Photosensitized Nickel Catalysis Enabled Silyl Radical Mediated Direct Activation of Carbamoyl Chlorides to Access (Hetero)aryl Carbamides

The transformation of a readily available molecule to a medicinally relevant functionality is the heart of organic synthesis which literally unfolds new direction in the field of drug discovery and development. Accordingly, synthetic chemistry fraternity is constantly striving to introduce a range of avant-garde techniques to construct an incredibly important fundamental entity like “amide bonds” which connect the amino acids in proteins and exist as a prevalent structural motif in biomolecules. In this context, we want to introduce the concept of cross-electrophile coupling by merging the photoredox and transition metal catalysis to construct carbamides from superabundant (hetero)aryl chlorides or bromides along with commercially feasible carbamoyl chlorides. However, there is barely any report on direct activation of carbamoyl chloride so far. To circumvent the challenge, we employ the intrinsic affinity of silyl radical species towards halogen atom to harness the carbamoyl radical directly from carbamoyl chlorides which is seemingly the first of its kind. The success of this protocol relies on the prior formation of ‘aryl halides to Ni-catalyst’ oxidative addition intermediate that assists in generation of the vital carbamoyl radical. The breadth of application of this technique is significantly demonstrated by the synthesis of a plethora of (hetero)aryl carbamides with diverse functionalities. As stated earlier, we outline the direct utility of this protocol by the late-stage amidation of halide containing drug molecules and pharmacophores.

Trehalose amide glycolipids as Mincle ligands: Towards new vaccine adjuvants

<p>The development of new vaccines to respond to infectious diseases requires new vaccine adjuvants, which improve vaccine efficacy and shape the immune response. Trehalose glycolipids, consisting of α,α'-trehalose esterified at the 6- and 6'- positions with lipids, exhibit adjuvant activity by binding and activating Macrophage inducible C-type lectin (Mincle). However, the adjuvant activity of trehalose glycolipids could potentially be improved by substituting the ester linkages for more physiologically stable amide bonds. This thesis presents a short protecting group free route to trehalose amide glycolipids, thus allowing for the synthesis of the straight chain glycolipid amides 1a-e in four steps and in excellent (53-61%) overall yields (Figure 1). Amide glycolipids 1a-e were demonstrated to be Mincle agonists with comparable activity to their ester counterparts, as determined using a green fluorescent protein (GFP) reporter cell line assay. A second generation of trehalose amide glycolipids, the lipidated brartemicin amide analogues 2a-c, were subsequently synthesised (Figure 1). This report is the first example of trehalose amide glycolipids acting as Mincle agonists, and further studies into the potential of the amides as vaccine adjuvants will be undertaken in due course.</p>

Trehalose amide glycolipids as Mincle ligands: Towards new vaccine adjuvants

<p>The development of new vaccines to respond to infectious diseases requires new vaccine adjuvants, which improve vaccine efficacy and shape the immune response. Trehalose glycolipids, consisting of α,α'-trehalose esterified at the 6- and 6'- positions with lipids, exhibit adjuvant activity by binding and activating Macrophage inducible C-type lectin (Mincle). However, the adjuvant activity of trehalose glycolipids could potentially be improved by substituting the ester linkages for more physiologically stable amide bonds. This thesis presents a short protecting group free route to trehalose amide glycolipids, thus allowing for the synthesis of the straight chain glycolipid amides 1a-e in four steps and in excellent (53-61%) overall yields (Figure 1). Amide glycolipids 1a-e were demonstrated to be Mincle agonists with comparable activity to their ester counterparts, as determined using a green fluorescent protein (GFP) reporter cell line assay. A second generation of trehalose amide glycolipids, the lipidated brartemicin amide analogues 2a-c, were subsequently synthesised (Figure 1). This report is the first example of trehalose amide glycolipids acting as Mincle agonists, and further studies into the potential of the amides as vaccine adjuvants will be undertaken in due course.</p>

Collectivism in a Replication Network of Minimal Nucleobase Sequences

A major challenge for understanding the origins of life is to explore how replication networks can engage in an evolutionary process. Herein, we shed light on this problem by implementing a network constituted by two different types of extremely simple biological components: the amino acid cysteine and the canonical nucleobases adenine and thymine, connected through amide bonds to the cysteine amino group and oxidation of its thiol into three possible disulfides. Supramolecular and kinetic analyses revealed that both self- and mutual interactions between such dinucleobase compounds drive their assembly and replication pathways. Those pathways involving sequence complementarity led to enhanced replication rates, suggesting a potential bias for selection. The interplay of synergistic dynamics and competition between replicators was then simulated in an open reactor with experimental kinetic data, showing the selective amplification of different species depending on the initial mixture composition. Overall, this network configuration can favor a collective adaptability to changes in the availability of feedstock molecules, with disulfide exchange reactions serving as 'wires' that connect the different individual auto- and cross-catalytic pathways.

Conformational rearrangements enable iterative backbone N-methylation in RiPP biosynthesis

Peptide backbone α-N-methylations change the physicochemical properties of amide bonds to provide structural constraints and other favorable characteristics including biological membrane permeability to peptides. Borosin natural product pathways are the only known ribosomally encoded and posttranslationally modified peptides (RiPPs) pathways to incorporate backbone α-N-methylations on translated peptides. Here we report the discovery of type IV borosin natural product pathways (termed ‘split borosins’), featuring an iteratively acting α-N-methyltransferase and separate precursor peptide substrate from the metal-respiring bacterium Shewanella oneidensis. A series of enzyme-precursor complexes reveal multiple conformational states for both α-N-methyltransferase and substrate. Along with mutational and kinetic analyses, our results give rare context into potential strategies for iterative maturation of RiPPs.

Diversification of LytM Protein Functions in Polar Elongation and Cell Division of Agrobacterium tumefaciens

LytM-domain containing proteins are LAS peptidases (lysostaphin-type enzymes, D-Ala-D-Ala metallopeptidases, and sonic hedgehog) and are known to play diverse roles throughout the bacterial cell cycle through direct or indirect hydrolysis of the bacterial cell wall. A subset of the LytM factors are catalytically inactive but regulate the activity of other cell wall hydrolases and are classically described as cell separation factors NlpD and EnvC. Here, we explore the function of four LytM factors in the alphaproteobacterial plant pathogen Agrobacterium tumefaciens. An LmdC ortholog (Atu1832) and a MepM ortholog (Atu4178) are predicted to be catalytically active. While Atu1832 does not have an obvious function in cell growth or division, Atu4178 is essential for polar growth and likely functions as a space-making endopeptidase that cleaves amide bonds in the peptidoglycan cell wall during elongation. The remaining LytM factors are degenerate EnvC and NlpD orthologs. Absence of these proteins results in striking phenotypes indicative of misregulation of cell division and growth pole establishment. The deletion of an amidase, AmiC, closely phenocopies the deletion of envC suggesting that EnvC might regulate AmiC activity. The NlpD ortholog DipM is unprecedently essential for viability and depletion results in the misregulation of early stages of cell division, contrasting with the canonical view of DipM as a cell separation factor. Finally, we make the surprising observation that absence of AmiC relieves the toxicity induced by dipM overexpression. Together, these results suggest EnvC and DipM may function as regulatory hubs with multiple partners to promote proper cell division and establishment of polarity.

Dispersion Stability And Tribological Properties of Covalently Modified Graphene As A Lubricating Oil Additive

Graphene has excellent mechanical properties with a low coefficient of friction and wear resistance and has a wide range of tribological applications. However, the stable dispersion of graphene in lubricating media is challenging. In this study, graphene is processed via covalent modification. A mild oxidation method selectively grafts carboxyl groups on the edge of the graphene sheet, before connecting tertiary alkyl primary amines through amide bonds. The alkyl chain allows graphene to be stably dispersed in hydrocarbon solvents.. FT-IR, XPS, Raman, XRD, SEM, etc. are used to characterize the covalently modified graphene (MG). Dispersion stability experiments showed that MG exhibited stable dispersion in 500N base oil and 15w-40 commercial lubricants, with stability for over 2 months. Tribological test results show that MG in 500N and 15w-40 significantly reduces the friction and wear of steel-steel friction pairs. The stable dispersion of MG in lubricating oil enables the formation of a stable chemical reaction film and graphene physical deposition film during the friction, protects the worn surface, and reduces direct contact, thereby significantly reducing friction and wear.

Preparation of Soluble POSS-Linking Polyamide and Its Application in Antifogging Films

In this study, we prepared a polyhedral oligomeric silsesquioxane (POSS)-linking polyamide (POSS polyamide) by a polycondensation of ammonium-functionalized POSS (POSS-A) and carboxyl-functionalized POSS (POSS-C) in dehydrated dimethyl sulfoxide (DMSO) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) as condensing agents. The obtained POSS polyamide was soluble in various highly polar solvents, and it could form a self-standing film. FT-IR, 1H NMR, and 29Si NMR analyses showed that POSS polyamide is a polymer in which POSS-A and POSS-C are linked almost linearly by amide bonds. Furthermore, the cast film obtained by heat-treating the polymer at 150 °C for 30 min exhibited excellent transparency and hard-coating (pencil scratch test: 5H) and antifogging properties (evaluation by water vapor exposure).