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1.
ACS Infect Dis ; 10(6): 1935-1948, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38757505

ABSTRACT

Schistosomiasis, caused by a parasitic blood fluke of the genus Schistosoma, is a global health problem for which new chemotherapeutic options are needed. We explored the scaffold of gallinamide A, a natural peptidic metabolite of marine cyanobacteria that has previously been shown to inhibit cathepsin L-type proteases. We screened a library of 19 synthetic gallinamide A analogs and identified nanomolar inhibitors of the cathepsin B-type protease SmCB1, which is a drug target for the treatment of schistosomiasis mansoni. Against cultured S. mansoni schistosomula and adult worms, many of the gallinamides generated a range of deleterious phenotypic responses. Imaging with a fluorescent-activity-based probe derived from gallinamide A demonstrated that SmCB1 is the primary target for gallinamides in the parasite. Furthermore, we solved the high-resolution crystal structures of SmCB1 in complex with gallinamide A and its two analogs and describe the acrylamide covalent warhead and binding mode in the active site. Quantum chemical calculations evaluated the contribution of individual positions in the peptidomimetic scaffold to the inhibition of the target and demonstrated the importance of the P1' and P2 positions. Our study introduces gallinamides as a powerful chemotype that can be exploited for the development of novel antischistosomal chemotherapeutics.


Subject(s)
Cathepsin B , Schistosoma mansoni , Cathepsin B/antagonists & inhibitors , Cathepsin B/metabolism , Animals , Schistosoma mansoni/enzymology , Schistosoma mansoni/drug effects , Crystallography, X-Ray , Schistosomicides/pharmacology , Schistosomicides/chemistry , Protein Binding , Models, Molecular
2.
J Nat Prod ; 87(5): 1487-1492, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38695619

ABSTRACT

Scientific conferences and meetings are valuable opportunities for researchers to network, communicate, and develop knowledge. For early career scientists, conferences can also be intimidating, confusing, and overwhelming, especially without having adequate preparation or experience. In this Perspective, we provide advice based on previous experiences navigating scientific meetings and conferences. These guidelines outline parts of the hidden curriculum around preparing for and attending meetings, navigating conference sessions, networking with other scientists, and participating in social activities while upholding a recommended code of conduct.


Subject(s)
Congresses as Topic , Curriculum , Humans
3.
J Nat Prod ; 87(6): 1513-1520, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38781491

ABSTRACT

Current small-molecule-based SARS-CoV-2 treatments have limited global accessibility and pose the risk of inducing viral resistance. Therefore, a marine algae and cyanobacteria extract library was screened for natural products that could inhibit two well-defined and validated COVID-19 drug targets, disruption of the spike protein/ACE-2 interaction and the main protease (Mpro) of SARS-CoV-2. Following initial screening of 86 extracts, we performed an untargeted metabolomic analysis of 16 cyanobacterial extracts. This approach led to the isolation of an unusual saturated fatty acid, jobosic acid (2,5-dimethyltetradecanoic acid, 1). We confirmed that 1 demonstrated selective inhibitory activity toward both viral targets while retaining some activity against the spike-RBD/ACE-2 interaction of the SARS-CoV-2 omicron variant. To initially explore its structure-activity relationship (SAR), the methyl and benzyl ester derivatives of 1 were semisynthetically accessed and demonstrated acute loss of bioactivity in both SARS-CoV-2 biochemical assays. Our efforts have provided copious amounts of a fatty acid natural product that warrants further investigation in terms of SAR, unambiguous determination of its absolute configuration, and understanding of its specific mechanisms of action and binding site toward new therapeutic avenues for SARS-CoV-2 drug development.


Subject(s)
Antiviral Agents , Metabolomics , SARS-CoV-2 , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Humans , Cyanobacteria/chemistry , Structure-Activity Relationship , Fatty Acids/chemistry , Fatty Acids/pharmacology , COVID-19 , Molecular Structure , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism
4.
Nat Commun ; 13(1): 4619, 2022 08 08.
Article in English | MEDLINE | ID: mdl-35941113

ABSTRACT

The identity and biological activity of most metabolites still remain unknown. A bottleneck in the exploration of metabolite structures and pharmaceutical activities is the compound purification needed for bioactivity assignments and downstream structure elucidation. To enable bioactivity-focused compound identification from complex mixtures, we develop a scalable native metabolomics approach that integrates non-targeted liquid chromatography tandem mass spectrometry and detection of protein binding via native mass spectrometry. A native metabolomics screen for protease inhibitors from an environmental cyanobacteria community reveals 30 chymotrypsin-binding cyclodepsipeptides. Guided by the native metabolomics results, we select and purify five of these compounds for full structure elucidation via tandem mass spectrometry, chemical derivatization, and nuclear magnetic resonance spectroscopy as well as evaluation of their biological activities. These results identify rivulariapeptolides as a family of serine protease inhibitors with nanomolar potency, highlighting native metabolomics as a promising approach for drug discovery, chemical ecology, and chemical biology studies.


Subject(s)
Metabolomics , Protease Inhibitors , Chromatography, Liquid/methods , Magnetic Resonance Spectroscopy/methods , Metabolomics/methods , Protease Inhibitors/pharmacology , Tandem Mass Spectrometry/methods
5.
Mar Drugs ; 18(10)2020 Oct 14.
Article in English | MEDLINE | ID: mdl-33066480

ABSTRACT

The tropical marine cyanobacterium Moorena bouillonii occupies a large geographic range across the Indian and Western Tropical Pacific Oceans and is a prolific producer of structurally unique and biologically active natural products. An ensemble of computational approaches, including the creation of the ORCA (Objective Relational Comparative Analysis) pipeline for flexible MS1 feature detection and multivariate analyses, were used to analyze various M. bouillonii samples. The observed chemogeographic patterns suggested the production of regionally specific natural products by M. bouillonii. Analyzing the drivers of these chemogeographic patterns allowed for the identification, targeted isolation, and structure elucidation of a regionally specific natural product, doscadenamide A (1). Analyses of MS2 fragmentation patterns further revealed this natural product to be part of an extensive family of herein annotated, proposed natural structural analogs (doscadenamides B-J, 2-10); the ensemble of structures reflect a combinatorial biosynthesis using nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) components. Compound 1 displayed synergistic in vitro cancer cell cytotoxicity when administered with lipopolysaccharide (LPS). These discoveries illustrate the utility in leveraging chemogeographic patterns for prioritizing natural product discovery efforts.


Subject(s)
Amides/chemistry , Amides/pharmacology , Aquatic Organisms/chemistry , Biological Products/chemistry , Biological Products/isolation & purification , Chemistry Techniques, Analytical/methods , Computational Chemistry/methods , Cyanobacteria/chemistry , Cytotoxins/chemistry , Cytotoxins/isolation & purification , Drug Discovery/methods , Pyrroles , Amides/isolation & purification , Animals , Biological Products/pharmacology , Cell Line, Tumor , Chromatography, Liquid , Cytotoxins/pharmacology , Drug Synergism , Humans , Lipopolysaccharides/pharmacology , Mass Spectrometry , Metabolic Networks and Pathways , Mice , Pyrroles/chemistry , Pyrroles/pharmacology
7.
Org Lett ; 21(3): 793-796, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30673235

ABSTRACT

The total synthesis of majusculamide D (MJS-D) is described, a lipopentapeptide originally isolated from Lyngbya majuscula and reisolated from a Moorea sp. MJS-D possesses selective and potent cancer cell toxicity. A scalable and convergent strategy with a minimal number of purifications produced significant quantities of MJM-D for in vivo evaluations. The absolute configuration of the 1,3-dimethyl-octanamide motif was determined by synthesis of this fragment via ZACA chemistry.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cyanobacteria/chemistry , Lipopeptides/chemical synthesis , Lipopeptides/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Chemistry Techniques, Synthetic , Humans , Lipopeptides/chemistry , Stereoisomerism
8.
J Nat Prod ; 80(8): 2328-2334, 2017 08 25.
Article in English | MEDLINE | ID: mdl-28783331

ABSTRACT

A recent untargeted metabolomics investigation into the chemical profile of 10 organic extracts from cf. Symploca spp. revealed several interesting chemical leads for further natural product drug discovery. Subsequent target-directed isolation efforts with one of these, a Panamanian marine cyanobacterium cf. Symploca sp., yielded a phenethylamide metabolite that terminates in a relatively rare gem-dichlorovinylidene moiety, caracolamide A (1), along with a known isotactic polymethoxy-1-alkene (2). Detailed NMR and HRESIMS analyses were used to determine the structures of these molecules, and compound 1 was confirmed by a three-step synthesis. Pure compound 1 was shown to have in vitro calcium influx and calcium channel oscillation modulatory activity when tested as low as 10 pM using cultured murine cortical neurons, but was not cytotoxic to NCI-H460 human non-small-cell lung cancer cells in vitro (IC50 > 10 µM).


Subject(s)
Cyanobacteria/chemistry , Ion Channels/chemistry , Phenethylamines/chemistry , Carcinoma, Non-Small-Cell Lung , Drug Screening Assays, Antitumor , Humans , Lung Neoplasms , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Phenethylamines/isolation & purification , Phenethylamines/pharmacology
9.
Bioorg Med Chem Lett ; 26(22): 5378-5383, 2016 11 15.
Article in English | MEDLINE | ID: mdl-27765505

ABSTRACT

In recent years, there has been an exponential rise in the number of reports describing synthetic methods that utilize catalytic sp3 and sp2 C-H bond activation. Many have emerged as powerful synthetic tools for accessing biologically active motifs. Indeed, application to C-C and C-heteroatom bond formation, provides new directives for the construction of new pharmaceutical entities. Herein, we highlight some recent novel C-H activation processes that exemplify the utility of these transformations in medicinal chemistry.


Subject(s)
Chemistry Techniques, Synthetic/methods , Drug Discovery/methods , Heterocyclic Compounds/chemical synthesis , Hydrocarbons, Aromatic/chemical synthesis , Pharmaceutical Preparations/chemical synthesis , Catalysis , Chemistry, Pharmaceutical/methods , Heterocyclic Compounds/chemistry , Hydrocarbons, Aromatic/chemistry , Pharmaceutical Preparations/chemistry
10.
Org Chem Front ; 1(2): 135-139, 2014 Apr 01.
Article in English | MEDLINE | ID: mdl-24910777

ABSTRACT

Herein, we report the effects of fusarisetin A on cell morphology focusing in particular on actin and microtubules dynamics. We also report the synthesis and structure-function studies of a designed library of synthetic fusarisetins in cell-based assays.

11.
Chem Sci ; 3(12): 3378-3386, 2012 Jan 01.
Article in English | MEDLINE | ID: mdl-23227303

ABSTRACT

Fusarisetin A (1) is a recently isolated natural product that displays an unprecedented chemical motif and remarkable bioactivities as a potent cancer migration inhibitor. We describe here our studies leading to an efficient and scalable total synthesis of 1. Essential to the strategy was the development of a new route for the formation of a trans-decalin moiety of this compound and the application of an oxidative radical cyclization (ORC) reaction that produces fusarisetin A (1) from equisetin (2) via a bio-inspired process. TEMPO-induced and metal/O(2)-promoted ORC reactions were evaluated. Biological screening in vitro confirms the reported potency of (+)-1. Importantly, ex vivo studies show that this compound is able to inhibit different types of cell migration. Moreover, the C(5) epimer of (+)-1 was also identified as a potent cancer migration inhibitor, while (-)-1 and 2 were found to be significantly less potent. The optimized synthesis is applicable on gram scale and provides a solid platform for analogue synthesis and methodical biological study.

12.
J Am Chem Soc ; 134(11): 5072-5, 2012 Mar 21.
Article in English | MEDLINE | ID: mdl-22390338

ABSTRACT

A concise, protecting group-free total synthesis of (-)-fusarisetin A (1) was efficiently achieved in nine steps from commercially available (S)-(-)-citronellal. The synthetic approach was inspired by our proposed biosynthesis of 1. Key transformations of our strategy include a facile construction of the decalin moiety that is produced via a stereoselective IMDA reaction and a one-pot TEMPO-induced radical cyclization/aminolysis that forms the C ring of 1. Our route is amenable to analogue synthesis for biological evaluation.


Subject(s)
Antineoplastic Agents/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Antineoplastic Agents/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Molecular Conformation , Stereoisomerism
13.
Chem Asian J ; 7(5): 1052-60, 2012 May.
Article in English | MEDLINE | ID: mdl-22415793

ABSTRACT

An efficient formal synthesis of (-)-englerin A (1) is reported. The target molecule is a recently isolated guaiane sesquiterpene that possesses highly potent and selective activity against renal cancer cell-lines. Our enantioselective strategy involved the construction of the BC ring system of compound 1 through a Rh(II)-catalyzed [4+3] cycloaddition reaction followed by subsequent attachment of the A ring through an intramolecular aldol condensation reaction. As such, this strategy allows the synthesis of truncated englerins. Evaluation of these analogues with the A498 renal cancer cell-line suggested that the A ring of englerin is crucial to its antiproliferative activity. Moreover, evaluation of these analogues led to the identification of potent growth-inhibitors of CEM cells with GI(50) values in the range 1-3 µM.


Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Cell Proliferation/drug effects , Phyllanthus/chemistry , Sesquiterpenes, Guaiane/chemical synthesis , Sesquiterpenes, Guaiane/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Catalysis , Cell Line, Tumor , Cyclization , Humans , Inhibitory Concentration 50 , Kidney Neoplasms/drug therapy , Models, Molecular , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Rhodium/chemistry , Sesquiterpenes, Guaiane/chemistry , Stereoisomerism
14.
Org Lett ; 12(16): 3708-11, 2010 Aug 20.
Article in English | MEDLINE | ID: mdl-20669919

ABSTRACT

An enantioselective formal synthesis of (-)-englerin A (1) is reported. Key to the strategy is a Rh-catalyzed [4 + 3] cycloaddition reaction between furan 10 and diazo ester 11 that, following an intramolecular aldol condensation, produces the tricyclic scaffold of englerin. This strategy also provides a rapid, efficient, and stereoselective access to the biologically significant core motif of the guaiane sesquiterpenes.


Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Furans/chemistry , Rhodium/chemistry , Sesquiterpenes, Guaiane/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Catalysis , Cyclization , Molecular Structure , Sesquiterpenes, Guaiane/chemistry , Sesquiterpenes, Guaiane/pharmacology , Stereoisomerism
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