Small molecule agonists of toll-like receptors 7 and 8: a patent review 2014 - 2020.

INTRODUCTION: Toll-like receptors 7 and 8 (TLR7 and TLR8) are endosomal immune receptors that initiate an innate immune response and can facilitate activation of the adaptive immune system. Both preclinical and clinical studies have shown the downstream inflammatory response from TLR7 and TLR8 agonism results in preliminary efficacy for the treatment of cancer, viral infections, and for use as a vaccine adjuvant. AREAS COVERED: This patent review covers recent developments in small molecule TLR7 and TLR8 agonists published between January 2014 - February 2020. We summarize relevant chemical scaffolds, observed structure-activity relationships, and where available, preliminary animal models, and clinical data. EXPERT OPINION: In the last 6 years, there has been significant progress in the optimization of novel TLR7 and TLR8 small molecule agonists. These novel compounds are currently being evaluated in the clinic for multiple antiviral and oncology indications. Clinical data from these trials will provide a clearer outlook on 1) the TLR7/8 engagement necessary to obtain the desired immune response, 2) safety margin improvement using directed delivery, and 3) potential synergistic effects with checkpoint inhibitor combination therapies.

A Mild and General Larock Indolization Protocol for the Preparation of Unnatural Tryptophans.

A mild and general protocol for the Pd(0)-catalyzed heteroannulation of o-bromoanilines and alkynes is described. Application of a Pd(0)/P((t)Bu)3 catalyst system enables the efficient coupling of o-bromoanilines at 60 °C, mitigating deleterious side reactions and enabling access to a broad range of useful unnatural tryptophans. The utility of this new protocol is demonstrated in the highly convergent total synthesis of the bisindole natural product (-)-aspergilazine A.

Copper-catalyzed diastereoselective arylation of tryptophan derivatives: total synthesis of (+)-naseseazines A and B.

A copper-catalyzed arylation of tryptophan derivatives is reported. The reaction proceeds with high site- and diastereoselectivity to provide aryl pyrroloindoline products in one step from simple starting materials. The utility of this transformation is highlighted in the five-step syntheses of the natural products (+)-naseseazine A and B.

A Copper-Catalyzed Arylation of Tryptamines for the Direct Synthesis of Aryl Pyrroloindolines.

An operationally simple, copper-catalyzed arylation of N-tosyltryptamines provides direct access to C3-aryl pyrroloindolines. A range of electron-donating and electron-withdrawing substituents is tolerated on both the indole backbone and the aryl electrophile. These reactions occur under ambient temperatures and with equimolar quantities of the coupling partners.

Enantioselective synthesis of tryptophan derivatives by a tandem Friedel-Crafts conjugate addition/asymmetric protonation reaction.

The tandem Friedel-Crafts conjugate addition/asymmetric protonation reaction between 2-substituted indoles and methyl 2-acetamidoacrylate is reported. The reaction is catalyzed by (R)-3,3'-dibromo-BINOL in the presence of stoichiometric SnCl(4), and is the first example of a tandem conjugate addition/asymmetric protonation reaction using a BINOL·SnCl(4) complex as the catalyst. A range of indoles furnished synthetic tryptophan derivatives in good yields and high levels of enantioselectivity, even on a preparative scale. The convergent nature of this transformation should lend itself to the preparation of unnatural tryptophan derivatives for use in a broad array of synthetic and biological applications.

A series of molecular dynamics and homology modeling computer labs for an undergraduate molecular modeling course.

As computational modeling plays an increasingly central role in biochemical research, it is important to provide students with exposure to common modeling methods in their undergraduate curriculum. This article describes a series of computer labs designed to introduce undergraduate students to energy minimization, molecular dynamics simulations, and homology modeling. These labs were created as part of a one-semester course on the molecular modeling of biochemical systems. Students who completed these activities felt that they were an effective component of the course, reporting improved comfort with the conceptual background and practical implementation of the computational methods. Although created as a component of a larger course, these activities could be readily adapted for a variety of other educational contexts. As well, all of these labs utilize software that is freely available in an academic environment and can be run on fairly common computer hardware, making them accessible to teaching environments without extensive computational resources.