Natural products from the human microbiome: an emergent frontier in organic synthesis and drug discovery.

Often referred to as the "second genome", the human microbiome is at the epicenter of complex inter-habitat biochemical networks like the "gut-brain axis", which has emerged as a significant determinant of cognition, overall health and well-being, as well as resistance to antibiotics and susceptibility to diseases. As part of a broader understanding of the nexus between the human microbiome, diseases and microbial interactions, whether encoded secondary metabolites (natural products) play crucial signalling roles has been the subject of intense scrutiny in the recent past. A major focus of these activities involves harvesting the genomic potential of the human microbiome bioinformatics guided genome mining and culturomics.

C-H modification of natural products: a minimalist enabling tactic for drug discovery, API processing and bioconjugation.

Intrusion into the C-H chemical space of natural products through the strategic deployment of C-H functionalization reactions could lead to incredibly new molecular diversities with an unforeseen impact on biological functions. Based on this hypothesis, semisynthetic C-H modification of natural products is emerging as a minimalist tactic in natural product based drug discovery. Several examples of C-H modification of natural products, resulting in functional gains in key pharmacological attributes potency, aqueous solubility and DMPK profile, along with opportunities in allied areas such as API processing, bioconjugation, and target deconvolution, continue to surface in the recent literature.

C-H activation reactions of nitroarenes: current status and outlook.

Ring substitution reactions of nitroarenes remain an under-developed area of organic synthesis, confined to the narrow domains of SAr and SArH reactions. While searching for alternative methodologies, we took stock of the C-H activation reactions of nitroarenes which unearthed a variety of examples of nitro directed regioselective C-H functionalization reactions such as -arylation, -benzylation/alkylation, and -allylation, oxidative Heck and C-H arylation reactions on (hetero)aromatic rings. A collective account of these reactions is presented in this review to showcase the existing landscape of C-H activation reactions of nitroarenes, to create interest in this field for further development and propagate this strategy as a superior alternative for ring substitution reactions of nitroarenes.

Macrocyclization via C-H functionalization: a new paradigm in macrocycle synthesis.

The growing emphasis on macrocycles in engaging difficult therapeutic targets such as protein-protein interactions and GPCRs via preferential adaptation of bioactive and cell penetrating conformations has provided impetus to the search for de novo macrocyclization strategies that are efficient, chemically robust and amenable to diversity creation. An emerging macrocyclization paradigm based on the C-H activation logic, of particular promise in the macrocyclization of complex peptides, has added a new dimension to this pursuit, enabling efficacious access to macrocycles of various sizes and topologies with high atom and step economy. Significant achievements in macrocyclization methodologies and their applications in the synthesis of bioactive natural products and drug-like molecules, employing strategic variations of C-H activation are captured in this review.

Modifications of amino acids using arenediazonium salts.

Aryl transfer reactions from arenediazonium salts have started to make their impact in chemical biology with initial forays in the arena of arylative modifications and bio-conjugations of amino acids, peptides and proteins. The unique multimodal reactivity of arenediazonium salts, ranging from thermal or photochemical radical chain reactions, Pd-catalyzed coupling to arylazo-coupling reactions, all under distinct but mild conditions, provides multiple options for side chain modifications of amino acids and peptides and in addition, site-selective protein conjugation and labelling, protein immobilization, azo-bridged macrocyclization, etc. under bio-ambient conditions.

Biaryl synthesis with arenediazonium salts: cross-coupling, CH-arylation and annulation reactions.

The rich legacy of arenediazonium salts in the synthesis of unsymmetrical biaryls, built around the seminal works of Pschorr, Gomberg and Bachmann more than a century ago, continues to make important contributions at various evolutionary stages of modern biaryl synthesis. Based on in-depth mechanistic analysis and design of novel pathways and reaction conditions, the scope of biaryl synthesis with arenediazonium salts has enormously expanded in recent years through applications of transition metal/photoredox-catalysed cross-coupling, thermal/photosensitized radical chain CH-arylation of (hetero)arenes and arylative radical annulation reactions with alkynes. These recent developments have provided facile synthetic access to a wide variety of unsymmetrical biaryls of pharmaceutical, agrochemical and optoelectronic importance with green scale-up options and created opportunities for late-stage modification of peptides, nucleosides, carbon nanotubes and electrodes, the details of which are captured in this review.

Natural products as modulators of the cyclic-AMP pathway: evaluation and synthesis of lead compounds.

It is now well recognized that the normal cellular response in mammalian cells is critically regulated by the cyclic-AMP (cAMP) pathway through the appropriate balance of adenylyl cyclase (AC) and phosphodiesterase-4 (PDE4) activities. Dysfunctions in the cAMP pathway have major implications in various diseases like CNS disorders, inflammation and cardiac syndromes and, hence, the modulation of cAMP signalling through appropriate intervention of AC/PDE4 activities has emerged as a promising new drug discovery strategy of current interest. In this context, synthetic small molecules have had limited success so far and therefore parallel efforts on natural product leads have been actively pursued.

Metal-Free S-Arylation of Cysteine Using Arenediazonium Salts.

A mild chemoselective method for S-arylation of cysteine has been developed in an open-flask procedure under metal-free conditions using arenediazonium salts in methanol.

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34 Stem/Progenitor Cells.

Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation.

Debio 0617B Inhibits Growth of STAT3-Driven Solid Tumors through Combined Inhibition of JAK, SRC, and Class III/V Receptor Tyrosine Kinases.

Tumor survival, metastases, chemoresistance, and escape from immune responses have been associated with inappropriate activation of STAT3 and/or STAT5 in various cancers, including solid tumors. Debio 0617B has been developed as a first-in-class kinase inhibitor with a unique profile targeting phospho-STAT3 (pSTAT3) and/or pSTAT5 in tumors through combined inhibition of JAK, SRC, ABL, and class III/V receptor tyrosine kinases (RTK). Debio 0617B showed dose-dependent inhibition of pSTAT3 in STAT3-activated carcinoma cell lines; Debio 0617B also showed potent antiproliferative activity in a panel of cancer cell lines and in patient-derived tumor xenografts tested in an in vitro clonogenic assay.

A tetraphenylmethane based dendritic tolan-anthracene dyad: synthesis and energy transfer properties.

In order to synthesize a peripherally rigid dendritic donor-acceptor dyad for energy transfer studies, a tritolan dendron based on a tetraphenylmethane scaffold was prepared from New Fuchsin. The dendron showed a small degree of homoconjugation but a large hypochromic effect. Coupling of two such dendrons with an anthracene core led to a dendritic tolan-anthracene dyad whose steady state photophysical studies (UV, PL, PLE) showed vectorial transfer of excitation energy from the surface tolan units to the anthracene core.