Natural Product Analogues Research Articles

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.

Synthesis and Neurotrophic Activity Studies of Illicium Sesquiterpene Natural Product Analogues.

Neurotrophic natural products hold potential as privileged structures for the development of therapeutic agents against neurodegeneration. However, only a few studies have been conducted to investigate a common pharmacophoric motif and structure-activity relationships (SARs). Here, an investigation of structurally more simple analogues of neurotrophic sesquiterpenes of the illicium family is presented. A concise synthetic route enables preparation of the carbon framework of (±)-Merrilactone A and (±)-Anislactone A/B on a gram scale. This has allowed access to a series of structural analogues by modification of the core structure, including variation of oxidation levels and alteration of functional groups. In total, 15 derivatives of the natural products have been synthesized and tested for their neurite outgrowth activities. Our studies indicate that the promising biological activity can be retained by structurally simpler natural product analogues, which are accessible by a straightforward synthetic route.

Silver-Mediated Oxidative Decarboxylative Trifluoromethylthiolation of Coumarin-3-carboxylic Acids.

The introduction of trifluoromethylthio groups into organic compounds, in particular heterocycles, is important because of the prevalence of these structures in medicinally and agriculturally relevant molecules. Herein, the silver-mediated oxidative decarboxylative trifluoromethylthiolation of coumarin-3-carboxylic acids is reported. This methodology utilizes existing carboxylic acid functionalities for the direct conversion to CF3S groups and results in a broad scope of 3-trifluoromethylthiolated coumarins, including analogues of natural products, in moderate to excellent yields.

Natural product analogues: towards a blueprint for analogue-focused synthesis.

For the first time a general overview of approaches to the synthesis of natural product analogues is presented. This reflects a process of evolution of natural product synthesis which has accelerated in the years since the implementation of diversity-oriented synthesis, which has emerged in parallel with collective synthesis, diverted total synthesis and the preparation of truncated natural products optimised for biological activity. A method involving computational assessment for the validation of core-modified natural product analogues is discussed.

Bluegenics: Bioactive Natural Products of Medicinal Relevance and Approaches to Their Diversification.

Nature provides a valuable resource of medicinally relevant compounds, with many antimicrobial and antitumor agents entering clinical trials being derived from natural products. The generation of analogues of these bioactive natural products is important in order to gain a greater understanding of structure activity relationships; probing the mechanism of action, as well as to optimise the natural product's bioactivity and bioavailability. This chapter critically examines different approaches to generating natural products and their analogues, exploring the way in which synthetic and biosynthetic approaches may be blended together to enable expeditious access to new designer natural products.

A multicomponent macrocyclization strategy to natural product-like cyclic lipopeptides: synthesis and anticancer evaluation of surfactin and mycosubtilin analogues.

A multicomponent macrocyclization strategy towards cyclic lipopeptides is described. The approach relies on the utilization of the Ugi and Passerini multicomponent reactions for the cyclization of peptides and oxo-peptides, and here it is employed for the construction of a small library of analogues of the natural products mycosubtilin and surfactin A. A key feature of this method is the simultaneous incorporation of either one or two exocyclic lipid tails along with the macrocyclic ring closure, which is only possible due to the multicomponent nature of the macrocyclization step. The evaluation of the anticancer activity of the lipopeptide library showed that the installation of a second lipid moiety in the surfactin scaffold leads to a more potent cytotoxicity in cancer cells. This is a new example of the multicomponent reaction potential in rapidly producing natural product analogues for biological screening.

First chemo-enzymatic synthesis of the (R)-Taniguchi lactone and substrate profiles of CAMO and OTEMO, two new Baeyer\u2013Villiger monooxygenases

This study investigates the substrate profile of cycloalkanone monooxygenase and 2-oxo-Δ3-4,5,5-trimethylcyclopentenylacetyl-coenzyme A monooxygenase, two recently discovered enzymes of the Baeyer–Villiger monooxygenase family, used as whole-cell biocatalysts. Biooxidations of a diverse set of ketones were performed on analytical scale: desymmetrization of substituted prochiral cyclobutanones and cyclohexanones, regiodivergent oxidation of terpenones and bicyclic ketones, as well as kinetic resolution of racemic cycloketones. We demonstrated the applicability of the title enzymes in the enantioselective synthesis of (R)-(−)-Taniguchi lactone, a building block for the preparation of various natural product analogs such as ent-quinine.Graphical abstract

Scalable Synthesis of (-)-Thapsigargin.

Total syntheses of the complex, highly oxygenated sesquiterpenes thapsigargin (1) and nortrilobolide (2) are presented. Access to analogues of these promising bioactive natural products has been limited to tedious isolation and semisynthetic efforts. Elegant prior total syntheses demonstrated the feasibility of creating these entitites in 36–42 step processes. The currently reported route proceeds in a scalable and more concise fashion by utilizing two-phase terpene synthesis logic. Salient features of the work include application of the classic photosantonin rearrangement and precisely choreographed installation of the multiple oxygenations present on the guaianolide skeleton.

Optimized one-pot synthesis of monoarylidene and unsymmetrical diarylidene cycloalkanones

Ionic liquid dimethylammonium dimethylcarbamate (DIMCARB) catalyzed reaction for the synthesis of monoarylidene and unsymmetrical diarylidene cycloalkanones has been developed. Catalytic amount of DIMCARB was used in green solvent (water and ethanol) for different reaction of cyclic and acyclic ketones with different electron donating and withdrawing substituted aldehydes. Yields were recorded from low to excellent. This synthetic methodology provides mild, efficient, and environmentally friendly access to unsymmetrical curcuminoid analogs, avoiding the use of excess catalysts, chlorinated organic solvent, and high temperature reaction. It is green and environmentally sound alternative to the existing protocols for the synthesis of pharmaceutically important unsymmetrical natural product analogs.

Formation and reductive ring opening reactions of indolyl bicyclic-isoxazolidines-II:7 access to novel natural product analogs

Attempted reductive cleavage of indolyl-bicyclic-isoxazolidines (4a,b; R=benzyl, phenyl) with ammonium formate, methanol-THF solvents, at ambient temperature, in the presence of Pd/C lead to facile synthesis of indolyl-α-hydroxy-γ-lactams (5a–b), derived from reductive cleavage of the NO bond of bicyclic-isoxazolidines, followed by intramolecular recyclization. On the other hand, reaction of 4c (R=ethyl) under identical conditions follows a different course affording 6, an analogue of naturally occurring marine alkaloid, aplysinopsin. A mechanistic rationale of observed reactivity behavior, supported by DFT calculations, is provided.

A Synthetic Study towards the Marmycins and Analogues

A methodological study towards the total synthesis of marmycin A/B is described exploiting a commercial anthraquinone molecule as model compound. The challenging synthetic pathway uncovers a copper-catalysed Ullmann cross-coupling to attach the sugar backbone by means of C–N bond formation and, finally, an intramolecular Friedel–Crafts C–C glycosylation to successfully afford the core structure of marmycin A. This methodology has been successfully applied to the genuine anthraquinone moiety leading to the natural product and simpler structural analogues.

Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues.

Conventional chemotherapy is commonly used for advanced stages of transitional cell carcinoma (TCC) with modest success and high morbidity; however, TCC eventually develops resistance. Muscle invasive bladder cancer (MIBC) is recognized as a lethal disease due to its poor response to traditional chemotherapy. Numerous studies have implicated β-catenin, a critical effector in Wnt–mediated pathway associated with epithelial-mesenchymal transition and cancer stem cell, is involved in TCC progression, and furthermore closely associated with chemo-resistance. In this study, we discovered a novel natural product analogue CYD 6-17 that has a potent inhibitory effect on TCC cells exhibiting drug resistance to various chemotherapeutics, with an IC50 at nM range. Delivery of CYD 6-17 significantly inhibited the tumor growth using xenograft model but without detectable side effects. Mechanistically, it targeted β-catenin gene transcription by decreasing the binding of XBP1 to the promoter region, which appeared to be a new regulatory mechanism for β-catenin gene expression. Clinically, XBP1 expression correlated with the poor overall survival of patients. Overall, this study unveils unique mechanism of β-catenin gene regulation in advanced TCC and also offers a potential rational therapeutic regimen to MIBC.

Synthesis of Aza-Rocaglates via ESIPT-Mediated (3+2) Photocycloaddition.

Synthesis of aza-rocaglates, nitrogen-containing analogues of the rocaglate natural products, is reported. The route features ESIPT-mediated (3+2) photocycloaddition of 1-alkyl-2-aryl-3-hydroxyquinolinones with the dipolarophile methyl cinnamate. A continuous photoflow reactor was utilized for photocycloadditions. An array of compounds bearing the hexahydrocyclopenta[b]indole core structure was synthesized and evaluated in translation inhibition assays.

Abstract 3013: Identification of PHF5A as a common cellular target of splicing-modulating chemical probes

Abstract Recent discoveries that splicing factors such SF3B1, U2AF1, SRSF2 are frequently mutated in multiple hematological malignancies including chronic lymphocytic leukaemia and myelodysplastic syndromes have generated interest in therapeutic approaches to target the splicesome dependency in cancer cells bearing mutations in splicing factors. Previously, several structurally unrelated natural compounds including pladienolide, herboxidiene, and FR901464 have been shown to exert potent anti-proliferative effects in cancer cells grown in vitro. Further optimization has led to the discovery of natural product analogs (e.g. E7107) with anti-tumor efficacy in vivo in xenograft models. Target identification has revealed the SF3B complex of the splicesome as the common action site for these compounds. Recent work has demonstrated biological and genetic evidence that single amino acid substitution (R1074H) in SF3B1 completely abolished the anti-proliferative effect of pladienolide derivative E7107, suggesting that SF3B1 is the direct binding partner for pladienolides. However, the same SF3B1 R1074H mutation does not provide equal level of protections for cells treated with herboxidiene derivatives, indicating differential mechanism of action for these two classes of splicing modulators. To identify targets for herboxidiene-like compounds, we have generated resistant HCT116 clones upon continuous administration of herboxidiene derivative H3B-37045 in vitro. Whole exome sequencing from 6 resistant clones revealed a common Y36C mutation in SF3B subunit component PHF5A (SF3B14b). Over-expression of PHF5A Y36C but not the wild-type form in parental HCT116 cells confirmed the protective effect of this mutation to H3B-37045. Surprisingly, PHF5A Y36C expression also conferred resistance to the pladienolide derivative E7107, which indicates that, unlike the SF3B1 R1074H mutation, PHF5A resides within a common node of action site among different splicing modulators. RNA-seq, biochemical and structure homology-modeling analysis suggested that PHF5A Y36C mutation disrupted the action of splicing modulators through interfering with the compounds’ interaction with the SF3B complex. Detailed analysis of the function of the Y36C mutant and wild-type PHF5A in the SF3B complex is currently ongoing. Understanding the function of PHF5A in splicing and the molecular mechanism of Y36C mutation shall provide new insights of the biological role of splicesome, and guide the development of next generation splicesome inhibitors. Citation Format: Teng Teng, Xiaoling Puyang, Shouyong Peng, Jacob Feala, Betty Chan, Jennifer Tsai, Benjamin Caleb, Craig Karr, Eunice Park, Laura Corson, Yoshiharu Mizui, Peter Smith, Nicholas Larsen, Lihua Yu, Markus Warmuth, Ping Zhu, Agustin Chicas. Identification of PHF5A as a common cellular target of splicing-modulating chemical probes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3013.

Synthesis of hybrid natural product analogues with anti-tumour properties

High yielding and diastereoselective conjugate addition reactions of a (−)-quinic acid derived enone have provided access to a small library of hybrid analogues of the anti-tumour natural products antheminone A and COTC. The novel compounds were assessed for their antiproliferative activities towards the A549 non-small-cell lung cancer cell line revealing some useful structure-activity relationships.

ChemInform Abstract: Function‐Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?

AbstractReview: [39 refs.

Global profiling and rapid matching of natural products using diagnostic product ion network and in silico analogue database: Gastrodia elata as a case study

Rapid discovery of novel compounds of a traditional herbal medicine is of vital significance for pharmaceutical industry and plant metabolic pathway analysis. However, discovery of unknown or trace natural products is an ongoing challenge. This study presents a universal targeted data-independent acquisition and mining strategy to globally profile and effectively match novel natural product analogues from an herbal extract. The famous medical plant Gastrodia elata was selected as an example. This strategy consists of three steps: (i) acquisition of accurate parent and adduct ions (PAIs) and the product ions data of all eluting compounds by untargeted full-scan MSE mode; (ii) rapid compound screening using diagnostic product ions (DPIs) network and in silico analogue database with SUMPRODUCT function to find novel candidates; and (iii) identification and isomerism discrimination of multiple types of compounds using ClogP and ions fragment behavior analyses. Using above data mining methods, a total of 152 compounds were characterized, and 70 were discovered for the first time, including series of phospholipids and novel gastroxyl derivatives. Furthermore, a number of gastronucleosides and phase II metabolites of gastrodin and parishins were discovered, including glutathionylated, cysteinylglycinated and cysteinated compounds, and phosphatidylserine analogues. This study extended the application of classical DPIs filter strategy and developed a structure-based screening approach with the potential for significant increase of efficiency for discovery and identification of trace novel natural products.

Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?

It is important to pursue function-oriented synthesis (FOS), a strategy for the design of less structurally complex targets with comparable or superior activity that can be made in a practical manner, because compared to synthetic drugs, many biologically relevant natural products possess large and complex chemical structures that may restrict chemical modifications in a structure-activity relationship study. In this account, we describe recent efforts to simplify complex nucleoside natural products including caprazamycins. Considering the structure-activity relationship study with several truncated analogues, three types of simplified derivatives, namely, oxazolidine, isoxazolidine, and lactam-fused isoxazolidine-containing uridine derivatives, were designed and efficiently synthesized. These simplified derivatives have exhibited promising antibacterial activities. A significant feature of our studies is the rational and drastic simplification of the molecular architecture of caprazamycins. This study provides a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria.

Recent Research And Development Of Annonaceous Acetogenins

Studies on the Annonaceous acetogenins began after the first cytotoxic acetogenin, uvaricin, was isolated in 1982 [1]. This attractive finding made many medicinal and natural product chemists direct their efforts on the isolation and identification of these classes of compounds. As more Annonaceous acetogenins were isolated, more information about them was uncovered. From their structural identification to the total synthesis of natural product analogues and from cell-based screening and molecular-based targeting to animal testing, the mechanisms of action of the Annonaceous acetogenins became clearer [2]. The aim of this study is to give an account of recent studies on this class of compounds and their analogues, which will aid us not only in clarifying how the Annonaceous acetogenins act but also in establishing principles for the further development of this class of compounds.

Alteration of Polyketide Stereochemistry from anti to syn by a Ketoreductase Domain Exchange in a Type I Modular Polyketide Synthase Subunit.

Polyketide natural products have broad applications in medicine. Exploiting the modular nature of polyketide synthases to alter stereospecificity is an attractive strategy for obtaining natural product analogues with altered pharmaceutical properties. We demonstrate that by retaining a dimerization element present in LipPks1+TE, we are able to use a ketoreductase domain exchange to alter α-methyl group stereochemistry with unprecedented retention of activity and simultaneously achieve a novel alteration of polyketide product stereochemistry from anti to syn. The substrate promiscuity of LipPks1+TE further provided a unique opportunity to investigate the substrate dependence of ketoreductase activity in a polyketide synthase module context.