Anticancer Molecule Discovery via C2-Substituent Promoted Oxidative Coupling of Indole and Enolate

Abstract

C2, C3-disubstituted indole is one of the most frequently encountered motifs in bioactive alkaloids and medicinal chemistry. Thus, developing novel, concise, and efficient access to it is highly desired in drug discovery. Herein, we present such an approach to this scaffold by direct oxidative coupling of C2-substituted indoles and enolates. Compared with indole bearing no C2-substituent, higher yields (up to 96%) were obtained for C2-substituted indoles in most cases. Mechanistic studies showed the reaction went through a Fe-chelated radical-anion oxidative coupling procedure promoted by C2-substituent on indole by two means: (1) stabilizing C2-radical intermediate during the reaction; (2) reducing indole homocoupling. This approach serves as a synthetic useful tool to quickly build up bioactive small molecule library of C2, C3-disubstituted indoles, and several products showed promising anticancer activities. Besides, indomethacin and its analogs were conveniently prepared in three-step sequence efficiently, indicating the potential application of our approach in medicinal chemistry.

Isovalerylspiramycin I suppresses non-small cell lung carcinoma growth through ROS-mediated inhibition of PI3K/AKT signaling pathway

“…The issues of toxic side effect and multidrug resistance (MDR) remain a challenge in the treatment and clinical management of NSCLC recently [31]. It is crucial to find some small molecules with good therapeutic potentials and low toxicity to act as a novel drug candidate for comprehensive treatment of NSCLC [24]. Repurposing old drugs in treating other diseases is a technique with many advantages including time and cost savings, since the safety and toxicity of candidate drugs have already been clearly studied [17].…”

“…2C showed that ISP-I treatment for 48h obviously ascended the abundance of cells in G2/M phase. The transition from G2 phase to mitosis was initiated by activated cyclin B1/cdc2 complex, which could be inhibited by the increased p21 [24,25]. As shown in Fig.…”

Target-based anticancer indole derivatives and insight into structure‒activity relationship: A mechanistic review update (2018–2021)

“…The following section focus on summarizing the recent advances (2018–2021) made towards synthesis of indole core in the design of anti-cancer compounds that may act via various targets such as topoisomerase, tubulin, aromatase, kinases, etc. The review also discusses the SAR of potential lead accountable for anticancer activity 31 .…”

Improved Method for Preparation of 3-(1H-Indol-3-yl)benzofuran-2(3H)-ones

“…Since both indole and benzo–furanone structural fragments are omnipresent in nature and listed as privileged scaffolds for drug discovery, chimeric indigo-, or isoindigo-like molecules possessing both these moieties also attracted certain attention. There are several reports describing the preparation of these unique compounds and studies of their applications in medicinal chemistry and material sciences [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. A common theme described in these reports is the metal-catalyzed C-C bond-forming reactions to accomplish the coupling between the indole and benzofuranone building blocks [ 1 , 5 , 8 , 10 ].…”

“…There are several reports describing the preparation of these unique compounds and studies of their applications in medicinal chemistry and material sciences [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. A common theme described in these reports is the metal-catalyzed C-C bond-forming reactions to accomplish the coupling between the indole and benzofuranone building blocks [ 1 , 5 , 8 , 10 ]. Other approaches used a Lewis acid-mediated reaction of indole derivatives with properly functionalized aromatic precursors (typically phenols or quinones) to furnish a five-membered lactone cycle in benzofurane [ 2 , 6 , 7 ].…”