Synthesis of Isoquinuclidines via Dearomative Diels-Alder Reaction of Cyclic Amidines with Indoles.

The development and utilization of new dienes and dienophiles for the controlled synthesis of isoquinuclidines is highly appealing. Herein, we describe a novel strategy for diastereoselective synthesis of indoline-fused isoquinuclidines via copper-catalyzed dearomative Diels-Alder reaction of cyclic amidines with indoles. This protocol avoids the use of unstable DHPs and activated alkenes, offering a more efficient and selective approach to synthesize isoquinuclidines.

Organocatalytic enantioselective construction of axially chiral (1H)-isochromen-1-imines.

Heterocycloalkenyl atropisomers, derived from biaryl atropisomers and axially chiral styrenes, have emerged as a new class of nonbiaryl C-C atropisomers due to the benefit in improving the pharmacological activity and structural diversity. This paper proposes an intramolecular annulation strategy for constructing the heterocycloalkenyl atropisomers (1H)-isochromen-1-imines by organocatalysis. Various heterocycloalkenyl atropisomers (1H)-isochromen-1-imines were prepared in good to excellent yields with excellent enantioselectivity (up to 98% ee), and could be easily converted to atropisomeric lactones isocoumarins.

M335, a novel small-molecule STING agonist activates the immune response and exerts antitumor effects.

In the context of antitumor immune responses, the activation of the stimulator of interferon genes (STING) assumes a critical role and imparts enhanced immunogenicity. An effective strategy for exogenously activating the immune system involves the utilization of STING agonists, and prior investigations primarily concentrated on modifying endogenous cyclic dinucleotides (CDNs) to achieve this. Nevertheless, the practical utility of CDNs was restricted due to limitations associated with their physicochemical attributes and administration protocols. In this article, we present the discovery of a novel small-molecule agonist denoted as M335, identified through high-throughput screening using surface plasmon resonance (SPR). M335 demonstrates the ability to activate the TBK1-IRF3-IFN axis in a STING-dependent manner in vitro. Through experimentation on mouse models bearing tumors, we observed that the administration of M335 resulted in the activation of immune cells. Notably, significant antitumor effects were achieved with both intratumoral and intraperitoneal administration of M335. These findings suggest the potential of M335 as a promising agent for cancer immunotherapy, which will promote the development of STING agonists in anti-tumor applications.