Highly Potent and Intestine Specific P-Glycoprotein Inhibitor to Enable Oral Delivery of Taxol.

Taxol is widely used in cancer chemotherapy; however, the oral absorption of Taxol remains a formidable challenge. Since the intestinal p-glycoprotein (P-gp) mediated drug efflux is one of the primary causes, the development of P-gp inhibitor is emerging as a promising strategy to realize Taxol's oral delivery. Because P-gp exists in many tissues, the non-selective P-gp inhibitors would lead to toxicity. Correspondingly, a potent and intestine specific P-gp inhibitor would be an ideal solution to boost the oral absorption of Taxol and avoid exogenous toxicity. Herein, we would like to report a highly potent and intestine specific P-gp inhibitor to enable oral delivery of Taxol in high efficiency. Through a multicomponent reaction and post-modification, various benzofuran-fused-piperidine derivatives were achieved and the biological evaluation identified 16c with potent P-gp inhibitory activity. Notably, 16c was intestine specific and showed almost none absorption (F = 0.82%), but possessing higher efficacy than Encequidar to improve the oral absorption of Taxol. In MDA-MB-231 xenograft model, the oral administration of Taxol and 16c showed high therapeutic efficiency and low toxicity, thus providing a valuable chemotherapy strategy.

A multicomponent reaction for modular assembly of indole-fused heterocycles.

Indoles are privileged chemical entities in natural products and drug discovery. Indole-fused heterocycles, particularly seven-membered ones, have received increasing attention due to their distinctive chemical characteristics and wide spectrum of bioactivities. However, the synthetic access to these compounds is highly limited. Herein, we report a unique multicomponent reaction (MCR) for modular assembly of indole-fused seven-membered heterocycles. In this process, indole, formaldehyde and amino hydrochloride could assemble rapidly to yield indole-fused oxadiazepines, and another addition of sodium thiosulphate would furnish indole-fused thiadiazepines. The biological evaluation disclosed the promising anticancer activity of these compounds. Furthermore, this MCR could be applicable in the late-stage and selective modifications of peptides. Therefore, this work provides a powerful strategy for indole functionalization and valuable tool for construction of seven-membered heterocycles.

Chemical Evolution and Biological Evaluation of Natural Products for Efficient Therapy of Acute Lung Injury.

Acute lung injury (ALI) is one of the most common complications in COVID-19 and also a syndrome of acute respiratory failure with high mortality rates, but lacks effective therapeutic drugs. Natural products provide inspiration and have proven to be the most valuable source for bioactive molecule discovery. In this study, the chemical evolution of the natural product Tanshinone IIA (Tan-IIA) to achieve a piperidine-fused scaffold through a synthetic route of pre-activation, multi-component reaction, and post-modification is presented. Through biological evaluation, it is pinpointed that compound 8b is a standout candidate with remarkable anti-inflammation and anti-oxidative stress properties, coupled with low toxicity. The mechanistic study unveils a multifaceted biological profile of 8b and shows that 8b is highly efficient in vivo for the treatment of ALI. Therefore, this work not only provides an effective strategy for the treatment of ALI, but also offers a distinctive natural product-inspired drug discovery.