Ring structures such as pyridine, cyclopentane or their combinations are important motifs in bioactive molecules. In contrast to previous cycloaddition reactions that necessitated a directly bonded initiating functional group, this work demonstrated a novel through-(hetero)arene radical transmission concept for selective activation of a remote bond. An efficient, metal-free and atom-economical [3+2] cycloaddition between 4-pyridinyl cyclopropanes and alkenes or alkynes has been developed for modular synthesis of pyridine-substituted cyclopentanes, cyclopentenes and bicyclo[2.1.1]hexanes that are difficult to access using known methods. This complexity-building reaction was catalyzed by a very simple and inexpensive diboron(4) compound and took place via dearomative/rearomative processes. The substrate scope was broad and more than 100 new compounds were prepared in generally high yields. Mechanistic experiments and density function theory (DFT) investigation supported a radical relay catalytic cycle involving alkylidene dihydropyridine radical intermediates and boronyl radical transfer.

Considering blood-sucking habits of leeches from surviving strategy of view, it can be hypothesized that leech saliva has analgesia or anesthesia functions for leeches to stay undetected by the host. However, no specific substance with analgesic function has been reported from leech saliva although clinical applications strongly indicated that leech therapy produces a strong and long lasting pain-reducing effect. Herein, a novel family of small peptides (HSTXs) including 11 members which show low similarity with known peptides was identified from salivary glands of the leech Haemadipsa sylvestris. A typical HSTX is composed of 22–25 amino acid residues including four half-cysteines, forming two intra-molecular disulfide bridges, and an amidated C-terminus. HSTX-I exerts significant analgesic function by specifically inhibiting voltage-gated sodium (NaV) channels (NaV1.8 and NaV1.9) which contribute to action potential electrogenesis in neurons and potential targets to develop analgesics. This study reveals that sodium channel inhibitors are analgesic substances in the leech. HSTXs are excellent candidates or templates for development of analgesics.

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Ring structures such as pyridine, cyclopentane or their combinations are important motifs in bioactive molecules. In contrast to previous cycloaddition reactions that necessitated a directly bonded initiating functional group, this work demonstrated a novel through‐(hetero)arene radical transmission concept for selective activation of a remote bond. An efficient, metal‐free and atom‐economical [3+2] cycloaddition between 4‐pyridinyl cyclopropanes and alkenes or alkynes has been developed for modular synthesis of pyridine‐substituted cyclopentanes, cyclopentenes and bicyclo[2.1.1]hexanes that are difficult to access using known methods. This complexity‐building reaction was catalyzed by a very simple and inexpensive diboron(4) compound and took place via dearomative/rearomative processes. The substrate scope was broad and more than 100 new compounds were prepared in generally high yields. Mechanistic experiments and density function theory (DFT) investigation supported a radical relay catalytic cycle involving alkylidene dihydropyridine radical intermediates and boronyl radical transfer.