl compound 43 showed improved cytotoxic potency (average IC 50 of 9.75 nM vs 55.75 nM) and metabolic stability in human liver microsomes (half-life time was 56.3 min vs. 45.4 min) as compared to previously reported 42. It was also shown to be effective against P-glycoprotein (P-gp) mediated multiple drug resistance (MDR) and taxol resistance.

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

“…Jianhong et al reported the ability of millepachine to evade MDR in an A2780CP (P‐gp overexpressing) model and demonstrated that it irreversibly interacted with the colchicine site of β tubulin and retained full activity toward MDR cells. DJ101 targeted the colchicine binding site, which was confirmed through X‐ray crystallography, potently reduced cell viability in MDR cell lines, and also significantly inhibited tumor growth in taxane‐resistant prostate cancer xenografts without causing toxicity to the mice . SSE15206 also circumvented drug resistance in KB‐V1 and A2780‐Pac‐Res cell lines that overexpressed P‐gp .…”

“…There have been tremendous efforts in developing numerous natural and synthetic small molecules capable of binding to and affecting MT dynamics . However, these MT‐targeting agents offer broad diversity in terms of their chemical structures and tubulin protein binding sites, suggesting a potential affinity to bind to proteins other than tubulin .…”

“…There have been tremendous efforts in developing numerous natural and synthetic small molecules capable of binding to and affecting MT dynamics. 39,116,121,122,125,126,132 However, these MT-targeting agents offer broad diversity in terms of their chemical structures and tubulin protein binding sites, suggesting a potential affinity to bind to proteins other than tubulin. 39,[133][134][135][136][137][138] Likewise, many cellular kinases play crucial roles in diverse cellular processes, including cell growth as well as differentiation.…”

“…DJ101 targeted the colchicine binding site, which was confirmed through X-ray crystallography, potently reduced cell viability in MDR cell lines, and also significantly inhibited tumor growth in taxane-resistant prostate cancer xenografts without causing toxicity to the mice. 125,126 SSE15206 also circumvented drug resistance in KB-V1 and A2780-Pac-Res cell lines that overexpressed P-gp. 127 IMB5046 was not a P-gp substrate and displayed potent cytotoxicity against a panel of tumor cell lines and multidrug-resistant cell lines that were resistant to colchicine, vincristine, and paclitaxel treatment.…”

First Report on 3‐(3‐oxoaryl) Indole Derivatives as Anticancer Agents: Microwave Assisted Synthesis, In Vitro Screening and Molecular Docking Studies

“…2‐phenylindole derivatives are attractive anti‐breast cancer agents as shown in Figure ,. These derivatives can overcome multi‐drug resistance in cancer by interacting into the colchicine binding site on tubulin . Due to such enormous medicinal applications, the synthesis of various indole derivatives, particularly 2‐phenylindole derivatives using newer and efficient methodology is of immense interest in recent years .…”