Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure–activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents.
Esters are bulk and fine chemicals and ubiquitous in polymers, bioactive compounds, and natural products. Their traditional synthetic approach is the esterification of carboxylic acids or their activated derivatives with alcohols. Herein, a bimetallic relay catalytic protocol was developed for the aerobic esterification of one alcohol in the presence of a slowly oxidizing alcohol, which has been identified as methanol. A concise synthesis of phlomic acid was executed to demonstrate the practicality and potential of this reaction.
Abstract The reaction of 7‐mercapto‐4‐methylcoumarin (4) with 1‐mono‐ and 1,1‐dimethyl propargyl alcohols in H3PO4 afforded the corresponding β‐(7‐coumarinthio)ketones with a rearrangement of the carbon chain of propargyl. A possible mechanism of this rearrangement was proposed.
Abstract Peptide multifunctionalization is a crucial technique to develop peptide‐based agents for various purposes. Porphyrin‐peptide conjugates are a class of popular multifunctional peptides renowned for their multifunctional and multimodal properties. However, the tedious synthetic works for porphyrin building blocks are involved in most previous studies. In this work, a modular solid‐phase synthetic approach is reported to construct trans ‐AB 2 C porphyrin on peptide chains without presynthesized porphyrin building blocks. The products from this approach, which inherit both functionalities from the porphyrins and the modules employed for constructing porphyrins, show potential in biomedical and biomaterial applications. Furthermore, by extending this synthetic approach, the first example of “resin‐to‐resin” reaction is reported to link two peptides together along the construction of porphyrin motifs to give porphyrin‐peptide conjugates with two different peptide chains.
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