Discovery of a novel series of pyridone amides as NaV1.8 inhibitors.

The NaV1.8 channel, mainly found in the peripheral nervous system, is recognized as one of the key factors in chronic pain. The molecule VX-150 was initially promising in targeting this channel, but the phase II trials of VX-150 did not show expected pain relief results. By analyzing the interaction mode of VX-150 and NaV1.8, we developed two series with a total of 19 molecules and examined their binding affinity to NaV1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the NaV1.8 channel and showed effective pain relief in models of chronic inflammatory pain and neuropathic pain. Our research points to 2j as a strong contender for developing safer pain-relief treatments.

Research progress of indole-fused derivatives as allosteric modulators: Opportunities for drug development.

Allosteric modulation is a direct and effective method for regulating the function of biological macromolecules, which play vital roles in various cellular activities. Unlike orthosteric modulators, allosteric modulators bind to sites distant from the protein's orthosteric/active site and can have specific effects on the protein's function or activity without competing with endogenous ligands. Compared to traditional orthosteric modulators, allosteric modulators offer several advantages, including reduced side effects, greater specificity, and lower toxicity, making them a promising strategy for developing novel drugs. Indole-fused architectures are widely distributed in natural products and bioactive drug leads, displaying diverse biological activities that attract the interest of both chemists and biologists in drug discovery. Currently, an increasing number of indole-fused compounds have exhibited potent activities in allosteric modulation. In this review, we provide a brief summary of examples of allosteric modulators based on the indole-fused complex architecture, highlighting the strategies for drug design/discovery and the structure-activity relationships of allosteric modulators from the perspective of medicinal chemistry.

One-Step Synthesis of Hydropyrrolo[3,2-b]indoles via Cascade Reactions of Oxindole-Derived Nitrones with Allenoates.

Hydropyrrolo[2,3-b]indole is a privileged indoline motif, while its analogue, hydropyrrolo[3,2-b]indole, has been much less explored. Herein, we developed a cascade reaction of oxindole-derived nitrones with allenoates, providing straightforward access to the tetracyclic hydropyrrolo[3,2-b]indole scaffolds. Formation of multiple C-C/C-X bonds and cleavage could be achieved within one synthetic step using a simple catalyst (Gimeracil) under mild conditions. The reaction pathway may involve the generation of spiro-hydroazepinone as the key intermediate.

Discovery of 4-cyclopropyl-3-(2-((1-cyclopropyl-1H-pyrazol-4-yl) amino) quinazolin-6-yl)-N-(3-(trifluoromethyl) phenyl) benzamides as potent discoidin domain receptor inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with a median survival time of 3-5 years. Inaccurate diagnosis, limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent need. In recent years, it was reported that DDRs are potential targets in anti-fibrosis treatment. Based on previous work we carried out further structure modifications and led to a more selective inhibitor 47 by averting some fibrosis-unrelated kinases, such as RET, AXL and ALK. Extensive profiling of compound 47 has demonstrated that it has potent DDR1/2 inhibitory activities, low toxicity, good pharmacokinetic properties and reliable in vivo anti-fibrosis efficacy. Therefore, we confirmed that discoidin domain receptors are promising drug targets for IPF, and compound 47 would be a promising candidate for further drug development.

Design and development of a novel series of oral bivalent BET inhibitors with potent anticancer activities.

Bromodomain and extraterminal domain (BET) subfamily members are intriguing targets for cancer treatment. Most of the reported BET inhibitors were monovalent inhibitors. Recently, some bivalent inhibitors were disclosed, which bound to two bromodomains simultaneously. They had good activities, however, most of them also showed unsatisfactory pharmacokinetic properties, which were caused by long chain linkers. Based on our previous work on monovalent BRD4 inhibitors, we designed and synthesized a series of novel bivalent inhibitors with short and hydrophilic linkers. These compounds exhibited better activities than the corresponding monovalent inhibitors and good pharmacokinetic properties. Compound 21 showed excellent in vitro activities. And it also demonstrated potent in vivo antitumor efficacy under oral administration and was well tolerated in in vivo tests.

Asymmetric [4 + 2] Annulation of Cyclobutenones and Pyrazolone 4,5-Diones: Access to Novel δ-Lactone-Fused Spiropyrazolones.

Although numerous chiral pyrazolones with a six-membered spirocyclic center at the C4 position have been developed, the asymmetric construction of six-membered oxa-spiropyrazolones is still a challenging task in organic synthesis. Herein, we describe the [4 + 2] annulation of cyclobutanones and pyrazoline-4,5-diones for the efficient synthesis of δ-lactone-fused spiropyrazolone derivatives with generally high yields and good enantioselectivities under mild conditions. The successful scale-up synthesis and further transformation of the final product highlight the practicality and reliability of this reaction.

Advances in indole-containing alkaloids as potential anticancer agents by regulating autophagy.

Cancer is a leading cause of death worldwide, and cancer development is often associated with disturbances in the autophagy process. Autophagy is a catabolic process involved in many physiological processes, crucial for cell growth and survival. It is an intracellular lysosomal/vacuolar degradation system. In this system, inner cytoplasmic cell membrane is degraded by lysosomal hydrolases, and the products are released back into the cytoplasm. Indole alkaloids are natural products extensively found in nature and have been proven to possess various pharmacological activities. In recent years, pharmacological studies have demonstrated another potential of indole alkaloids, autophagy regulation. The regulation may contribute to the efficacy of indole alkaloids in preventing and treating cancer. This review summarizes the current understanding of indole alkaloids' effect on tumor cells and autophagy. Then, we focus on mechanisms by which indole alkaloids can target the autophagy process associated with cancer, including the PI3K/Akt/mTOR signaling pathway, MAPK signaling pathway, ROS signaling pathway, Beclin-1, and so on. Literature has been surveyed primarily from 2009 to Nov. 2021, and some semisynthetic or fully synthetic indole derivatives are also discussed.

Construction of CF3-Functionalized Fully Substituted Benzonitriles through Rauhut-Currier Reaction Initiated [3 + 3] Benzannulation.

Though numerous cyanation reactions have been developed for the synthesis of benzonitriles, the construction of valuable fully substituted benzonitriles is still a challenging task. Herein, we reported a tertiary amine-catalyzed [3 + 3]-benzannulation for the green synthesis of CF3-functionalized fully substituted benzonitriles. This strategy features exclusive chemoselectivity, high atom-economy, and good step-economy with environment-friendly reagents and mild conditions. Unique triphenyl-substituted dicyanobenzoate products could be rapidly constructed using this method. The practicality and reliability of this reaction were proved by the successful scale-up synthesis. A mechanistic study indicates that the [3 + 3]-benzannulation was initiated by an intermolecular Rauhut-Currier reaction.

Stereoselective synthesis of trifluoroethyl 3,2'-spirooxindole γ-lactam through the organocatalytic cascade reaction of 3-((2,2,2-trifluoroethyl)amino)indolin-2-one.

Newly designed 3-((2,2,2-trifluoroethyl)amino)indolin-2-ones were used for the facile synthesis of chiral fluoroalkyl-containing 3,2'-spirooxindole γ-lactam products. The secondary amine-catalysed Michael/hemiaminalization cascade reaction of 3-((2,2,2-trifluoroethyl)amino)indolin-2-one with α,ß-unsaturated aldehydes followed by oxidation can easily produce the desired products in high yields (up to 86%) with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to >95 : 5 dr).