Evolution of a strategy for preparing bioactive small molecules by sequential multicomponent assembly processes, cyclizations, and diversification

Abstract

A strategy for generating diverse collections of small molecules has been developed that features a multicomponent assembly process (MCAP) to efficiently construct a variety of intermediates possessing an aryl aminomethyl subunit. These key compounds are then transformed via selective ring-forming reactions into heterocyclic scaffolds, each of which possesses suitable functional handles for further derivatizations and palladium-catalyzed cross coupling reactions. The modular nature of this approach enables the facile construction of libraries of polycyclic compounds bearing a broad range of substituents and substitution patterns for biological evaluation. Screening of several compound libraries thus produced has revealed a large subset of compounds that exhibit a broad spectrum of medicinally-relevant activities.

Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease

“…As part of a broad effort to identify novel compounds with possible applications in neuroscience (Martin ; Sahn et al . ), we screened collections of substituted heterocyclic compounds against a variety of CNS proteins in the Psychoactive Drug Screening Program (PDSP) (Besnard et al . ).…”

“…As part of a broad effort to identify novel compounds with possible applications in neuroscience (Martin 2013;Sahn et al 2014), we screened collections of substituted heterocyclic compounds against a variety of CNS proteins in the Psychoactive Drug Screening Program (PDSP) (Besnard et al 2012). We thus identified a subclass of substituted norbenzomorphans that bind to Sig2R with high affinity (Sahn and Martin 2012;Sahn et al 2016).…”

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…Indeed, after unveiling the original concept, 215 we applied this approach to the synthesis of numerous heterocyclic scaffolds that could be easily diversified. 216,217 …”

Small molecule modulators of σ2R/Tmem97 reduce alcohol withdrawal-induced behaviors

“…Toward discovering novel compounds for biological screening, we developed a general platform for preparing diverse collections of substituted heterocyclic scaffolds, and we discovered a set of analogs of norbenzomorphans 1 and methanobenzazocines 2 (Fig. 1) that exhibit high affinity and selectivity for σ2R/Tmem97 [19][20][21][22]. Several of these σ2R/Tmem97 modulators show therapeutic effects in animal models of central nervous system (CNS) disorders [23,24].…”