Squaramide Formation for DNA-Encoded Library Synthesis.

DNA-encoded libraries (DELs) can be considered as one of the most powerful tools for the discovery of small molecules of biological interest. However, the ability to access large DELs is contingent upon having chemical transformations that work in aqueous phase and generate minimal DNA alterations and the availability of building blocks compatible with on-DNA chemistry. In addition, accessing scaffolds of interest to medicinal chemists can be challenging in a DEL setting because of inherent limitations of DNA-supported chemistry. In this context, a squaramide formation reaction was developed by using a two-step process. The mild and high-yielding reaction tolerates a wide array of functional groups and was shown to be safe for DNA, thereby making this methodology ideal for DELs.

Urotensin II Receptor Modulation with 1,3,4-Benzotriazepin-2-one Tetrapeptide Mimics.

Urotensin II receptor (UT) modulators that differentiate the effects of the endogenous cyclic peptide ligands urotensin II (UII) and urotensin II-related peptide (URP) offer potential for dissecting their respective biological roles in disease etiology. Selective modulators of hUII and URP activities were obtained using 1,3,4-benzotriazepin-2-one mimics of a purported bioactive γ-turn conformation about the Bip-Lys-Tyr tripeptide sequence of urocontrin ([Bip4]URP). Considering an active ß-turn conformer about the shared Phe-Trp-Lys-Tyr sequence of UII and URP, 8-substituted 1,3,4-benzotriazepin-2-ones were designed to mimic the Phe-Bip-Lys-Tyr tetrapeptide sequence of urocontrin, synthesized, and examined for biological activity. Subtle 5- and 8-position modifications resulted in biased signaling and selective modulation of hUII- or URP-induced vasoconstriction. For example, p-hydroxyphenethyl analogs 17b-d were strong Gα13 and ßarr1 activators devoid of Gαq-mediated signaling. Tertiary amides 15d and 17d negatively modulated hUII-induced vasoconstriction without affecting URP-mediated responses. Benzotriazepinone carboxamides proved to be exceptional tools for elucidating the pharmacological complexity of UT.

1,3,5,8-Tetrasubstituted 1,3,4-Benzotriazepin-2-one Scaffolds for ß-Turn Mimicry without Stereogenic Carbon Centers: Synthesis and Conformational Analysis.

Topological mimicry of peptide ß-turn secondary structures has been investigated using a 1,3,5,8-tetrasubstituted 1,3,4-benzotriazepin-2-one scaffold. Approaches were conceived for the synthesis of tetrasubstituted benzotriazepinones from 4-acetyl-3-aminobenzoate based on aza-amino acid chemistry and different orthogonal protection strategies. Installation of an 8-position carboxylate on the aromatic ring enabled a diverse array of substituents to be introduced for mimicry of the i-position residue. Benzotriazepin-2-one crystallization and X-ray analysis demonstrated that in spite the absence of a stereogenic carbon center, the scaffold could serve as type I and I' ß-turn mimics, because pyramidalization of the N3-nitrogen in the benzotriazepin-2-one provides potential for adoptive chirality. 1,3,5,8-Tetrasubstituted 1,3,4-benzotriazepin-2-one scaffolds offer interesting potential for the cost-effective synthesis of nonpeptide ß-turn surrogates for peptide mimicry in various recognition events.

Applications of γ,δ-Unsaturated Ketones Synthesized by Copper-Catalyzed Cascade Addition of Vinyl Grignard Reagents to Esters.

γ,δ-Unsaturated ketones, so-called homoallylic ketones, have served as versatile building blocks for the synthesis of a variety of heterocycles, carbocycles, natural products, and reactive intermediates. Procured by a variety of processes, including conjugate addition of vinyl organometallic reagents to unsaturated ketones, allylation of silyl enol ethers, and rearrangements, homoallylic ketones are often synthesized by step-intensive methods. The cascade addition of 2 equiv of vinyl Grignard reagent to a carboxylate was reported by the Lubell laboratory in 2003 to give effective access to homoallylic ketones from a variety of aromatic, aliphatic, and α-amino methyl esters. Employing readily accessible vinyl magnesium halides in the presence of a catalytic amount of copper salt, this cascade reaction provides high yields of homoallylic ketones with minimal side product by a process featuring the assembly and collapse of a tetrahedral intermediate with expulsion of alkoxide ion, followed by conjugate addition to the resulting enone. Application of the cascade reaction to the synthesis of various homoallylic ketones has provided versatile building blocks for the synthesis of targets for different applications. For example, by employing (hetero)aryl di- and tricarboxylates as precursors, copper-catalyzed cascade additions have provided donor-acceptor and star-shaped monomers for optical-electronic materials. Amino ester starting materials have given homoallylic ketones for the synthesis of various peptidomimetics, including heteroarylalanines, hydroxyethylene isoesters, and diazepinone turn mimics. Moreover, anthranilate has served as building block to prepare various pyrrole, quinoline, benzodiazepine, and benzotriazepine heterocyles. In addition, cascade additions on hydroxyprolinates have given access to bipyrrole precursors of the prodigiosin family of natural products. In the interest to highlight the utility of the copper-catalyzed cascade addition of vinyl Grignard reagents to carboxylates, this Account provides details on the broad scope of substrates that deliver homoallylic ketone products as well as an overview of the wide range of applications in which this method may impact including materials and peptide science, heterocycle and natural product synthesis, and medicinal chemistry.

Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics.

Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the urotensin II receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Effectively synthesized, benzotriaepin-2-one turn mimics offer the potential to differentiate the respective roles, signaling pathways, and phenotypic outcomes of hUII and URP in the UT system.

Chemoselective Alkylation for Diversity-Oriented Synthesis of 1,3,4-Benzotriazepin-2-ones and Pyrrolo[1,2][1,3,4]benzotriazepin-6-ones, Potential Turn Surrogates.

1,3,4-Benzotriazepin-2-ones garner interest for medicinal applications, in part due to their relationship with benzodiazepinones. Ten 1,3,4-benzotriazepin-2-ones 6 and 19 and six pyrrolo[1,2][1,3,4]benzotriazepin-6-ones 7 and 23 were prepared in four to seven steps and 4-60% overall yields by a divergent strategy from methyl anthranilate employing chemoselective alkylations of common linear and cyclic precursors to diversify three triazepinone ring positions (N1, N3, and C5). X-ray crystallography demonstrated that benzotriazepinone 19g may serve as a γ-turn mimic.

Synthesis and evaluation of antimalarial properties of novel 4-aminoquinoline hybrid compounds.

Pharmacophore hybridization has recently been employed in the search for antimalarial lead compounds. This approach chemically links two pharmacophores, each with their own antimalarial activity and ideally with different modes of action, into a single hybrid molecule with the goal to improve therapeutic properties. In this paper, we report the synthesis of novel 7-chloro-4-aminoquinoline/primary sulfonamide hybrid compounds. The chlorinated 4-aminoquinoline scaffold is the core structure of chloroquine, an established antimalarial drug, while the primary sulfonamide functional group has a proven track record of efficacy and safety in many clinically used drugs and was recently shown to exhibit some antimalarial activity. The activity of the hybrid compounds was determined against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. While the hybrid compounds had lower antimalarial activity when compared to chloroquine, they demonstrated a number of interesting structure-activity relationship (SAR) trends including the potential to overcome the resistance profile of chloroquine.