Structure–Activity Relationship Studies of 3‐Aroylindoles as Potent Antimitotic Agents

Abstract

The concise synthesis and structure-activity relationship (SAR) studies of 3-aroylindoles were carried out in an effort to improve the potency and solubility of anticancer drug candidate BPR0L075 (8) by exploring structure modifications through three regimens: substitution of the B ring, at the N1 position, and of the 3-carbonyl linker. The SAR information revealed that the methoxy group of the B ring could be replaced with an electron-donating group such as methyl (in compound 9) or N,N-dimethylamino (in compound 13) while retaining both strong cytotoxic and antitubulin activities. The introduction of amide (compounds 30-33) and carbamate (compounds 34-37) functionalities at the N1 position of 8 gave analogues with potent antiproliferative activities. The cytotoxic potency of 8 was improved by replacing the carbonyl group with sulfide (compound 41) or oxygen (compound 43), indicating that the carbonyl moiety is important but not essential. The N,N-dimethylamino derivative 13 not only displayed potent cytotoxicity and antitubulin activity, but also showed a markedly improved physicochemical profile relative to the parent compound.

Application of computational methods for anticancer drug discovery, design, and optimization

“…The most potent compound of these four active molecules was also found to inhibit the proliferation of other cancer cell lines like MCF-7 (breast cancer), NCI-H460 (human non-small-cell lung cancer), and SF-268 (human central nervous system cancer), with IC50 values of 236 nM, 285 nM, and 319 nM, respectively. 58 Another example of small molecules designed using a computational approach is the case of an I-Kappa-B Kinase ␤ (IKK-␤) inhibitor. 59 IKK-␤, which is a key player in the NF-B signaling pathway, represents yet another potential target for the treatment of cancer in addition to inflammation.…”

Computational Strategies in Cancer Drug Discovery

“…However, due to these unfavorable properties, researchers have devoted substantial effort to discover new agents with more tolerable and effective properties, especially since it is believed that antimitotic agents could work to diminish blood supply to cancerous tumors. The authors of this study based their model generation on a set of 21 indole-derivatives synthesized originally (Liou et al 2006) for potential tubulin inhibition by this research group and used structure-activity relationship (SAR) analysis to drive it. These compounds were chosen such that their inhibitory half-maximal concentration (IC 50 ) values spanned over three orders of magnitude, from 1.2 nM to 6 μM (Liou et al 2006).…”

“…The authors of this study based their model generation on a set of 21 indole-derivatives synthesized originally (Liou et al 2006) for potential tubulin inhibition by this research group and used structure-activity relationship (SAR) analysis to drive it. These compounds were chosen such that their inhibitory half-maximal concentration (IC 50 ) values spanned over three orders of magnitude, from 1.2 nM to 6 μM (Liou et al 2006). Based on the chemical similarities of these compounds, the authors selected four common pharmacophoric features, including a hydrogen bond donor (HBD), a hydrogen bond acceptor (HBA), hydrophobic group (HY), and a hydrophobic aromatic group (HYA).…”

Design and Synthesis of Aminostilbene–Arylpropenones as Tubulin Polymerization Inhibitors

“…Some of the indole-containing compounds exhibit excellent antimitotic activity such as D-64131, D-24851, BPR0L075, BLF 61-3, and methyl 5-methoxy-3-((3,4,5trimethoxyphenyl)thio)-1H-indole-2-carboxylate (ATI ) derivatives. [22] Thus, it is clear from the background presented above that the pharmacophores represented by aminostilbene 1 c and ar-ylpropenones 2 a offer excellent possibilities for hybridization towards the design of improved tubulin polymerization inhibitors. [20,21] Indibulin {N-(pyridin-4-yl)-[1-(4-chlorbenzyl)indol-3-yl]glyoxyl amide, D-24851; Figure 1 a} is a synthetic small molecule with microtubule destabilizing activity.…”