Ring-Opening Coupling of Cyclopropanol with 1,2,3-Triazole for the Synthesis of Fused Triazoles.

A radical ring-opening arylation of cyclopropanol with 1,2,3-triazole has been achieved. This synthetic protocol provides straightforward access to a wide range of structurally diverse and chiral 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyridines with high efficiency from readily available chiral cyclopropanols.

A Bischler-Napieralski and homo-Mannich sequence enables diversified syntheses of sarpagine alkaloids and analogues.

Sarpagine alkaloids offer signicant opportunities in drug discovery, yet the efficient total syntheses and diverse structural modifications of these natural products remain highly challenging due to the architectural complexity. Here we show a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction enables a protecting-group-free, redox economic, four-step access to the tetracyclic sarpagine core from L-tryptophan esters. Based on this advancement, diversified syntheses of sarpagine alkaloids and analogues are achieved in a short synthetic route. The systematic anticancer evaluation indicates that natural products vellosimine and Na-methyl vellosimine possess modest anticancer activity. Intensive structural optimization of these lead molecules and exploration of the structure-activity relationship lead to the identification of analogue 15ai with an allene unit showing a tenfold improvement in anticancer activities. Further mechanism studies indicate compound 15ai exertes antiproliferation effects by inducing ferroptosis, which is an appealing non-apoptotic cell death form that may provide new solutions in future cancer therapies.

A Homo-Mannich Reaction Strategy Enables Collective Access to Ibophyllidine, Aspidosperma, Kopsia, and Melodinus Alkaloids.

We report here a homo-Mannich reaction of cyclopropanol with an iminium ion, generated by an asymmetric allylic dearomatization of indole, to construct a tricyclic hydrocarbazole core, which is shared by a variety of monoterpenoid indole alkaloids across families. Through this approach, an all-carbon quaternary stereogenic center as well as an allyl and a ketone group were installed. Using this functionalized hydrocarbazole as the structural platform, D ring and E rings of different sizes (i.e., five-, six-, and seven-membered) were successively or simultaneously assembled, leading to a collective asymmetric synthesis of seven alkaloids belonging to the ibophyllidine, Aspidosperma, Kopsia, and Melodinus alkaloid families.

Enantioselective Synthesis and Biological Evaluation of Pyrrolidines Bearing Quaternary Stereogenic Centers.

Molecular complexity plays an increasingly important role in the modern pharmaceutical industry. Setting up multiple stereogenic centers in privileged substructures may give rise to improved or even unprecedented bioactivities; however, this area remains largely unexplored due to the tremendous synthetic challenges. Herein, we report a series of multisubstituted pyrrolidines with four continuous stereogenic centers, including up to two aza-QSCs (quaternary stereogenic centers). Systematic evaluations, including phenotypic screening, molecular docking, molecular dynamics, bioinformatics, and bioactivity analysis, have been performed to screen entities with pharmacological properties of interest. Among them, compound 4m with two QSCs was identified to be a potent antiproliferation agent through disturbing mitosis exit, and the presence of QSCs was found to be crucial for anticancer efficacy. This work illustrates that the introduction of QSCs in privileged scaffolds not only helps to expand the unpatented chemical space but also provides new opportunities for the discovery of novel therapeutic agents.

A bridged backbone strategy enables collective synthesis of strychnan alkaloids.

Bridged frameworks are of high chemical and biological significance, being ubiquitous in pharmaceutical molecules and natural products. Specific structures are usually preformed to build these rigid segments at the middle or late stage in the synthesis of polycyclic molecules, resulting in decreased synthetic efficiency and target-specific syntheses. As a logically distinct synthetic strategy, we constructed an allene/ketone-equipped morphan core at the outset through an enantioselective α-allenylation of ketones. Experimental and theoretical results revealed that the high reactivity and enantioselectivity of this reaction are attributed to the cooperative effects of the organocatalyst and metal catalyst. The bridged backbone generated was employed as a structural platform to guide and facilitate the assembly of up to five fusing rings, and the allene and ketone groups thereon were used to precisely install various functionalities at C16 and C20 at the late stage, leading to a concise, collective total synthesis of nine strychnan alkaloids.

Arylation of Cyclopropanol with Pyrrole: Asymmetric Synthesis of Indolizidine 167B, Indolizidine 209D, and Monomorine I.

A Fe(NO3)3-mediated ring-opening arylation of cyclopropanol with the electron-rich pyrrole has been developed, which might proceed through oxidative radical ring opening of cyclopropanol followed by cyclization to the pyrrole motif and then aromatization. This method enables direct arylation of cyclopropanol without prefunctionalization and thus allows rapid access to a diverse array of chiral 5,6,7,8-tetrahydroindolizines from easily available chiral amino acid esters. The synthetic utility has been demonstrated by the asymmetric synthesis of alklaoids (-)-indolizidine 167B, (+)-indolizidine 209D, (+)-monomorine I, and a natural product analogue.

An updated patent review of IDO1 inhibitors for cancer (2018-2022).

INTRODUCTION: Indoleamine 2,3-dioxygenase 1 (IDO1) is highly related to the immune evasion of a wide range of malignancies due to its role in the immune suppression caused by the depletion of tryptophan (Trp) and the accumulation of kynurenine (Kyn). The combination of IDO1 inhibitors with other treatments represents a promising strategy in immunotherapy, although considerable challenges lie ahead. AREAS COVERED: This review focuses on patent publications searched from Espacenet and Google Scholar, and related to IDO1 inhibitors with potential anti-cancer utilization during the period 2018-2022. EXPERT OPINION: Despite the clinical trial failure of the first-in-class IDO1 inhibitor epacadostat in combination with pembrolizumab, numerous studies have been carried on to pursue more efficient IDO1-based immune-modulating therapeutic solutions. A large number of IDO1 inhibitors with new structures and design concepts have been produced with the impetus of crystallographic studies, and have shown great research potential. The elaboration on the combination of IDO1 inhibitors with other targeting agents, the more precise selection of patients, the identification of more reliable biomarkers for evaluating the IDO1 treatment, and the investigation of possible toxicity, are critical factors to promote IDO1-based immunotherapies from bench to bedside.

Generation and [2,3]-Sigmatropic Rearrangement of Ammonium Ylides from Cyclopropyl Ketones for Chiral Indolizidines with Bridgehead Quaternary Stereocenters.

A sequence of nucleophilic ring opening of cyclopropyl ketones, N-quaternization, deprotonation, and [2,3]-sigmatropic rearrangement of ammonium ylides has been developed. This method enables efficient synthesis of bicyclic indolizidines bearing bridgehead aza-quaternary stereocenters from easily available chiral cyclopropyl ketones. The reactions proceeded with an excellent level of chirality transfer and tolerated various functional groups, providing a diverse array of allenyl- or allyl-substituted indolizidines with high enantiomeric purities (up to >99% ee).

Asymmetric Total Syntheses of Schizozygane Alkaloids.

The concise, collective, and asymmetric total syntheses of four schizozygane alkaloids, which feature a "Pan lid"-like hexacyclic core scaffold bearing up to six continuous stereocenters, including two quaternary ones, are described. A new method of dearomative cyclization of cyclopropanol onto the indole ring at C2 was developed to build the ABCF ring system of the schizozygane core with a ketone group. Another key skeleton-building reaction, the Heck/carbonylative lactamization cascade, ensured the rapid assembly of the hexacyclic schizozygane core and concurrent installation of an alkene group. By strategic use of these two reactions and through late-stage diversifications of the functionalized schizozygane core, the first and asymmetric total syntheses of (+)-schizozygine, (+)-3-oxo-14α,15α-epoxyschizozygine, and (+)-α-schizozygol and the total synthesis of (+)-strempeliopine have been accomplished in 11-12 steps from tryptamines.

A patent review of mTOR inhibitors for cancer therapy (2011-2020).

INTRODUCTION: The mammalian target of rapamycin (mTOR) kinase is a central component in the PI3K/Akt/mTOR pathway and plays a crucial role in tumor biology, making it one appealing therapeutic target. In the past decade, the mTORi (mTOR inhibitor) development field has made great progress, with more agents entering key trials and the proposal of third-generation mTORi concept. Yet to achieve significant clinical success, combined efforts from multiple disciplines are ever needed. AREAS COVERED: This review focuses on the progress of mTORi development with anticancer potential from the perspective of the patent literature proposed between 2011 and 2020. EXPERT OPINION: The highly complex regulatory mechanism network of mTOR proposes huge challenges to the development of clinically efficient mTORis. While in-depth biological research and fundamental medchemistry research are of importance to provide guidelines for improving mTORis, new technologies to pre-diagnose applicable populations is another key to provide precise personal cancer treatment. New mTOR agents are ever needed to tackle the common problems of side effects and drug resistance.

Artificial Intelligence and Cheminformatics-Guided Modern Privileged Scaffold Research.

With the rapid development of computer science in scopes of theory, software, and hardware, artificial intelligence (mainly in form of machine learning and more complex deep learning) combined with advanced cheminformatics is playing an increasingly important role in drug discovery process. This development has also facilitated privileged scaffold-related research. By definition, a privileged scaffold is a structure that frequently occurs in diverse bioactive molecules, either has a diverse family affinity or is selective to multiple family members in a superfamily, whilst it is different from the"frequent hitters", or the "pan-assay interference compounds". The long history of the use of this concept has witnessed a functional shift from stand-alone technology towards an integrated component in the drug discovery toolbox. Meanwhile, continuous efforts have been dedicated to deepening the understandings of the features of known privileged scaffolds. In this contribution, we focus on the current privileged scaffold-related research driven by state-of-art artificial intelligence approaches and cheminformatics. Representative cases with an emphasis on distinct research aspects are presented, including an update of the knowledge on privileged scaffolds, proofof- concept tools, and workflows to identify privileged scaffolds and to carry on de novo design, informatic SAR models with diversely complex data sets to provide an instructive prediction on new potential molecules bearing privileged scaffolds.

Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids.

We report here a concise, collective, and asymmetric total synthesis of sarpagine alkaloids and biogenetically related koumine alkaloids, which structurally feature a rigid cage scaffold, with L-tryptophan as the starting material. Two key bridged skeleton-forming reactions, namely tandem sequential oxidative cyclopropanol ring-opening cyclization and ketone α-allenylation, ensure concurrent assembly of the caged sarpagine scaffold and installation of requisite derivative handles. With a common caged intermediate as the branch point, by taking advantage of ketone and allene groups therein, total synthesis of five sarpagine alkaloids (affinisine, normacusine B, trinervine, Na -methyl-16-epipericyclivine, and vellosimine) with various substituents and three koumine alkaloids (koumine, koumimine, and N-demethylkoumine) with more complex cage scaffolds has been accomplished.

Cyclin-dependent kinase 4/6 inhibitors for cancer therapy: a patent review (2015 - 2019).

INTRODUCTION: Cyclin-dependent kinases 4 and 6 (CDK4/6) along with their upstream/downstream components are pivotal regulators for the cell cycle progression. The dysfunction of CDK4/6 is the common feature and promoting factor in various cancer types. In-depth research on CDK4/6 inhibitors has afforded therapeutic agents, while new challenges and ideas are emerging concomitantly. AREAS COVERED: This review focuses on patent publications related to CDK4/6 inhibitors which could be utilized for anti-cancer purposes during the period 2015-2019. EXPERT OPINION: The increasingly comprehensive and thorough understanding of CDK4/6 inhibitors facilitates them to break through the current limitations. Hence the utilization of CDK4/6 inhibitors for cancer therapy in the near future is likely to be performed in diverse forms and for distinct purposes. Selectivity over kinases is still crucial to new agent development but shall be prudently dealt with. The gradually revealing of resistance and adverse events proposed another issue that calls for new tackling strategies.

Design, synthesis, biological evaluation of benzoyl amide derivatives containing nitrogen heterocyclic ring as potential VEGFR-2 inhibitors.

For the purpose of synthesizing drug candidates with desirable bioactivity, a class of benzoyl amide containing nitrogen heterocyclic ring derivatives targeting VEGFR-2 was designed and screened out using Discovery Studio. Eighteen target compounds were synthesized and then selected by some biological trials sequentially including inhibition of VEGFR-2, anti-proliferation in vitro, flow cytometry. Among them, compound 8h showed the best inhibitory activity (IC50 = 0.34 ±â€¯0.02 µM against VEGFR-2, IC50 = 1.08 ±â€¯0.06 µM and 2.44 ±â€¯0.15 µM against MCF-7 and HepG-2, respectively, which were at the same inhibitory level with the commercially antitumor drug: vandetanib). In addition, flow cytometry demonstrated that compound 8h induced MCF-7 cell apoptosis through a cell membrane-mediated pathway. This research highlights the therapeutic potential of novel VEGFR-2 inhibitors in treating cancers and provides a promising strategy for drug discovery.

A patent review of BRAF inhibitors: 2013-2018.

Introduction: As a key element in arguably the most important pathway MAPK signaling, the BRAF kinase gives rise to severe diseases including cancers when pathologically activated. Extensive research on BRAFi (BRAF inhibitor) has been carried out to profile the characters for optimized agents and to elaborate the therapeutic strategies for the related cancer treatment. Areas covered: This review gives an overview of recently approved BRAF agents on function mode, therapeutic efficacy, and deficiency, based on which current challenges and corresponding strategies were presented. New entities as BRAFi for medical purpose in patent literature during the period 2013-2018 were also briefly introduced. Expert opinion: With the disclosure of paradox-breaker BRAFi PLX7904 crystal in complex with BRAF, the rational design for next-generation BRAFi is becoming ever more feasible. Accompanying therapeutic strategies in BRAFi elaboration may also provide flexible choice in the future 'personal medicine'. Further digging in the greatly enriched BRAFi pool will greatly benefit the drug design processes such as FBDD- and SBDD-driven development.

Identification and Biological Evaluation of Novel Type†II B-RafV600E Inhibitors.

The mitogen-activated protein kinase (MAPK) pathway plays a vital role in signal transduction networks. Severe diseases may be triggered if it is disturbed by mutated components, especially the kinase B-RafV600E . New inhibitors of the kinase are needed as cases of relapse and resistance with the known drugs have been widely reported in the clinic. In the present work, a new class of B-RafV600E inhibitors was identified by fragment linking. In vitro and in vivo assays were used to demonstrate the pharmacological properties of the compounds. 3-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}-N-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]benzamide was the most potent agent with IC50 values of 0.035±0.004 µm (B-RafV600E kinase) and 0.39±0.04 µm (A375 cells). Furthermore, no obvious toxicity was observed. Collectively, the results favored justified the design rationale and hinted that this new chemotype might be worth studying further to develop novel B-Raf inhibitor candidates.

Design, synthesis, and biological evaluation of new B-RafV600E kinase inhibitors.

The association of deregulated signal pathways with various diseases has long been a research hotspot. One of the most important signal pathways, the MAPK (mitogen-activated protein kinase) signal pathway, plays a vital role in transducing extracellular signals into vital intracellular mechanisms. While mutations on its key component Raf kinase lead to sever diseases, targeted inhibition has thereby become an attractive therapeutic strategy. Several drugs have been approved for the treatment of Raf relevant diseases, yet more candidates are ever needed as the known drugs have confronted resistance and side effects. In the present study, we primarily investigated the binding modes of type I/II and type II inhibitors with B-Raf kinase. Based on the current knowledge, these ligands were fragmented and recombined to provide new interesting insights. Afterwards, a series of derivatives has been synthesized after the validation of hit compound. In addition, in vitro assays were carried out to profile the pharmacological properties of all the entities. Of all the compounds, compound 5h showed the best profile and may be used in the future study.

Naphthoquinones: A continuing source for discovery of therapeutic antineoplastic agents.

Naturally occurring naphthoquinones, usually in forms of botanical extracts, have been implicated with human life since ancient time, far earlier than their isolation and identification in modern era. The long use history of naphthoquinones has witnessed their functional shift from the original purposes as dyes and ornaments toward medicinal benefits. Hitherto, numerous studies have been carried out to elucidate the pharmacological profile of both natural and artificial naphthoquinones. A number of entities have been identified with promising therapeutic potential. Apart from the traditional effects of wound healing, anti-inflammatory, hemostatic, antifertility, insecticidal and antimicrobial, etc., the anticancer potential of naphthoquinones either in combination with other treatment approaches or on their own is being more and more realized. The molecular mechanisms of naphthoquinones in cells mainly fall into two categories as inducing oxidant stress by ROS (reactive oxygen species) generation and directly interacting with traditional therapeutic targets in a non-oxidant mechanism. Based on this knowledge, optimized agents with naphthoquinones scaffold have been acquired and further tested. Hereby, we summarize the explored biological mechanisms of naphthoquinones in cells and review the application perspective of promising naphthoquinones in cancer therapies.

Identification of new shikonin derivatives as STAT3 inhibitors.

The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design. In this study, we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold, guided by computational modelling. By tests, PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast cancer cells, especially for the MDA-MB-231 cells. For the cellular mechanisms research, PMMB-187 was found to induce cell apoptosis in MDA-MB-231 cells, associated with the reduction of mitochondrial membrane potential, production of ROS and alteration of the levels of apoptosis-related proteins. Furthermore, PMMB-187 inhibited constitutive/inducible STAT3 activation, transcriptional activity, nuclear translocation and downstream target genes expression in STAT3-dependent breast cancer cells MDA-MB-231. Besides, no obvious inhibitory effect on activation of STAT1 and STAT5 was observed with PMMB-187 treatment. Most notably, the in vivo studies further revealed that PMMB-187 could dramatically suppress the MDA-MB-231 cells xenografted tumor growth. The in vitro and in vivo results collectively suggest that PMMB-187 may serve as a promising lead compound for the further development of potential therapeutic anti-neoplastic agents.

Exploring gene expression changes in the amphioxus gill after poly(I:C) challenge using digital expression profiling.

Amphioxus, a cephalochordate, is a key model animal for studying the evolution of vertebrate immunity. Recently, studies have revealed that microRNA (miRNA) expression profiles change significantly in the amphioxus gill after immune stimulation, but it remains largely unknown how gene expression responds to immune stress. Elucidating gene expression changes in the amphioxus gill will provide a deeper understanding of the evolution of gill immunity in vertebrates. Here, we used high-throughput RNA sequencing technology (RNA-seq) to conduct tag-based digital gene expression profiling (DGE) analyses of the gills of control Branchiostoma belcheri and of those exposed to the viral mimic, poly(I:C) (pIC). Six libraries were created for the control and treatment groups including three biological replicates per group. A total of 1999 differently expressed genes (DEGs) were obtained, with 571 and 1428 DEGs showing up- or down-regulation, respectively, in the treatment group. Enrichment analysis of gene ontology (GO) terms and pathways revealed that the DEGs were primarily related to immune and defense response, apoptosis, human disease, cancer, protein metabolism, enzyme activity, and regulatory processes. In addition, eight DEGs were randomly selected to validate the RNA-seq data using real-time quantitative PCR (qRT-PCR), and the results confirmed the accuracy of the RNA-seq approach. Next, we screened eight key responding genes to examine the dynamic changes in expression levels at different time points in more detail. The results indicated that expressions of TRADD, MARCH, RNF31, NF-κb, CYP450, TNFRSF6B, IFI and LECT1 were induced to participate in the antiviral response against pIC. This study provides a valuable resource for understanding the role of the amphioxus gill in antiviral immunity and the evolution of gill immunity in vertebrates.