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 via bioinformatics guided genome mining and culturomics. Through these efforts, an impressive number of structurally intriguing antibiotics, with enhanced chemical diversity vis-à-vis conventional antibiotics have been isolated from human commensal bacteria, thereby generating considerable interest in their total synthesis and expanding their therapeutic space for drug discovery. These developments augur well for the discovery of new drugs and antibiotics, particularly in the context of challenges posed by mycobacterial resistance and emerging new diseases. The current landscape of various synthetic campaigns and drug discovery initiatives on antibacterial natural products from the human microbiome is captured in this review with an intent to stimulate further activities in this interdisciplinary arena among the new generation.

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 SNAr and SNArH 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 ortho-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. The prospect of merging the C-H activation of nitroarenes with C-NO2 activation, thereby harnessing NO2 as a transformable multitasking directing group, is also illustrated.

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. It is expected that this timely account will foster interest in newer ways of macrocycle construction among practitioners of organic synthesis and chemical biology to advance the field.

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.

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. The purpose of this review is to highlight these recent advances and to stimulate interest towards broader applications of arenediazonium salts as aryl transfer agents in bioconjugation reactions.

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.

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. The early promise of using the diterpene forskolin and its semi-synthetic analogs as AC activators has given way to new leads in the last decade from novel natural products like the marine sesterterpenoids alotaketals and ansellones and the 9,9'-diarylfluorenone cored selaginpulvilins, etc. and their synthesis has drawn much attention. This review captures these contemporary developments, particularly total synthesis campaigns and structure-guided analog design in the context of AC and PDE-4 modulating attributes and the scope for future possibilities.

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 viz. 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. The strategy has already recorded commercial success in the development of antineoplastic drugs topotecan and irinotecan and in industrial production of pravastatin, calcitriol and artemisinin. This Feature Article highlights the broad contours of this evolving paradigm at the interface of natural product and synthetic chemistry research to accelerate and widen the scope of natural product-based drug discovery.

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. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34+ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34+ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses. Mol Cancer Ther; 16(8); 1497-510. ©2017 AACR.

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. Debio 0617B showed in vivo efficacy by inhibiting tumor growth in several mouse xenograft models. To increase in vivo efficacy and STAT3 inhibition, Debio 0617B was tested in combination with the EGFR inhibitor erlotinib in a non-small cell lung cancer xenograft model. To evaluate the impact of in vivo STAT3 blockade on metastases, Debio 0617B was tested in an orthotopic tumor model. Measurement of primary tumor weight and metastatic counts in lung tissue demonstrated therapeutic efficacy of Debio 0617B in this model. These data show potent activity of Debio 0617B on a broad spectrum of STAT3-driven solid tumors and synergistic activity in combination with EGFR inhibition. Mol Cancer Ther; 15(10); 2334-43. ©2016 AACR.

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.