RESUMEN
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.
Asunto(s)
Catepsina B , Schistosoma mansoni , Catepsina B/antagonistas & inhibidores , Catepsina B/metabolismo , Animales , Schistosoma mansoni/enzimología , Schistosoma mansoni/efectos de los fármacos , Cristalografía por Rayos X , Esquistosomicidas/farmacología , Esquistosomicidas/química , Unión Proteica , Modelos MolecularesRESUMEN
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.
Asunto(s)
Antivirales , Metabolómica , SARS-CoV-2 , SARS-CoV-2/efectos de los fármacos , Antivirales/farmacología , Antivirales/química , Antivirales/aislamiento & purificación , Humanos , Cianobacterias/química , Relación Estructura-Actividad , Ácidos Grasos/química , Ácidos Grasos/farmacología , COVID-19 , Estructura Molecular , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismoRESUMEN
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.
Asunto(s)
Amidas/química , Amidas/farmacología , Organismos Acuáticos/química , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Técnicas de Química Analítica/métodos , Química Computacional/métodos , Cianobacterias/química , Citotoxinas/química , Citotoxinas/aislamiento & purificación , Descubrimiento de Drogas/métodos , Pirroles , Amidas/aislamiento & purificación , Animales , Productos Biológicos/farmacología , Línea Celular Tumoral , Cromatografía Liquida , Citotoxinas/farmacología , Sinergismo Farmacológico , Humanos , Lipopolisacáridos/farmacología , Espectrometría de Masas , Redes y Vías Metabólicas , Ratones , Pirroles/química , Pirroles/farmacologíaRESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Cianobacterias/química , Lipopéptidos/síntesis química , Lipopéptidos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Técnicas de Química Sintética , Humanos , Lipopéptidos/química , EstereoisomerismoRESUMEN
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.
Asunto(s)
Técnicas de Química Sintética/métodos , Descubrimiento de Drogas/métodos , Compuestos Heterocíclicos/síntesis química , Hidrocarburos Aromáticos/síntesis química , Preparaciones Farmacéuticas/síntesis química , Catálisis , Química Farmacéutica/métodos , Compuestos Heterocíclicos/química , Hidrocarburos Aromáticos/química , Preparaciones Farmacéuticas/químicaRESUMEN
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.
RESUMEN
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.
RESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Antineoplásicos/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Conformación Molecular , EstereoisomerismoRESUMEN
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.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Proliferación Celular/efectos de los fármacos , Phyllanthus/química , Sesquiterpenos de Guayano/síntesis química , Sesquiterpenos de Guayano/farmacología , Antineoplásicos Fitogénicos/química , Catálisis , Línea Celular Tumoral , Ciclización , Humanos , Concentración 50 Inhibidora , Neoplasias Renales/tratamiento farmacológico , Modelos Moleculares , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Rodio/química , Sesquiterpenos de Guayano/química , EstereoisomerismoRESUMEN
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.